Transcript Document

Extended-Spectrum -lactamases:
Current situation, Diagnosis & Management
Siriluck Anunnatsiri, MD
Infectious Diseases & Tropical Medicine
Faculty of Medicine
Khon Kaen University
Extended-spectrum -lactamases
•Mutant, plasmid-mediated -lactamases enzymes
derived from amino acid substitutions in native lactamases, particularly TEM-1, TEM-2, and SHV-1
•Their ability permit hydrolyze all penicillins,
cephalosporins (except cephamycins), and monobactams
•Typically associated with multidrug resistance
(fluoroquinolones, co-trimoxazole, aminoglycosides)
Extended-spectrum -lactamases
• Most commonly produced by Klebsiella spp.,
Escherichia coli but can occur in other GNB,
including Enterobacter, Salmonella, Proteus, and
Citrobacter spp., Morganella morganii, Serratia
marcescens, Shigella dysenteriae, Pseudomonas
aeruginosa, and Burkholderia cepacia
Major groups of -lactamases
Functional Major Molecular
group
subgroup
class
Functional group
Inhibition by
clavulanate
C
Cephalosporinases, often chromosomal enzymes in GNB but may
be plasmid-encoded, confer resistance to all classes of -lactams,
except carbapenems (unless combine with porin change)
-
2a
A
Penicillinases, confer resistance to all penicillins, primarily from
Staphylococcus and enterococci
+
2b
A
Broad-spectrum -lactamases (penicillinases/cephalosporinases) ,
primarily from GNB.
+
2be
A
ESBLs, confer resistance to oxyimino-cephalosporins and
monobactams.
+
2br
A
Inhibitor-resistant TEM (IRT) -lactamases
2c
A
Carbenicillin-hydrolyzing enzymes
1
2
- (+ for
tazobactam)
+
Shah AA, et al. Research in Microbiology 2004; 155: 409-421.
Major groups of -lactamases
Functional Major Molecular
group
subgroup
class
2
3
4
Functional group
Inhibition by
clavulanate
2d
D
Cloxacillin- (oxacillin)- hydrolyzing enzymes
+/-
2e
A
Cephalosporinases, confer resistance to monobactams
+
2f
A
Carbapenem-hydrolyzing enzymes with active site serine (serine
based carbapenemases)
+
3a, 3b, 3c
B
Metallo--lactamases (zinc based carbapenemases), confer
resistance to carbapenems and all -lactam classes, except
monobactams.
-
Miscellaneous unsequenced enzymes that do not fit into other
groups
-
Functional group classified by Bush-Jacoby-Medeiros.
Molecular group classified by Ambler.
Shah AA, et al. Research in Microbiology 2004; 155: 409-421.
Selected -lactamases of gram-negative bacteria
-lactamase
Broadspectrum
Extendedspectrum
Examples
Substrates
Inhibition by Ambler’s class /
clavulanate* Bush’s class
TEM-1, TEM-2, SHV-1
Penicillin G, aminopenicillins,
carboxypenicillins, piperacillin,
narrow-spectrum cephalosporins
+++
A / 2b
OXA family
Broad-spectrum group plus
cloxacillin, methicillin, and oxacillin
+
D / 2d
TEM family, SHV family
Broad-spectrum group plus
oxyimino-cephalosporins, and
monobactam (aztreonam)
++++
A / 2be
CTX-M family
Expanded-spectrum group plus, for
some enzymes, cefepime
++++
A
OXA family
Same as for CTX-M family
+
D / 2d
++++
A
Others (PER-1, PER-2,
Same as for TEM family and SHV
family
BES-1, GES/IBC family,
SFO-1, TLA-1, VEB-1, VEB2)
*+, +++ , and ++++ denote relative sensitivity to inhibition.
Peterson DL. Am J Med 2006; 119 (6 Suppl 1):S20-8.
Selected -lactamases of gram-negative
bacteria
-lactamase
AmpC
Examples
ACC-1, ACT-1, CFE-1,
CMY family, DHA-2, FOX
family, LAT family, MIR-1,
MOX-1, MOX-2
Substrates
Inhibition by
Ambler’s
clavulanate* class/ Bush’s
class
Expanded-spectrum group plus
cephamycins
0
C/ 1
Carbapenemase IMP family, VIM family,
Expanded-spectrum group plus
GIM-1, SPM-1 (metallo-enzymes) cephamycins and carbapenems
0
B/3
KPC-1, KPC-2, KPC-3
Same as for IMP family, VIM
family, GIM-1, and SPM-1
+++
A / 2f
OXA-23, OXA-24, OXA-25,
OXA-26, OXA-27, OXA-40,
OXA-48
Same as for IMP family, VIM
family, GIM-1, and SPM-1
+
D / 2d
*+, +++ , and ++++ denote relative sensitivity to inhibition.
Peterson DL. Am J Med 2006; 119 (6 Suppl 1):S20-8.
Major sources of extended-spectrum -lactamases
Type
TEM, SHV
Major sources
E. coli, K. pneumoniae
Cefotaxime hydrolyzing S. Typhimurium, E. coli, K. pneumoniae
(CTX-M)
Oxacillin hydrolyzing
(OXA)
P. aeruginosa
PER-1
PER-2
P. aeruginosa, A. baumanii, S. Typhimurium
S. Typhimurium
VEB-1
E. coli, P. aeruginosa
Prevalence of ESBL-producing isolates in Europe
(1997-2004) and USA (1999-2004)
Europe
USA
Goossens H, Grabein B. Diagn Microbiol Infect Dis 2005; 53: 257-64.
%
Distribution of ESBL in E. coli
SMART, 2003, IAI, Asia-Pacific Countries
50
<48 hours
48 hours
40
30
20
10
0
Australia
China
Korea
Malaysia
New
Zealand
Philippines
Taiwan
Thailand
Paterson DL et al. J Antimicrob Chemother 2005;55:965-73.
%
Distribution of ESBL in Klebsiella spp.
SMART, 2003, IAI, Asia-Pacific Countries
60
<48 hours
48 hours
50
40
30
20
10
0
Australia
China
Korea
Malaysia
New
Zealand
Philippines
Taiwan
Thailand
Paterson DL et al. J Antimicrob Chemother 2005;55:965-73.
Prevalence of ESBL producing organisms
346 isolates of GNB, Siriraj Hospital, 2003
Chayakulkeeree M, et al. Southeast Asian J Trop Med Public Health 2005; 36: 1503-9.
Prevalence of ESBL-producing organisms
2974 isolates of GNB, Srinagarind Hospital, 2005
ESBLstrain
Non-ESBL strain
%
100
73.7
50
26.3
0
E. coli
95.6
89.3
63.3
36.7
10.7
K. pneumoniae
K. oxytoca
4.4
P. mirabilis
Risk factors associated with infection or
colonization with ESBL-producing pathogens
• Critically ill patients / Severely debilitated residents
– Prolonged hospital or ICU unit stay
– Invasive procedures:
indwelling catheter, central venous catheter, gastrostomy,
tracheostomy, endotracheal or nasogastric tube
– Residency in long-term care facility
– Decubitus ulcer
– Total dependence on health care workers
• Prior antibiotic use in last 3 months
– Exposure to 2nd-3rd cephalosporins, aztreonam, penicillins,
and quinolones
– Delayed appropriate therapy
CLSI screening criteria for ESBLs in
K. pneumoniae, K. oxytoca, and E.coli
Disk diffusion
zone (mm)
MIC (/g/ml)
Cefpodoxime
<17
>8
Ceftazidime
<22
>2
Aztreonam
<27
>2
Cefotaxime
<27
>2
Ceftriaxone
<25
>2
Antimicrobial
agents
Stürenburg E, Mark D. J Infect 2003; 47: 273-95.
Laboratory tests for ESBLs detection
Tests
Method
Presence of ESBLs if..
Enhanced inhibition
Double disk
approximation or
double disk synergy
Disk of 3rd cephalosporin
placed 30 mm from
amoxicillin-clavulanic acid
Combination disk
Uses 2 disks of 3rd
An increase of >5 mm in
cephalosporin alone and
zone inhibition with use of
combined with clavulanic acid the combination disk
Microdilution
A broth containing 1 g/mL
3rd cephalosporin
Presence of growth
Laboratory tests for ESBLs detection
Tests
Method
Presence of ESBLs if..
MIC broth dilution
MIC of 3rd cephalosporin alone A decrease in the MIC of
and combined with clavulanic the combination of >3
acid
log2 dilutions
E-test (MIC ESBL
strips)
Two-sided strip containing
ceftazidime on one side and
ceftazidime-clavulanic acid on
the other
Automated
instruments (e.g.,
Vitek)
Measures MICs and compares
the growth of bacteria in
presence of ceftazidime vs.
ceftazidime-clavulanic acid
Molecular (DNA
probes, PCR, RFLP)
Targets specific nucleotide sequences to detect different
variants of TEM and SHV genes
•MIC ceftazidime > 8
MIC combination
•Phantom zone
Confirmatory tests for ESBL detection
Stürenburg E, Mark D. J Infect 2003; 47: 273-95.
Multi-drug resistance in ESBL-producing organisms
Chayakulkeeree M, et al. Southeast Asian J Trop Med Public Health 2005; 36: 1503-9.
Resistance of ESBL-Producing E. coli and K. pneumoniae
1,182 Isolates, Srinagarind Hospital, Khon Kaen 2005
E. coli
%
K. pneumoniae
100
75.780.4
80
60
40
20
73
58
53.3
34.5
15.4
21.6
80.4
56.6
33
20
0
Amikacin
Gentamicin Netilmycin
Ofloxacin Levofloxacin Ciprofloxacin
Resistance of ESBL-Producing E. coli and K. pneumoniae
1,182 Isolates, Srinagarind Hospital, Khon Kaen 2005
E. coli
%
100
80
84.488
K. pneumoniae
91.692.6
60
74.1
56.1
48.2
40
32.2
20
0.30.2
0
Amoxi/cla Ampi/sul
Cefo/sul
Pip/taz
0 5.2
0.30.2
Imipenem Ertapenem Meropenem
Inadequate antimicrobial treatment of infections: a risk
factor for hospital mortality among critically ill patients
Independent risk factors for hospital mortality
Risks
Kollef MH et al. Chest 1999; 115: 462-74.
Adjusted
OR
95%CI
Inadequate antimicrobial therapy
4.26
3.35–5.44
Acquired organ system
derangements (1-organ increment)
3.25
2.98-3.54
Use of vasopressors
2.20
1.81-2.66
Underlying malignancy
1.81
1.44-2.27
APACHE II score
1.05
1.04-1.07
Increasing age (1-year increment)
1.02
1.01-1.03
Surgical patient
0.40
0.33-0.49
• Retrospective study, 32/187
(17%) patients died
• Inadequate initial
antimicrobial therapy
(IIAT) was a risk factor for
mortality
– OR 10.04, 95% CI (1.90-52.96)
• Risk factors for IIAT
– Infection with
multidrug-resistant
ESBLs (14.58 [1.91-111.36])
– Health care-acquired
ESBLs infection (4.32
[1.49-12.54])
Arch Intern Med 2005;165:1375-80.
Outcome of cephalosporin treatment for serious
infections due to apparently susceptible organisms
producing ESBL
MIC
(g/mL)
Patients, % (n)
Experienced failure of
cephalosporin therapy
Died of bacteremia
within 14 Days
8
100 (6/6)
33 (2/6)
4
67 (2/3)
0 (0/3)
2
33 (1/3)
0 (0/3)
<1
27 (3/11)
18 (2/11)
Total*
54 (15/28)
MIC = minimum inhibitory concentration
*Includes 5 patients with isolates for which MICs were recorded simply as 0.5 to 4 mg/L.
Peterson et al. J Clin Microbiol 2001; 39: 2206-12.
Clinical implications of ESBL-producing Klebsiella
species and Escherichia coli on cefepime effectiveness
• A retrospective, case–controlled study
• None-urine source (~80% from lung) of 10 ESBL-cases &
20 controls (non-ESBL) treated with cefepime (2
grams/day, adjusted for GFR)
Risk estimates for the effect of ESBL presence on cefepime outcomes
OR (95%CI)
Variables
Unsuccessful clinical response
Unsuccessful microbiological response
All-cause mortality
9.7 (1.4-68.8)
28.5 (2.6-306.6)
2.0 (0.396-10.1)
Infection-related mortality
4.7 (0.38-60.1)
Kotapati S, et al. J Infect 2005; 51: 211-7.
High-dose cefepime as an alternative treatment for infections
caused by TEM-24 ESBL-producing Enterobacter aerogenes in
severely-ill patients
• Retrospective study
• Seriously-ill patients infected with ESBL-producing
Enterobacter aerogenes, mostly TEM-24
• 21 treated with cefepime (6 grams/day) / 23 treated with
carbapenems (in combination with ciprofloxacin or amikacin)
Cefepime Carbapenems P-value
Clinical improvement
62%
70%
0.59
Bacteriological eradication 14%
22%
0.76
30-day mortality rate
33%
26%
0.44
• Nevertheless, a statistically significant increase in failure to
eradicate ESBL-producing E. aerogenes was observed as
the MICs of cefepime rose (p=0.017).
K. Goethaert et al. Clin Microbiol Infect 2006; 12: 56-62.
Cefepime versus Imipenem-Cilastatin for Treatment of
Nosocomial Pneumonia in Intensive Care Unit Patients: a
Multicenter, Evaluator-Blind, Prospective, Randomized Study
• A randomized, evaluator-blind, multicenter tria
• Compared cefepime (6 g/day) vs. imipenem-cilastatin (2
g/day) for the treatment of nosocomial pneumonia in 281
intensive care unit patients.
• In subgroup analysis, therapy of pneumonia caused
by an organism producing an extended spectrumlactamase failed in 4 of 13 patients (31%) in the
cefepime group but in none of 10 patients in the
imipenem group.
Zanetti G, et al. Antimicrobe Agents Chemother 2003; 47: 3442-7.
Bacteremia due to Klebsiella pneumoniae isolates producing
the TEM-52 extended-spectrum -lactamase: treatment
outcome of patients receiving imipenem or ciprofloxacin
• Retrospective study
• ESBL (TEM-52) – K. pneumoniae bacteremia, non-fatal
disease
• 10 treated with imipenem / 7 treated with ciprofloxacin
Ciprofloxacin* Imipenem P-value
• Treatment failure
5/7
2/10
0.03
* 2/7 = partial response
• Because the isolates had MICs of ciprofloxacin close to
the susceptibility breakpoint, treatment failure could be
ascribed to the inability of the drug to reach therapeutic
concentrations at infected sites.
Endimiani et al. Clin Infect Dis 2004; 38: 243-51.
•A prospective, observational study
•12 centers, 455 episodes
•18.7% with ESBL-K. pneumoniae
Pharmacodynamics of intermittent infusion
piperacillin/tazobactam and cefepime against ESBLproducing organisms
 Cefepime 1 gram q 12 hrs
 Cefepime 1 gram q 8 hrs
 Cefepime 2 gram q 12 hrs
 Pip/tazo 4.5 grams q 8 hrs
Pip/tazo 3.375 grams q 6 hrs
 Pip/tazo 3.375 grams q 4 hrs
Reese AM, et al. Int J Antimicrobe Agents 2005; 26: 114-9.
Pharmacodynamics of continuous infusion
piperacillin/tazobactam and cefepime against ESBLproducing organisms
 Cefepime 3 grams
 Cefepime 4 grams
 Pip/tazo 6.75 grams
Pip/tazo 13.5 grams
Reese AM, et al. Int J Antimicrobe Agents 2005; 26: 114-9.
Pharmacodynamics of levofloxacin, gatifloxacin,
and ciprofloxacin against ESBL-, and non-ESBL
producing organisms
Regimen
Probability (%) of achieving a free
AUC/MIC > 125
Non-ESBL
ESBL producers
producers (n=45)
(n=39)
Levofloxacin 500 mg q 24 hr
88
11
Levofloxacin 750 mg q 24 hr
91
13
Gatifloxacin 400 mg q 24 hr
85
8
Ciprofloxacin 400 mg q 12 hr
88
2
Moczygemba LR, et al. Clin Ther 2004; 26: 1800-7.
Summary of 3rd-generation cephalosporins on
treatment of ESBL-producing organisms
• Clinical significance of inoculum effect
• Poor clinical outcomes are observed when 3rdgeneration cephalosporins are used for treatment
– Higher fatal outcome
– Higher rate of clinical failure
• 3rd-generation cephalosporins should not be used
to treat serious infections with ESBL-producing
organisms, even in the presence of apparent
susceptibility.
Peterson et al. J Clin Microbiol 2001; 39: 2206-12.
Ariffin H et al. Int J Infect Dis 2000; 4: 21-5.
Wong-Beringer et al. Clin Infect Dis 2002; 34: 135-46.
Summary of 4th-generation cephalosporins on
treatment of ESBL-producing organisms
• More stable than 3rd-generation cephalosporins
againt some ESBLs and very stable against
AmpC-type -lactamases
• Inoculum effect, susceptible to SHV-type
• Need high dosage (> 4 grams/day) of cefepime for
achieving the T>MIC target, preferably in
combination with aminoglycoside for synergistic
effect
• Cefepime should not be used to treat serious
infections with ESBL-producing organisms.
Summary of -lactam/-lactamase inhibitor on
treatment of ESBL-producing organisms
• Limited clinical information
• Class A ESBLs are susceptible to clavulanate and
tazobactam in vitro, nevertheless many producers are
resistant to -lactamase inhibitor due to
– Hyperproduction of the ESBLs → overwhelm inhibitor
– Co-production of inhibitor-resistant penicillinases (e.g.
OXA-1) or AmpC enzyme
– Relative impermeability of the host strain
• -lactam/-lactamase inhibitor should not be used to treat
serious infections with ESBL-producing organisms.
Summary of cephamycins on treatment of
ESBL-producing organisms
• Limited clinical data
• Generally effective against Enterobacteriaceae
producing TEM-, SHV-, and CTX-M-derived ESBLs
• Cefotetan > cefoxitin : lower MICs
• Reports of cephamycins resistance development
during prolonged therapy
– Loss of outer membrane porin (porin deficient mutant)
– Acquisition of plasmid-mediated AmpC -lactamase
(ACT-1)
Summary of treatment recommendations for infections
with ESBL producers
No treatment
•Colonization with ESBL producers
Imipenem or meropenem
•Bloodstream infection
•Ventilator-associated pneumonia
•Any producers that appear to have reduced susceptibility to ertapenem
Ertapenem
•Complicated urinary tract infections
•Intra-abdominal infections
•Diabetic food infections
Quinolones
•Infections in patients with risk for allergy to carbapenems, if isolates are susceptible
Nitrofurantoin or fosfomycin
•Uncomplicated lower urinary tract infection
Tigecycline, colistin, or polymyxin B
•Isolates resistant to all other antibiotic options
•Patients allergic to -lactams
Livermore DM, Peterson DL. ESBLs in resistance 2006.
Carbapenem classification
GROUP 1
Carbapenems
(community acquired
infections)
Ertapenem
GROUP 2
Carbapenems
(hospital acquired
infections –
pseudomonas activity)
GROUP 3
Carbapenems
(hospital acquired
infections –
Pseudomonas and MRSA
activity)
Imipenem
Meropenem
Doripenem
Panipenem
CS-023
Dosage and Cost of Treatment in Patients with
ESBL-producing bacteria Infections
Dose / Day
Ertapenem
Cost / Unit
(Baht)
1 gm OD
Imipenem/Cilastatin 0.5 gm q 6 hr
Meropenem
1 gm q 8 hr
Cost / Day
(Baht)
1,735.00
1,735.00
750.00
3,000.00
1,390.00
4,170.00
Choice of Ertapenem can save cost of treatment about 1,265-2,435
Baht in patients with ESBL-producing bacteria infections.
* ราคายาโรงพยาบาลศรี นครินทร์ ณ วันที่ 21 มิถุนายน พ.ศ. 2549
Control of a Prolonged Outbreak of ESBLProducing Enterobacteriaceae in a University
Hospital
■ Imported ESBL-cases
Acquired ESBL-cases
Lucet JC, et al. Clin Infect Dis 1999; 29: 1411-8.
Class restriction of cephalosporin use to control total
cephalosporin resistance in nosocomial Klebsiella
Kg drug/month
1995
1996
Total cephalosporins
3rd-generation cephalosporins
Cefuroxime
Cefotetan
Cephazolin
Imipenem
No. cephalosporin-resistant Klebsiella
No. imipenem-resistant Pseudomonas
5.6
0.78
2.2
1.5
1.4
0.2
150
67
1.1
0.39
0.19
0.06
0.44
0.47
84*
113*
* P < 0.01
Rahal JJ, et al. JAMA 1998; 280: 1233-7.
OASIS I-II : Bowel Colonization with resistant
GNB after antimicrobial therapy of IAI
ESBL-producing Enterobacteriaceae
18.0%
17.2%
16.0%
ESBL-producing
Ertapenem
14.0%
12.0%
10.0%
9.3%
ESBL-producing
Pip/Taz
8.0%
6.0%
ESBL-producing
Ceftriaxone
4.0%
2.5%
2.6%
2.1%
2.0%
0.6%
0.0%
Baseline
1.6%
0.8%
0.0%
End of therapy
2 wk post-therapy
DiNubile MJ et al. Eur J Clin Microbiol Infect Dis 2005; 24: 443-9.
OASIS I-II : Bowel Colonization with resistant
GNB after antimicrobial therapy of IAI
P. aeruginosa resistance
1.4%
1.30%
1.30%
1.2%
Imipenem-resistant
Ertapenem
1.0%
0.8%
0.60%
0.6%
Imipenem-resistant
Pip/Taz
0.60%
0.4%
Pip/Taz-resistant
Pip/Taz
0.30%
0.2%
0.0%
0%
Baseline
0%
0
End of therapy
0%
2 wk post-therapy
DiNubile MJ et al. Eur J Clin Microbiol Infect Dis 2005; 24: 443-9.
Summary of interventions that could be used to
prevent problem with ESBL-producing bacteria in
hospitalized patients
Individual patient level
•Avoid use of 3rd-generation cephalosporins, aztreonam, or
cefuroxime
•Avoid unnecessary use of invasive devices
•Ensure good hand hygiene before and after patient-care activities
Institutional level
•Restrict use of 3rd-generation cephalosporins
•Introduce contact isolation precautions for patients documented to
have carriage or infection with ESBL-producing organisms
•Investigate envirinmental contamination if increased rates of
ESBL-producing organisms occur
Livermore DM, Peterson DL. ESBLs in resistance 2006.
Take Home Messages
• ESBL-producing bacterial infection is an emerging
problem worldwide.
• These organisms are associated with multi-drug
resistance causing high rate of mortality and treatment
failure.
• The significant risk factors for ESBL-producing
bacterial infection are prior use of antibiotics,
especially 3rd generation cephalosporins, and critically
ill or debilitated patients.
• Need the ESBL-laboratory testing for establish the
problem.
• Carbapenems is the drug of choice for serious ESBLproducing bacterial infection.
• Avoiding overuse or misuse of 3rd generation
cephalosporins and implementing isolation and contact
precaution to prevent and control the ESBL outbreak.