Extended Spectrum Beta Lactamases Esbl

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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

    1. 1. Extended Spectrum Beta-lactamases Temujin T. Chavez, M.D. LCDR MC USN Infectious Diseases Fellow
    2. 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. 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. 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. 5. ESBL Types
    6. 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. 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. 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. 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. 10. ESBL In Vitro Susceptibility
    11. 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. 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. 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. 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. 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. 16. ESBL Epidemiology
    17. 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. 18. Risk Factors
    19. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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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