Slide 1

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 2

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 3

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 4

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 5

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 6

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 7

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 8

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 9

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 10

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 11

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 12

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 13

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 14

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 15

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 16

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 17

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 18

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 19

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 20

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 21

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 22

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 23

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 24

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 25

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 26

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 27

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 28

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 29

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 30

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 31

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 32

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 33

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 34

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 35

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 36

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 37

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 38

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 39

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 40

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 41

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 42

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 43

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 44

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 45

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 46

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 47

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 48

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 49

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 50

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 51

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts


Slide 52

Emergence of ESBLs

“Extended Spectrum B-Lactamases”
Dr Ahmed Abu Samra
Holy Family Hospital
2008

Introduction
*The introduction of 3rd GCS in the early 1980s was
considered big step in the fight against b-lactamases.
* In 1983, report of plasmid-encoded B-lactamase (enzymes)
capable of hydrolyzing the extended spectrum CS was
published.
* TEM-1 and SHV-1
* The total no. of ESBLs now exceeds 200.
* >1300 relevant articles with >600 since 2001

What is a B-Lactam ATB?
• By definition, all β-lactam antibiotics
have a β-lactam ring in their
structure.

• The effectiveness of these
antibiotics relies on their ability to
reach the PBP [penicillin binding
protein] on the bacterial cell wall
intact and their ability to bind to it
and to disrupt cell wall synthesis
destruction of bacteria .

Modes of resistance
•

There are 2 main modes of bacterial
resistance to β-lactams.
1. The first mode of β-lactam resistance is
due to enzymatic hydrolysis of the βlactam ring.
2. The second mode of β-lactam resistance is
due to possession of altered penicillinbinding proteins.

Modes of resistance
• The first mode :
If the bacteria produces the
enzymes β-lactamase or
penicillinase, these enzymes will
break open the β-lactam ring of
the antibiotic, rendering the
antibiotic ineffective.

Modes of resistance
The genes encoding these enzymes may be
inherently present on the bacterial
1. chromosome
2. or may be acquired via plasmid transfer

β-lactamase gene expression may be induced
by exposure to beta-lactams.

Modes of resistance
• The ESBL enzymes are plasmid-mediated
enzymes capable of hydrolyzing and
inactivating a wide variety of ß-Lactams,
including third-generation cephalosporins,
penicillins, and aztreonam.
• These enzymes are the result of mutations
of TEM1, TEM2 and SHV1, all of which are ßLactamase enzymes commonly found in the
Enterobacteriaceae family.

Resistance
• ESBLs are generally well inhibited by ßLactamase inhibitors and usually retain
sensitivity to the =
• carbapenems
ertapenem, imipenem, meropenem
• cephamycins
cefoxitin
• beta-lactamase inhibitors
clavulanic acid, sulbactam
• However these antibiotics may be inactive
due to other resistance mechanisms

Mode of resistance
• The new plasmid [ mobile DNA] mediated
resistance allows transmission of genetic
material between the same bacterial clone as
well as different clones.
• i.e. genetic material can be transferred from
an E. coli to a Klebsiella or to another Klebsiella

Multi-resistant
Additionally these plasmids often carry genes for
resistance to other classes of antibiotics
• e.g. gentamicin, cotrimoxazole, ciprofloxacin
Isolates that have an ESBL are often multiresistant with few treatment options
Necessitates use of broad-spectrum carbapenems
for severe infections

Increased mortality related to delays in receiving
effective antibiotic

Mode of resistance
• The second mode of β-lactam resistance is due to
possession of altered penicillin-binding proteins.
• β-lactams cannot bind as effectively to these
altered PBPs, and, as a result, the β-lactams are
less effective at disrupting cell wall synthesis.
• Notable examples of this mode of resistance
include methicillin-resistant Staphylococcus aureus
(MRSA) and penicillin-resistant Streptococcus
pneumoniae.
• Altered PBPs do not necessarily rule out all
treatment options with β-lactam antibiotics.

Definition of ESBLs
* The ESBLs are B-lactamases capable of
conferring bacterial resistance to the
penicillins, 1st,2nd,3rd GCS, and aztreonam (but
not the cephamycins or carbapenemes) by
hydrolysis of these antibcs, and which are
inhibited by b-lactamase inhibitors such as
clavulanic acid.
* The most common ESBL producing organisms are
Klebsiella pneumonia, E.coli and other K.spp.

Epidemiology of ESBL

Europe
* Although the initial reports were from Germany and
England, the vast majority of reports in the first
decade were from France.

* 1986: first large outbreak; 54 pts in ICU were

infected and spread to 4 other wards then occurred
* By the early 1990s, 25-35% of nosocomially acquired
K.pneumonia isolates in France were ESBL producers.
* The proportion fell from 19.7% in 1996 to 7.9% in
2000.
* Outbreak of infection with ESBL producing organisms
have now been reported from every European
country

Europe
* Large study from >100 ICUs found that the
prevalence of ESBLs in Klebsiella ranged from
as low as 3% in Sweden to as high as 34% in
Portuglal.
* A survey done in turkey revealed that 58% of
193 Klebsiella spp isolated from ICUs harbored
ESBLs.

North America
* 1989: significant infections with TEM-10 producing
K.pneumonia were noted.
* NNIS from 1998 to 2002 reveal that:

1- 6.1% of K.pneumonia isolates from 110 ICUs were
resistant to 3rd GCSs.
2- In at least 10% of ICUs resistance exceeded
25%.
3- In non-ICUs inpt areas: 5.7%
4- outpt areas just 1.8% were ceftazideme
resistant

* Africa and middle east:
-documented in many countries.
-no national surveillance has published
-36.1% of K.pnemonia isolates collected in single
south Africa hospital in 1999 were ESBLs

* Australia:
-The 1st isolates detected were collected between
1986-1988.
-Overall, it appears that the proportion of
K.pneumonia ESBL is about 5%

Asia
* IN 1988, isolates of K.pneumonia from China which
contained SHV-2 were reported.

* In a major teaching hospital in Beijing, 27% of E.coli
and K.pneumonia blood Cx isolates between 1997-99
were ESBL producers.

* National survey have indicated that the rates of
ESBL production by K.pneumonia have been as low
as 5% in Japan and 20-50 % elsewhere in Asia

Molecular Epidemiology of ESBLs
* >50 studies have targeted the molecular typing

methods in the study of ESBL epidemiology,3000pt.

* Mostly K.pneumonia was addressed
* Klebseillae has the well noted adaptation to the

hospital environment, survive longer on hands and
environmental surfaces, facilitating cross infection
within hospital.

* A no. of outbreaks have been described with

dissemination of a single clone of genotypically
identical organism.

Molecular epidemiology
* Recent reports have described the clonal

dissemination of 5 diff ESBL producing Klebsiellae
strains in the same unit at the same time.

* Additionally, members of a single epidemic strain
may carry diff plasmids

* furthermore, genotypically nonrelated strains may

produce the same ESBL due to plasmid transfer
from species to another.
* The same strain at the same unit may be mediated
by diff plasmid via the effect of antibiotic
pressure or plasmid transfer

Molecular epidemiology
* Transfer from hospital to hospital, from city to

city, and from country to country has been
documented. A notable clone has been SHV-4 K.
which has spread to multiple hospitals in France and
Belgium.

* ICU are often the epicenter for ESBL production in
hospitals, in one large outbreak, more than 40% off
all the hospital ESBLs were from pts in intensive
care units.
* Other units: burn, neurosurgical, obs and gyn,
hematology and oncology, and geriatric units

Risk Factors for Colonization and
Infection with ESBLs

Risk Factors

• Seriously ill pts with prolonged hospital stay and in whom
invasive medical devices are present for prolonged duration.

• In one study, the median length of hospital stay prior to
isolation of an ESBL producer has ranged from 11-67 days.
• In another study, TPN was found in 94% of pts, MV was
applied in 69% of pts and central venous catheters were
found in 37% of pts.
* Heavy antibiotic use esp. 3rd GCS is also a major risk factor

Community acquired infections
• A survey of more than 2500 isolates of E.coli,
Klebsiellae, and Proteus mirabilis isolated from nonhospitalized pts in France in 1993 revealed no truly
community acquired infections.
• In the last 3 years there have been several reports
of true community acquired infections or
colonization with E.coli from Spain, Israel, UK,
Canada and Tanzania.

* The cause of this sudden upsurge isn't yet clear,

but associations with foodstuffs, animal
consumption of antibiotics and frequent pt contact
with health care facilities need to be explored.

Modes of spread within hospitals
• It seems that the most significant reservoir
of the microorganism is the GIT of colonized
pts and that transmission occurs mostly via
the hands of nursing staff.

• Hand carriage has been documented by most
investigators.

Modes of spread within hospitals
• In these instances, the hand isolates were
genotypically identical to isolates which
caused infection in pts.
• The use of artificial nails promotes long term
carriage and has been associated with at
least one outbreak

Modes of spread within hospitals
• Common environmental sources: US gel, BP cuffs,
glass thermometers, and bronchoscopes. These
isolates were resembling the infecting strains.

• For every pt with ESBL infection, at least one
other pt exists in the same unit who is colonized.
• GIT carriage has been documented in health care
workers, but its rare and seldom prolonged except
for Salmonella spp.

Infection control interventions appropriate to controlling
spread of ESBL-producing organisms within a hospital

• Identify patients infected with ESBL-producing
organisms by use of appropriate detection methods
in the clinical microbiology laboratory
• Identify colonized patients by use of rectal swabs
plated onto selective media
• Perform molecular epidemiologic analysis of strains
from infected or colonized patients (for example,
by use of pulsed-field gel electrophoresis)
• Institute contact isolation precautions, particularly
if clonal spread is demonstrated
• Institute controls on antibiotic use, particularly if
numerous strain types are demonstrated

Infection control…
*Although common environmental sources
of infection have rarely been
discovered, when they are recognized
their impact on arresting the outbreak
of infection can be dramatic.

Infection control…
In one outbreak of ESBLs, they found that the gel
used for U/S was contaminated with ESBLs, its
replacement quickly curtailed the outbreak.
• In another one, they found 12 thermometers were
colonized with ESBLs. their Disinfection curtailed
the outbreak.
Contact isolation: by the use of gloves and gowns
when contact colonized pts can lead to significant
reduction in horizontal spread of ESBLs.
• In one outbreak, they closed the unit temporarily in
order to adequately control this outbreak.

Infection control…
• Selective Digestive Decontamination:

- 3 groups successfully used SDD with
polymyxin,neomycin, and nalidixic acid,
colistin and tobramycin, or norfloxacin to
interrupt outbreaks of infection with ESBLs.
- drawback: resistance to quinolone and MDR
to aminoglycosides

Infection control…
• A recent study has utilized a nasal spray
with povidine-iodine as a means of
decolonizing the upper respiratory tract.

• In this study 10 pts had nasotracheal
colonization, upper airway decolonization led
to management of an outbreak.

Infection Control …
* Close attention to practices that may lead to •
breakdown in good infection control.
* Change in antibiotic policy may play a greater role •
in this setting.

* In 2 institutions in Texas, the use of ceftazidime
declined by 27% and 71% respectively, while the
use of piperacillin-tazobactam increased by 14%
and 40% respectively.

Infection Control
This resulted in a significant decline (50% and
32%,respectively)in ceftazidime-resistant
K.pneumonia.
Furthermore, the rate of piperacillinTazobactam resistant Klebsiella declined by
36% and 47% respectively, despite the
significant increase in use of piperacillintazobactam.

Treatment of ESBLs
* Resistance to many B-lactam antibiotics
* Furthermore,however,they carry resistance
to aminoglycoside and tri-sulfa.
* Increasing reports of quinolone resistance
will limit the role of these antibiotics in
the future.

Recommended Rx for ESBLs
Infection type

Rx of choice

2nd line Rx

UTI

Quinolone

Amox-clav acid

Bacteremia

carbapenem

Quinolone

Hospital acquired
pneumonia

carbapenem

quinolone

Intra-abdominal
infection

carbapenem

Quinolone+
metronidazole

meningitis

meropnem

Intrathecal
polymyxinB

Drawbacks…
* The carbapenems (including imipenem, meropnem,
and ertapenem) have the most consistent activity
against ESBL producing organisms

* Carbapenems-resistant k.pneumonia isolates:
- carbapenem resistant ESBLs remain exceedingly
rare.
- the epidemiology has yet to be studied
- 8 pts with carbapenem resistance were identified
in a single intensive care unit.

* All of them had previously been treated with
imipenem.
* Since no other antibiotic options were
available, 6 of the 8 pts died.
* The outbreak was halted by reinforcement
of infection control.
* Tigecycline or polymxins may be considered
in Rx of carbapenem-resistant
klebseilla

Outcome of ESBLs infections
* Increased morbidity and mortality.
* Increased duration of hospital stay:
Analysis of data from the Brooklyn Antibiotic
Resistance Task Force showed that pts with
infection due to ESBLs had a median length of
hospital stay postinfection of 29 days compared
to 11days in non-B-lactamase infected pts.
* Increased costs

ESBL effect with gram-ve neonatal
septicemia
outcome

Cases with
Cases with isolates
isolates producing
not producing
ESBL(%)
ESBL(%)

survival

38.7

64.2

death

61.2

35.7

Conclusion
•

The ESBL-producing organisms are a breed of multidrug-resistant pathogens
that are increasing rapidly and becoming a major problem in the area of
infectious diseases.

•

High rates of third-generation cephalosporin use have been impli-cated as a
major cause of this problem.

•

Problems associated with ESBLs include multidrug resistance, difficulty in
detection and treatment, and increased mortality.

•

Of all available anti-microbial agents, carbapenems are the most active and
reliable treatment options for infections caused by ESBL isolates.

•

However, overuse of carbapenems may lead to resistance of other gramnegative organisms.

•

Therefore, restricting the use of third-generation cephalo-sporins, along with
implementation of infection control measures, are the most effective means of
con-trolling and decreasing the spread of ESBL isolates.

The end
•
•
•
•

Use antibiotics wisely
treat infection not colonisation.
Prevent spread of Infection
Wash hands thoroughly

• Thank you

*

Diversity of ESBL Types

SHV
* Sulfhydryl variable
* SHV-1 as the usual B-lactamase enzyme
* In 1983,Germany, new enzyme isolated from
Klebsiella ozaenae, different from SHV-1 by
replacement of glycine by serine at the 238
position.
*This single mutation accounts for the extended
spectrum properties of this enzyme=SHV-2
* Found in wide range of enterobacteriaceae,
Pseudomonas aeruginosa and Acinetobacter
spp.

TEM
* TEM-1 first isolated from a pt in Greece named
TEMoneira. {E.coli}
* Over 100 TEM type, the majority are ESBLs.

* TEM-12 for example came from a neonatal
unit in UK which had been stricken by an
outbreak of Klebsiella oxytoca producing
TEM-1 and was treated with ceftazidime.

CTX-M and Toho B-lactamases
* The name CTX reflects the hydrolytic activity of
these B-lactamases against cefotaxime.
* The same organism may harbor both CTX-m type
and SHV type more antbc resistance.
* Toho-1 and Toho-2 are related structurally to
CTX-M type B-lactamases (Toho university)
* The no. of CTX-M type is rapidly expanding, they
have now been detected world wide although for
some years they were detected in certain
geographic areas: South America, Eastern Europe
, and Far East

OXA
* So named bcz of their oxacillin-hydrolyzing

abilities.
* they predominantly occur in P.aeruginosa, but have
been detected in many other gram -ve bacteria.
* OXA-1 which is the commonest OXA enzymes has
been found in 1-10% Of E.coli isolates.

* Originally discovered in Ankara.
* Later OXA-18,19,28 discovered in France.
* Frank resistance to cefotaxime and sometimes
ceftazideme and aztreonam.

OXA
* The simultaneous production of carbapenemhydrolyzing metaloenzyme and an aztreonam
hydrolyzing OXA enzyme can readily lead to
resistance to all B-lactam antibiotics

PER
* Share only around 25-27% homology with known
TEM and SHV type ESBLs
* PER-1 first detected in P.aeruginosa, and later in
Salmonella enterica and Acinetobacter isolates.
* In turkey, 11% of P.aeruginosa and 46% of
Acinetobacter were found to produce PER-1
* PER-2 has been detected in S.enterica, E.coli,
Klebsiella, Proteus, and Vibrio cholera.
* Worryingly, a P.aeruginosa strain producing PER-1
and the carbapenemase VIM-2 has been detected
in Italy resistance to all B-lactam antibiotics

Others
VEB-1: resistance to non B-lactam antibiotics
BES-1
GES.
TLA.
SFO.
IBC.

Infection Control When ESBLs are
Not Endemic

* When empirical antibiotic therapy inactive against

ESBL producers are used, this will increase the
morbidity and mortality.
* The initial stages of the infection control program
in a unit which has not been affected by ESBLs
should include:
1-performance of rectal swabs for colonization
2-evaluation of the presence of a common
environmental source of infection.
3-a campaign to improve hand hygiene
4-introduction of contact isolation for colonized
pts