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Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
Extended Spectrum Beta Lactamases Esbl
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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
  • Transcript

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

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