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Emerging Antimicrobial Resistance in Texas

Emerging Antimicrobial Resistance in Texas. The new ESBLs. Most Important Emerging Resistance. MRSA in the community Resistance to alternative drugs for MRSA, including vancomycin Re-emergence of DRSP ESBL in various gram-negative species Carbapenemases in various GNs

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Emerging Antimicrobial Resistance in Texas

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  1. Emerging Antimicrobial Resistance in Texas The new ESBLs

  2. Most Important Emerging Resistance • MRSA in the community • Resistance to alternative drugs for MRSA, including vancomycin • Re-emergence of DRSP • ESBL in various gram-negative species • Carbapenemases in various GNs • Multi-drug resistance in Pseudomonas, enterics, Acinetobacter, S. maltophilia

  3. To Review ESBL background……

  4. Extended Spectrum Beta-Lactamases • Most ESBL - mutations of TEM or SHV plasmid-mediated enzymes normally found in E. coli and Klebsiella • Now TEM-1 to 161, SHV-1 to 105 (as of 3-20-08) - Source: www.lahey.org/studies/webt.asp • Differences in substrate specificity -especially ceftaz vs. cefotax • Hydrolyze 3rd and 4th gen cephs and aztreonam at high bacterial inoculum

  5. Molecular Basis of ESBLs Enzyme Ceftaz Amino Acid Position MIC 104 164 240 TEM-1 0.12 Glu Arg Glu TEM-10 > 256 Glu Ser Lys TEM-12 16 Glu Ser Glu TEM-26 256 Lys Ser Glu from: Jacoby, IDCNA 11:875, 1997

  6. Different Substrate Affinities of ESBL Enzyme MICs Ceftaz Cefotax Aztreo TEM-1 0.12 0.06 0.12 TEM-10 > 256 1 128 TEM-12 16 0.12 1 TEM-26 256 0.5 64 from: Jacoby, IDCNA 11:875, 1997

  7. Inoculum Effect with ESBLs - MICs with SHV-3 producing C. freundii Inoculum 105 107 Cefotaxime 2 256 Ceftazidime 1 32 Cefepime 0.5 >128 Meropenem 0.06 0.06 Thomson, AAC45:3548, 2001

  8. Clinical Significance of ESBLs • Global bacteremia study in ‘96 and ‘97 • 455 K. pneumoniae • 18.7% (85) produced ESBLs • 9 treated with a cephalosporin that was CLSI Susceptible or Intermediate • 3 died, 5 required Rx change • Overall, 32 pts. Rx with a ceph (S or I) • 4/4 I’s failed; 15/28 S’s failed • 4/5 treated with cefepime failed D. Paterson, JCM 2001

  9. Two Step Process of Detection and Confirmation of ESBLs • Test “indicator” drugs with special “screening” breakpoints • cefpodoxime or look for elevated MICs of ceph 3s • Must confirm with clavulanate combos of cefotaxime and ceftazidime by MIC or disk • Report as ESBL if either clavulanate combo is positive

  10. Laboratory Reporting of ESBL-Producing Isolates • “Expertize” results to resistant for all penicillins, aztreonam, and “true cephalosporins” irrespective of individual test results and/or • Provide a warning comment that ESBL-producers should be considered clinically resistant to all penicillins, cephalosporins, and aztreonam

  11. Gram-Negative Species Known to Harbor ESBL • Klebsiella pneumoniae • Klebsiella oxytoca • E. coli • Proteus mirabilis • Salmonella spp. • Also in Citrobacter, Enterobacter, Serratia, Morganella, P. aeruginosa, Acinetobacter

  12. AmpC Beta-Lactamase • ampC gene is present in all Enterobacter, Citrobacter freundii, Morganella morganii, P. aeruginosa • Selection of resistant mutants with “up-regulated” production of ampC during therapy • Resistance to all cephs except cefepime • ampC can be plasmid-mediated in some E. coli and K. pneumoniae • Jacoby and Munoz-Price, NEJM 352:380, 2005

  13. ESBL Spectrum “extended” from parent enzyme Susceptible to cefotetan Inhibited by clavulanate Can hydrolyze cefepime at high inoculum Carbapenem susceptible ampC Spectrum not “extended,” although may be basal or hyperproducing level Resistant to cefotetan Not inhibited by clav Hydrolyzes cefepime poorly Carbapenem suscept ESBL vs. AmpC

  14. ESBL That Are Not Derived From TEM or SHV • CTX-M-1 thru 69 - hydrolyze cefotaxime better than ceftazidime • Derived from Kluyvera ascorbata • Most common ESBL in Latin America, Japan, Eastern Europe, and U.S.? • OXA-1 thru 119 (~11 ESBL) • Mostly in Eastern Europe • Usually in P. aeruginosa or Acinetobacter

  15. E. coli with “Cefotaximase”

  16. P. mirabilis with CTX-M15

  17. E. cloacae with CTX-M15: Use of cefepime + clavulanate

  18. Increasing Numbers of ESBLs Lewis, et al. AAC 51:4015, 2007

  19. “First Report of the Emergence of CTX-M Type ESBLs as the Predominant ESBL Isolated in a U.S. Healthcare System” • Retrieved all frozen ESBL isolates from 2000 - mid 2006 • Standard CLSI ESBL screening and confirmatory tests used throughout period • Screening by cefpodoxime disk and Vitek 2 • PCR and sequencing for TEM, SHV, CTX-M (and OXA in some) Lewis, et al, AAC, November, 2007

  20. Emergence of CTX-M ESBLs in San Antonio • Have emerged as predominant ESBL over last 3 years • %CTX-M in 2000-2002: 0-25% • %CTX-M in 2003-2006: 60-89% • CTX-M in E. coli, K. pneumoniae, K. oxytoca, P. mirabilis, Enterobacter spp., M. morganii • Now predominantly CTX-M15 in E. coli, often outpatient urines - 8% with 2nd ESBL • 86% fluoroquinolone resistant; 66% to SXT • Lewis, et al, AAC 2007

  21. Evolution of CTX-M ESBLs From Lewis, et al, AAC 51:4015, 2007

  22. ESBL Producers in 2007 • 64% (48) of ESBL in E. coli; 15% (11) in K. pneumoniae, 9.3% (7) K. oxytoca, 6.7% (5) Enterobacter, 2 Serratia, 1 P. mirabilis, 1C. koseri • 53% from urine; 22% from blood or BF • What are risk factors for OP E coli CTX-M UTI? • When is a urine culture needed? • What agents are available for therapy of OP E. coli ESBL?

  23. ESBL Producers in 2007 • 64% (48) of ESBL in E. coli; 15% (11) in K. pneumoniae, 9.3% (7) K. oxytoca, 6.7% (5) Enterobacter, 2 Serratia, 1 P. mirabilis, 1C. koseri • 53% from urine; 22% from blood or BF • What are risk factors for OP E coli CTX-M UTI? • When is a urine culture needed? • What agents are available for therapy of OP E. coli ESBL?

  24. Cefotaxime and Ceftazidime Zones with Different Species Producing CTX-M ESBLs

  25. The Newest Mechanisms of Concern - Carbapenemases • The alphabet soup of rapidly emerging carbapenemases • KPCs 1-4 • IMP 1-23 • VIM 1-18 • PER, SME, VEB • Some OXA enzymes Source: www.lahey.org/studies/webt.asp

  26. KPC Carbapenemases • Plasmid-mediated - KPCs 1-4 • Klebsiella pneumoniaecarbapenemase • Can hydrolyze all beta-lactams, including carbapenems • Often also resistant to FQs, SXT, aminoglycosides - Suscept to colistin, tigecycline • Have rapidly spread in the Eastern U.S. • Difficult to detect by commercial or ref. methods • Are they in Texas??

  27. How Do Labs Perform in Detection of KPCs? • CAP sample DA-05, 2007 illustrated problems of detection • Partial or inconsistent clavulanate effect - like ESBL • Some commercial systems (and disks) had a high false susceptible rate with imipenem • Meropenem also problematic • Best detection by testing ertapenem • Ertapenem > meropenem > imipenem

  28. Detection of KPCs • Look for resistance to all penicillins and cephalosporins • Look for carbapenem MICs > 1 • Perform “modified Hodge test” • PCR using primers for all KPC, and sequence product

  29. Modified Hodge Test

  30. Other Carbapenemases - Metallo-Beta-Lactamases • Mostly found in P. aeruginosa • IMP, VIM, SIM, GIM, and SPM • Europe, Asia, S. America, N. America (IMP, VIM) • Plasmid, chromosomal, or integrons • P. aeruginosa with VIM-2 in CAP DA-01, 2007 • Resistant to all carbapenems, cephs, pens • Suscept. to aztreonam, pip-tazo • Colistin suceptible

  31. Newer Beta-Lactamases are emerging in Texas • Labs must look for them • Physicians must be aware of their existence

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