Extended Spectrum Beta Lactamases Esbl
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Beta-lactamases confer resistance to penicillin, 1st 2nd & 3rd generation cephalosporins, and aztreonam

Beta-lactamases confer resistance to penicillin, 1st 2nd & 3rd generation cephalosporins, and aztreonam

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  • Amp C associated with clinical failure when 3rd gen ceph used. In general, 4th gen ceph, cefepime, clinically useful against AmpC type organisms.
  • Germany isolate with B-lactamase related to SHV-1
  • Amp C associated with clinical failure when 3rd gen ceph used. In general, 4th gen ceph, cefepime, clinically useful against AmpC type organisms.
  • Inoculum effect-K pneumo with mic 0.25ug/ml when 10*5cfu/ml but increases to >64ug/ml when 10*7 cfu/ml
  • NNIS=National Nosocomial Infection Surveillance National Nosocomial Infections Surveillance. 2002. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 to June 2002, issued August 2002. Am J Infect. Control 30:458-475.
  • NO clonal relatedeness discovered Unable to determine if plasmid mediated resistance Data not present shows that no clonal relationship between outpt and inpt samples

Extended Spectrum Beta Lactamases Esbl Presentation Transcript

  • 1. Extended Spectrum Beta-lactamases Temujin T. Chavez, M.D. LCDR MC USN Infectious Diseases Fellow
  • 2. 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. 2005;18:657-686
  • 3. ESBL Introduction
    • Total number of ESBLs exceeds 200
    • >1,300 relevant articles to ESBL since 2001
    • Published research in more than 30 countries
    Clin Microbiol Rev.18;2005:657-689.
  • 4. 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*
    PPID, 6th ed. 2005
  • 5. ESBL Types
  • 6. ESBL Types-SHV
    • 1st B-lactamase found in K. ozaenae Germany 1983
    • Most frequently found isolate
    • SHV refers to s ulf h ydryl v ariable
      • Repl glycine by serine @ pos 238
    • SHV-2 accounts for extended spectrum properties
    Clin Microbiol Rev. 2005;18:657-686.
  • 7. ESBL-TEM
    • 100+ TEM types derived from TEM-1 & TEM-2
    • TEM-1
      • 1st reported from E. coli isolate in pt named Tem oneira
      • 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.
  • 8. ESBL Other Types
    • OXA
      • Grp 2d
      • Hydrolyze Oxa cillin
      • Predominately occur in Pseudomonas aeruginosa
    • PER
      • Hydrolyze pcn and ceph
    • VEB-1
      • High level resistance to ceftaz, cefotaxime, & aztr
    • GES, BES, TLA, SFO, & IBC
    Clin Microbiol Rev. 2005;18:657-686.
  • 9. 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 US
        • Metallo- B -lactamases most prevalent in Europe
    Microb Drug Restance. 2006;12:223-230.
  • 10. ESBL In Vitro Susceptibility
  • 11. 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
    Clin Microbiol Rev. 2005;18:657-686 J Clin Microbiol.2001;39:2206-2212.
  • 12. 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.
  • 13. 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.
  • 14. 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
    J Clin Microbiol. 2001;39:2206-2212.
  • 15. 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)
    Clin Microbiol Infect. 2008;14:169-174.
  • 16. ESBL Epidemiology
  • 17. 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
    Clin Microbiol Rev. 2005;18:657-686.
  • 18. Risk Factors
  • 19. 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 Microbiol. 2004;42:1089-1094
  • 20. 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 Micobiol. 2004;42:1089-1094.
  • 21. 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
    J Clinical Microbiol. 2004;42:1089-1094.
  • 22. 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.
  • 23. 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.
  • 24. 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;40:1317-1324.
  • 25. 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
    CID. 2005;40:1317
  • 26. 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.
  • 27. ESBL Risk Factors
    • Production 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
    Annals of Int Med. 2004;140:26-32.
  • 28. 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
  • 29. 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
    Annals of Int Med. 2004;140:26-32.
  • 30. ESBL Risk Factors
    • Conflicting results
      • Difference in study populations, control populations, sample size, lab criteria
    • Generalizations
      • Severity index
      • Prolonged hospital stay
      • Invasive devices
  • 31. 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
    Clin Microbiol Rev. 2005;18:657-686.
  • 32. 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.