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


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)


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.


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.


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


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


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


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


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.

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Extended Spectrum Beta Lactamases Esbl