Extended Spectrum Beta Lactamases Esbl
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Transcript of Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta-lactamasesTemujin T. Chavez, M.D.
LCDR MC USNInfectious Diseases Fellow
Clin Microbiol Rev. 2005;18:657-686
ESBL Introduction 1940s: B-lactamase mediated resistance to S.
aureus 1970s: B-lactamase mediated resistance to H.
influenzae and Neisseria gonorrhea 1980s: 3rd generation ceph introduced in in
response to B-lactamase resistance to Amp in E. coli and K. pneumoniae
1983: K. ozaenae with plasmid mediated resistance to broad spectrum ceph
1989: 1st “substantial review” of ESBLs by Dr. Phillipon and colleagues in AAC 1989;33:1131-1136
Clin Microbiol Rev.18;2005:657-689.
ESBL Introduction
Total number of ESBLs exceeds 200 >1,300 relevant articles to ESBL since 2001 Published research in more than 30 countries
PPID, 6th ed. 2005
ESBL Introduction B-lactamases conferring resistance to the
penicillins, first-,second-, and third-generation cephalosporins and aztreonam
Mechanism is via hydrolysis Inhibited by B-lactamase inhibitors such as
clavulanic acid B-lactamases in group 2d and group 2be
Group 2b: TEM-1, TEM-2, & SHV-1 Group 2d: OXA
B-lactamase in group 1 AmpC*
ESBL Types
Clin Microbiol Rev. 2005;18:657-686.
ESBL Types-SHV1st B-lactamase found in K. ozaenae
Germany 1983Most frequently found isolate
SHV refers to ssulfhydryl variableRepl glycine by serine @ pos 238
SHV-2 accounts for extended spectrum properties
Clin Microbiol Rev. 2005;18:657-686.
ESBL-TEM 100+ TEM types derived from TEM-1 & TEM-
2 TEM-1
1st reported from E. coli isolate in pt named
Temoneira Hydrolyzes amp > carbenicillin, oxacillin, or
cephalothin Inhibited by clavulanic acid
First true ESBL is TEM-3 Plasmid-mediated B-lactamase CTX-1(cefotaxime)
Clin Microbiol Rev. 2005;18:657-686.
ESBL Other Types OXA
Grp 2d
Hydrolyze Oxacillin Predominately occur in Pseudomonas aeruginosa
PER Hydrolyze pcn and ceph
VEB-1 High level resistance to ceftaz, cefotaxime, & aztr
GES, BES, TLA, SFO, & IBC
Microb Drug Restance. 2006;12:223-230.
B-lactamases other types
AmpC Hydrolyze 3rd gen ceph Active against cephamycins Resistant to inhibition by clavulanic acid/b-lactamase
inh Sensitive to 4th gen ceph (cefepime)
Carbapapenemases Metallo-B-lactamases & serine carbapenemases SENTRY Antimicrobial Surveillance Program (2000-
2004)KPC-2, KPC-3, SME-2 most frequently isolated in USMetallo-B-lactamases most prevalent in Europe
ESBL In Vitro Susceptibility
Clin Microbiol Rev. 2005;18:657-686 J Clin
Microbiol.2001;39:2206-2212.
ESBL In Vitro Susceptiblity
NCCLs established breakpoints 1980s
In vitro, MICs of ceph rise as inoculum of ESBL prod organisms rise “inoculum effect”
NCCLs subcommittee convened working group recommending K. spp and E. coli screened for
ESBL prod Suspected ESBL tested for
phenotypic confirmation 1998 survey of 369 laboratories only
32% performed tests to detect ESBL production
Most liberal interpretation of ceph susceptibility by CLSI w/ MIC</=8ug/ml
J Clin Microbiol. 2001;39:2206-2212.
ESBL In Vitro Susceptibility
Increasing concern re: pt outcome w/ serious infxn due to ESBL producing organism in vitro susc/int
Prospective observational study by Dr. Paterson and colleagues of consecutive pts w/ K. pneumoniae bacteremia in 12 hospitals in US, Taiwan, Australia, S. Africa, Turkey, Belgium, & Argentina
Jan 1997 - Dec 1997 Monitored 1 month p bacteremia to assess clinical outcome
J Clin Microbiol. 2001;39:2206-2212.
ESBL In Vitro Susceptibility
Antibiotic susceptiblity by disc diffusion or automated broth microdilution methods
Stored isolates sent to central lab where identity of K. pneumoniae confirmed & MICs determined by E-test
Susceptible MICs </=8ug/ml: cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone </=16ug/ml: cefotetan
ESBL prod determined phenotypically by combination of clavulanic acid 4ug w/ K. sp isolates of cefotaxime and ceftaz to eval for decr 2fold MICs
J Clin Microbiol. 2001;39:2206-2212.
ESBL In Vitro Susceptibilty
455 episodes of K. pneumoniae bacteremia studies in 440 pts
18% were ESBL 1 isolate w/ resistant MIC but non
phenotypic response w/ clavulanic acid
6 pts w/ ESBL strain tx w/ ceph susceptible in vitro 2 pts died. 1 pt with fevers
until ∆ meropenem 3 pts w/ ESBL strain tx w/ ceph int
in vitro 1 pt died. 2 pts ∆ abx
Above combined with medline search of 26 pts w/ enterobacteriacea totaling 23 pts Stat sig incr in failure rate as
MICs incr
Clin Microbiol Infect. 2008;14:169-174.
ESBL In Vitro Susceptibilty
Currently accepted that cephalosporin breakpoints used in Europe (EUCAST) and US (CLSI) fail to detect most ESBL
Published data suggests that clinical outcome with 3rd gen ceph related more to MICs and not presence of ESBL arguing against “inoculum effect”
New breakpoints adopted by EUCAST March 2006 Existing breakpoints do not allow for detection of important resistance
mechanisms Question if breakpoints correlate with clinical outcome Controversy re: contradicting 3rd gen ceph as S or R is ESBL pos
CLSI Working Group on Enterobacteriacea have been proposed but not accepted as of Jan 2008
Suggested CLSI breakpoints for senstivity pre/post (ug/ml) Cefuroxime (8/8), Cefotaxime (8/1 ), Ceftriaxone (8/1), Ceftazidime (8/4),
Cefepime (8/8)
ESBL Epidemiology
Clin Microbiol Rev. 2005;18:657-686.
ESBL Epidemiology North America
National Nosocomial Infections Surveillance (NNIS) Jan 1998-June 2002
6.1% of Klebsiella pneumoniae isolates resistant to 3rd gen ceph in 110 ICUs
>10% of ICUs, resistance exceeds 25% Non-ICU inpt, 5.7% of Klebsiella pneumoniae isolates
resistant Outpt, 1.8% of Klebsiella pneumoniae resistant Prevalence of ESBL underestimated due to MIC S/I
Europe France in early 1990s, 25-35% of nococomial Klebsiella
pneumoniae were ESBL producing N. France in 2000, 7.9% of nosocomial Klebsiella pneumoniae
were ESBL producing Discordance between Western and Eastern Europe
Risk Factors
J Clinical Microbiol. 2004;42:1089-1094
ESBL Risk Factors
Case control study to identify risk factors for community acquired ESBL E. coli
49 case patients identified at Microbiology Laboratory of the Hospital Universitario Virgen Macarena Dept from Jan 2001 - May 2002
ESBLEC defined as resistance to the following antibiotics Ceftazidime and Cefoxitin +/- clavulanic acid
J Clinical Micobiol. 2004;42:1089-1094.
ESBL Risk Factors Median age 70yo 27 (55%) pts
admitted during preceding yr
37 (76%) pts with uti
6 (12%) pts w/ bacteremia requiring hospitalization
J Clinical Microbiol. 2004;42:1089-1094.
ESBL Risk Factors
82% of case pts had 2 or more risk factors Risk factors: previous hospital admission, DM, recurrent UTI, FQ in past 2 mos, older
age in males If only CTX clone considered risk factors are
Older age Higher Charleson index Previous fluoroquinolone use
CID. 2005;40:1317-1324.
ESBL Risk Factors
Case control study to identify risk factors for MDR ESBL E. coli and Klebsiella sp.
361 total isolated identified at HUP Clinical Micro Dept from June 1997 - Dec 2002
MDR ESBL EK defined as resistance to the following antibiotic classes Trimeth-sulfa, aminoglycosides, & quinolones Time period-relevant NCCLS guideline for detecting ESBL
CID. 2005;40:1317-1324.
ESBL Risk Factors
361 ESBL-EK isolates: 151 (48%) E. coli, 183 (50.7%) K. pneumoniae, 21 (5.8%) K. oxytoca
Compared 68 case pts w/ ESBL-EK with 293 control pts w/ ESBL-EK Case pts sig more likely to have CVC and to have been located in
an ICU at time of infection No differences between comorbidities Case pts more likely to have UT as site of infection
CID. 2005;40:1317-1324.
ESBL Risk Factors
Case and control w/o diff in abx used defined as total abx days or total # of abx
Case pts sig more likely to have received fq w/in 30 days prior to infxn
CID. 2005;40:1317
ESBL Risk Factors
Multivariate analysis Only independent risk factor for MDR-ESBL infxn was
pathogen (K. pneumoniae) Borderline assn with CVC and MDR ESBL-EK
Annals of Int Med. 2004;140:26-32.
ESBL Risk Factors
Multinational prospective observational study of 440 consecutive pts with 455 episodes of K. pneumoniae bacteremia
Enrollment Jan 1996-Dec 1997. 12 hospitals. 6 continents. Followed for 1 mo after bacteremia to assess clinical outcome. Antibiotics per physician discretion
Annals of Int Med. 2004;140:26-32.
ESBL Risk FactorsProduction of ESBL phenotypically
determined by broth dilution using NCCLS standards (1999) / Pulse-field gel electrophoresis used to establish genotype
Results 30.8% of nosocomial bacteremia due to ESBL prod
organism 3.5% of community acq bacteremai due to ESBL prod
organism 43.5% of ICU bacteremia due to ESBL prod organism
ESBL Risk Factors Episodes of nosocomial bacteremia due to ESBL prod
K. pneumoniae by country: 78% (7/9) in Turkey 59% (20/34) in Argentina 37% (28/76) in S. Africa 36% (12/33) in US 25% (3/12) in Belgium 12% (5/43) in Australia 7% (3/46) in Taiwan
Annals of Int Med. 2004;140:26-32.
ESBL Risk Factors
Factors not a/w ESBL nosocomial bacteremia bivariate analysis Sex, age, admission from NH, severity of illness, DM, liver dz, HIV, previous tranplant, surgery
w/in 30 days, corticosteroids, CVC, ET, feeding tube When analyzed for prior antibiotic use and bacteremia
Prior b-lactam w/ risk ration of 3.8
ESBL Risk FactorsConflicting results
Difference in study populations, control populations, sample size, lab criteria
GeneralizationsSeverity indexProlonged hospital stayInvasive devices
Clin Microbiol Rev. 2005;18:657-686.
ESBL Antibiotic Choice
Cefepime should not be used as first-line against ESBL-producing organisms MICs rise with inoculum effect size High dose 2 gm iv 12 +/- amikacin
B-lactam/B-lactamase inhibitor MICs rise with inoculum size Reduced activity in presence of porin loss and b-
lactamase production Quinolones option for complicated UTI due to ESBL organism
In vitro synergy with fq + b-lactam (cefotax) Carbapenems first line for serious ESBL organisms
Meropenem preferred over Imipenem for nosocomial meningitis
No evidence of combination superior to alone
References Paterson DL, Bonomo RA. Extended-Spectrum B-lactamases: a Clinical Update. Clinical
Microbiology Reviews. 2005;18(4):657-686. Phillipon A., R. Labia, and G. Jacoby. Extended-spectrum beta-lactamases. Antimicrob Agents
Chemother. 33:1131-1136 Antimicrobial Sensitivity Testing. Mandell, Bennet, & Dolin: Principles of Infectious Diseases, 6th
ed. Philadelphia, PA. 2005. Deshpande LM, et al. Occurrence and Characterization of Carbapenemase-Producing
Enterobacteriacea: Report from SENTRY Antimicrobial Surveillance Program (2000-2004). Microbiol Drug Resistance. 2006;12:223-230.
Paterson DL, KO WC, Von Gotttberg A. et al. Outcome of cephalosporing treatment for serious infections due to apparently susceptible organisms producing extended-spectrum beta-lactamases: implications for the clinical microbiology laboratory. J Clin Microbiol. 2001;39:2206-2212.
Khaltemeter G. Breakpoints for intravenously used cephalosporins in Enterobacteriacea-EUCAST and CLSI breakpoints. Clin Microbiol Infect. 2008;14:169-174.
Wiener, J., J.P. Quinn, P.A. Bradford, R.V. Goering, C. Nathan, K. Bush, and R.A. Weinstein. 1999. Multiple antibiotic resistant Klesiella and Escherichia coli in nursing homes. JAMA 281:517-523.
Paterson DL, et al. International Prospective Study of Klebsiella pneumoniae Bacteremia: Implications of Extended-Spectrum B-lactamase Production in Nosocomial Infections. Ann Intern Med 2004;140:26-32.
Rodriguez-Bano J, Navarro MD, Romero L, et al. Epidemiology and clinical features of infections caused by extended-spectrum beta-lactamases in the UK. J Clinical Microbiol. 2004;42:1089-1094.