Cephalosporins - Changing resistance
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Transcript Cephalosporins - Changing resistance
Dr.T.V.Rao MD
Dr.T.V.Rao MD
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Introduction to Cephalosporins..
Cephalosporins were
first isolated from
cultures of
Cephalosporium
acremonium from a
sewer in 1948 by
Italian scientist,
Giuseppe Brotzu
The first agent cephalothin
(cefalotin) was launched
by Eli Lilly in 1964
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Cephalosporins ….
B-Lactam antibiotics ( similar to
penicillin's)
Broad spectrum in action.
Act by inhibition of cell wall synthesis
Bactericidal
Inactive against : enterococci, MRSA,
legionella , mycoplasma, chlamydia
spp.
Widely used in surgical procedures to
reduce the risk of post operative infections
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Antimicrobial activity of
Cephalosporins
The site of action of beta-lactam antibiotics is the
penicillin binding proteins (PBPs) on the inner
surface of the bacterial cell membrane that are
involved in the synthesis of the cell wall
Cephalosporins are bactericidal agents
All bacterial cells have a cell wall that protects them.
Cephalosporins disrupt the synthesis of the
peptidoglycan layer of bacterial cell walls, which
causes the walls to break down and eventually the
bacteria die.
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Classification is based on
spectrum of activity
Cephalosporins are grouped
into "generations"
based on their spectrum
of antimicrobial activity.
The first cephalosporins
were designated first
generation while later,
more extended spectrum
cephalosporins were
classified as second
generation
cephalosporins.
So continued Generations
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Basis of Classification
…
Each newer generation
of cephalosporins has
significantly greater
gram-negative
antimicrobial
properties than the
preceding generation
Fourth generation
cephalosporins,
however, have true
broad spectrum activity
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st
1
generation
Cephalosporins
First generation cephalosporins
are moderate spectrum
agents
Effective against gram +ve
aerobes
They are effective for treating
staphylococcal and
streptococcal infections and
therefore are alternatives
for skin and soft-tissue
infections, as well as for
streptococcal pharyngitis.
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The 1st generation
cephalosporins are:
Cefadroxil
Cephalexin
Cephaloridine
Cephalothin
Cephapirin
Cefazolin
Cephradine
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st
1
Generation
Active against G+ cocci ( except. Enterococci &
MRSA ):
s.pneumoniae, s.pyogenes,s. aureus,
S. epidermidis
Indicated for streptococcal pharyngitis ( e.g.
cephalexin)
Commonly used ( eg. Cefazolin) as prophylactic
for surgical procedures.
Modest activity against G- bacteria
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nd
2
generation
Cephalosporins
Their antibacterial
spectrum is broader than
that of 1st generation
cephalosporins and
includes some gram -ve
pathogens
They are also more
resistant to beta-lactamase
They are useful agents
for treating upper and
lower respiratory tract
infections and sinusitis
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nd
2
generation cont...
These agents are also
active against E. coli,
Klebsiella and
Proteus, which makes
them potential
alternatives for
treating urinary tract
infections caused by
these organisms
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nd
2
Generation
Cephalosporins ..
Cefoxitin
Cefuroxime
Cefuroxime axetil
Cefaclor
Cefprozil
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rd
3
generation
Cephalosporins
They have an
extended
spectrum of
action against
gram -ve
organisms
Resistant to betalactamases
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rd
3
generation cont...
The parenteral third
generation
cephalosporins
(ceftriaxone and
cefotaxime) have excellent
activity against most
strains of Streptococcus
pneumoniae, including
the vast majority of those
with intermediate and
high level resistance to
penicillin
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Third Generation Cephalosporins
Ceftriaxone
Cefotaxime
Ceftazidime
Cefoperazone
Cefixime
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THIRD GENERATION
They have enhanced G- activity, H. influenza,
N. meningitidis, N.gonorrhea, P.
aeruginosae, M. catarrhalis, E.coli, most
Klebsiella
Ceftriaxone has long half-life . Not advised in
neonates (interferes with bilirubin
metabolism )
Cefotaxime preferred in neonate ( does not
interfere with bilirubin metabolism ), as may
ceftriaxone.
Ceftazidime & cefoperazone have excellent
activity against P.aeruginosa.
Cefixime has similar activity to amoxicillin &
Cefaclor for actute otitis media
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th
4
generation
cephalosporins
4th generation
cephalosporins are extended
spectrum agents with
similar activity against
gram-positive organisms as
first generation
cephalosporins.
They also have a greater
resistance to beta-lactamases
than the third generation
cephalosporins.
Many can cross blood brain
barrier and are effective in
meningitis.
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th
4
Generation
Cephalosporins...
Cefepime
Cefluprenam
Cefozopran
Cefpirome
Cefquinome
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Fourth Generation
Cefipime
Active against G+
bacteria > than
Cefazolin against s.
pyogenes,
S.pneumoniae but
lower against s.
aureus.
Similar to cefotaxime
against E.coli & K.
pneumoniae but < for
p. aeruginosa.
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Pharmacokinetic
consideration
They are organic acids and are hydrophilic
They generally have poor oral bioavailability as they
unstable in acid environments
They are readily excreted by the kidneys, via tubular
secretion in the proximal convoluted tubule. This
results in high concentrations of the drug in urine.
Exceptions are:
Cephalexin which is stable in acid and so suitable for
oral dosing.
Cefoperazone is excreted in bile rather than in urine.
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Why Cephalosporins are Widely
Prescribed Antibiotics
Broad spectrum of
activity
Stability to -lactamase
Oral and parenteral preparations
Widely accepted
Treats ‘day to day’ as well as
‘serious infections’
High safety profile
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Cephalosporins
Emerging resistance
patterns
-Limitations
III & IV generation
cephalosporins were
available only as
parenteral formulations
Pharmacoeconomics
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Why detect ESBL producers?
may:
ESBL producers
• Appear Sensitive to some
cephalosporins in vitro
• Show major inoculum effects
• Fail in therapy, despite appearing
susceptible
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Detection Strategy: step 1
Screen Enterobacteriaceae
with :
• Cefpodoxime- best general ESBL substrate
• Cefotaxime & ceftazidime- good substrates
for CTX-M & TEM/SHV, respectively
Spread of CTX-M into community means
screening must be wider than before
Dr.T.V.Rao MD
Ref http://www.hpa.org.uk
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Detection of ESBLs: step 2
Seek ceph/clav
synergy in ceph R
isolates
Double
disc
Combina
tion disc
Etest
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Ref http://www.hpa.org.uk
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Double Disk Method
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Etest for ESBLs
Cefotaxime
Cefotaxime
+
Clavulanate
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Pitfalls in ESBL detection
• Methods optimised for E. coli & Klebsiella
• More difficult with Enterobacter
– clavulanate induces AmpC; hides ESBL
• Best advice is to do synergy test
(NOT SCREEN) with 4th gen
cephalosporins
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Synergy tests with 4-gen
cephalosporins
Cefepime/clav (Mast & AB Biodisk)
Cefpirome clav (Oxoid)
Devt. driven by spread of clonal E. aerogenes
with TEM-24 in Belgium & France
Sensitivity for weak ESBLs remains to be
proven
Cefpirome & cefepime products need
comparison
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Bacteria not to test for ESBLs
Acinetobacter
–Often S to clavulanate alone
S. maltophilia
–+ve result by inhibition of L-2
chromosomal -lactamase,
ubiquitous in the species
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Role of CLSI in Revising Breakpoints in
Antibiotic Resistance
Briefly, revising breakpoints involves systematic
review of microbiological, pharmacologic, and
clinical data. Recognized experts, sponsors
(pharmaceutical industry), and regulators participate
in the process which includes discussions at public
meetings of the CLSI Subcommittee on
Antimicrobial Susceptibility Testing that take place
twice a year. When establishing original breakpoints
for new agents, controlled clinical trial data are
required
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Follow the New
Guidelines CLSI 2010
Guidelines for
cephalospins for
Enterobacteriaceae in
accordance with the
2010 Clinical
Laboratory Standards
Institute (CLSI)
recommendations. The
following changes will
be made to comply
with the CLSI.
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Why do breakpoints sometimes
need to be
revised?
Breakpoints need to be
revised due to changing
resistance mechanisms
and bacterial population
distributions, changing
science leading to a better
understanding of the
pharmacologic
determinants of clinical
response, and adoption of
“best practices” by
clinicians.
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Enterobacteriaceae Rapid Spread of resistance
The rapid and
disturbing spread of:
extended-spectrum ßlactamases
AmpC enzymes
carbapenem resistance
metallo-β-lactamases
KPC and OXA-48 βlactamases
quinolone resistance
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What breakpoints were revised in
2010?
Select cephalosporin
and aztreonam
breakpoints for
Enterobacteriaceae
were revised as noted
below (for comparison,
the old breakpoints are
included):
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Extended-Spectrum βLactamases
β-lactamases capable of conferring bacterial
resistance to
the penicillin's
first-, second-, and third-generation cephalosporins
aztreonam
(but not the cephamycins or carbapenems)
These enzymes are derived from group 2b βlactamases (TEM-1, TEM-2, and SHV-1)
differ from their progenitors by as few as one AA
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CTCTX-M-type ESBLs
X-M-type ESBLs
Until 2000, most ESBL producers were hospital
Klebsiella spp. with TEM and SHV mutant βlactamases
Now, the dominant ESBLs across most of Europe
and Asia are CTX-M enzymes, which originated as
genetic escapes from Kluyvera spp
Currently recognized as the most widespread and
threatening mechanism of antibiotic resistance, both
in clinical and community settings
80% of ESBL-positive E. coli from bacteraemias in the UK
and Ireland are resistant to fluoroquinolones
40% are resistant to gentamicin
Dr.T.V.Rao MD
Livermore, DM J. Antimicrob. Chemother 2009
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Enterobacteriaceae: Revised
Breakpoints for Cephalosporins
CLSI 2009
Agent
CLSI 2010
S
I
R
S
I
R
Cefazolin
≤8
16
≥32
≤1
2
≥4
Cefotaxime
≤8
16-32
≥64
≤1
2
≥4
Ceftriaxone
≤8
16-32
≥64
≤1
2
≥4
Ceftazidime
≤8
16
≥32
≤4
8
≥16
Aztreonam
≤8
16
≥32
≤4
8
≥16
Cefipime
≤8
16
Dr.T.V.Rao MD
≥32
≤8
16
≥32
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Disk diffusion breakpoints (mm):
Agent
Cefazolin
Cefotaxime
Ceftizoxime
Ceftriaxone
Ceftazidime
Aztreonam
Old (M100-S19)
S
≥18
≥23
≥20
≥21
≥18
≥22
I
15-17
15-22
15-19
14-20
15-17
16-21
R
≤14
≤14
≤14
≤13
≤14
≤15
Revised (M100-S20)
S
I
R
NA
NA
NA
≥26
23-25 ≤22
≥25
22-24 ≤21
≥23
20-22 ≤19
≥21
18-20 ≤17
≥21
18-20 ≤17
S – susceptible
I – Intermediate
R – Resistant.
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Following MIC breakpoints were reevaluated
for Enterobacteriaceae but were not revised
Agent
M100-S19
S
Cefuroxime ≤8
Cefepime ≤8
Cefotetan ≤16
Cefoxitin ≤8
M100-S20
I
R
S
I
R
16
16
32
16
≥32
≥32
≥64
≥32
≤8
≤8
≤16
≤8
16
16
32
16
≥32
≥32
≥64
≥32
S – susceptible
I – Intermediate
R – Resistant
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Why were the breakpoints for cefepime
and cefuroxime (parenteral) not revised?
The cefepime breakpoints
were not revised based
upon clinical trial data
and PK-PD evaluations.
The clinical trial data
showed cefepime efficacy
for patients infected with
isolates that tested
cefepime susceptible
(MIC ≤8 μg/ml), but
produced an ESBL
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Why are there no disk diffusion
breakpoints for Cefazolin?
Studies have not yet been
completed to identify the
zone diameter
breakpoints that correlate
with the revised MIC
breakpoints for Cefazolin.
Initial studies did not
reveal clear zone diameter
breakpoints and disk
diffusion testing of
Cefazolin may require a
new disk with alternate
disk content.
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Cephalothin group
Cephalothin is now
classified under
Test/Report Group U for
Enterobacteriaceae.
Results for cephalothin
can be used to represent
activities of several other
oral FDA-approved
agents for treatment of
urinary tract infections
which include cefadroxil,
cefpodoxime, cephalexin,
and loracarbef.
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Need for Changing
Recommendations
The ESBL testing recommendations were to be a
short term solution to address a new mechanism of
resistance. Subsequently, additional mechanisms of
resistance have been identified (e.g., new types of
ESBLs and AmpC-like enzymes) and with increased
frequency multiple enzymes are identified in a single
isolate which can complicate ESBL testing (1). These
issues coupled with improved understanding of the
PK-PD determinants of efficacy with cephalosporins
and monobactams resulted in the decision to revise
the breakpoints.
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Measuring the Revised
Zones is Advantageous
The revised breakpoints eliminate the need to
perform ESBL screen and confirmatory tests for
making treatment decisions. Phenotypic tests for
ESBL detection and confirmation are less accurate
when multiple enzymes are present (e.g., falsenegative results occur when isolates express both
ESBLs and AmpC-type enzymes) (13) and the
presence of multiple enzymes are more common in
contemporary isolates (4, 8). The MIC of an isolate
correlates better with clinical outcome than
knowledge of resistance mechanisms (e.g., ESBLs)
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