Carbapenem Resistance in Enterobacteriaceae

1. Carbapenem Resistance in Enterobacteriaceae Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team Division of Healthcare Quality Promotion

2. Carbapenems

3. Spectrum of Activity

4. How are Carbapenems Used? Use by Clinical Isolate • Acinetobacter spp. • Pseudomonas aeruginosa • Alcaligenes spp. • Enterobacteriaceae • Mogenella spp. • Serratia spp. • Enterobacter spp. • Citrobacter spp. • ESBL or AmpC + E. coli and Klebsiella spp. Uses by Clinical Syndrome • Bacterial meningitis • Hospital-associated sinusitis • Sepsis of unknown origin • Hospital-associated pneumonia Reference: Sanford Guide

5. Emerging Carbapenem Resistance in Gram-Negative Bacilli • Significantly limits treatment options for life-threatening infections • No new drugs for gram-negative bacilli • Emerging resistance mechanisms, carbapenemases are mobile, • Detection of carbapenemases and implementation of infection control practices are necessary to limit spread

6. Carbapenem Resistance: Mechanisms

7. Carbapenemases

8. Carbapenemases in the U.S.

9. Klebsiella Pneumoniae Carbapenemase • KPC is a class A b-lactamase • Confers resistance to all b-lactams including extended-spectrum cephalosporins and carbapenems • Occurs in Enterobacteriaceae • Most commonly in Klebsiella pneumoniae • Also reported in: K. oxytoca, Citrobacter freundii, Enterobacter spp., Escherichia coli, Salmonella spp., Serratia spp., • Also reported in Pseudomonas aeruginosa (Columbia)

10. Susceptibility Profile of KPC-Producing K. pneumoniae

11. KPC Enzymes • Located on plasmids; conjugative and nonconjugative • blaKPC is usually flanked by transposon sequences • blaKPC reported on plasmids with: • Normal spectrum b-lactamases • Extended spectrum b-lactamases • Aminoglycoside resistance

12. KPC’s in Enterobacteriaceae Pseudomonas aeruginosa – Columbia & Puerto Rico

13. Geographical Distribution of KPC-Producers Frequent Occurrence Sporadic Isolate(s)

14. Geographical Distribution of KPC-Producers in New Jersey

15. KPC Outside of United States • France (Nass et al. 2005. AAC 49:4423-4424) • Singapore (report from survey) • Puerto Rico (ICAAC 2007) • Columbia (Villegas et al. 2006. AAC 50:2880-2882 & ICAAC 07) • Brazil (ICAAC 2007) • Israel (Navon-Venezia et al. 2006. AAC 50:3098-3101) • China (Wei Z, et al. 2007. AAC 51: 763-765)

16. Inter-Institutional & Inter-State Spread of KPC-Producing K. pneumoniae

17. Intra-institution, Interspecies KPC Plasmid Transfer Cf Ko Cf Ko

18. Laboratory Detection of KPC-Producers Problems: 1) Some isolates demonstrate low-level carbapenem resistance 2) Some automated systems fail to detect low-level resistance

19. Susceptibility of KPC-Producers to Imipenem S* I R *12% of isolates test susceptible to imipenem

20. Susceptibility of KPC-Producers to Meropenem S* I R *9% of isolates test susceptible to meropenem

21. Susceptibility of KPC-Producers to Ertapenem S I R None of the isolates test susceptible to ertapenem

22. Can Carbapenem Susceptibility of I or R Detect KPC-Producers? *N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

23. CAP Results (D-05)KPC-producing Klebsiella pneumoniae

24. Carbapenem MIC ≥ 2 mg/ml to Detect KPC-producers *N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

25. When to Suspect a KPC-Producer • Enterobacteriaceae – especially Klebsiella pneumoniae that are resistant to extended-spectrum cephalosporins: • MIC range for 151 KPC-producing isolates • Ceftazidime 32 to >64 mg/ml • Ceftriaxone ≥ 64 mg/ml • Cefotaxime ≥ 64 mg/ml • Variable susceptibility to cefoxitin and cefepime

26. Reading Disk Diffusion & Etest

27. Phenotypic Tests for Carbapenemase Activity • Modified Hodge Test • 100% sensitivity in detecting KPC; also positive when other carbapenemases are present • 100% specificity Procedure described by Lee et al. CMI, 7, 88-102. 2001.

28. Modified Hodge Test Lawn of E. coli ATCC 25922 1:10 dilution of a 0.5 McFarland suspension Test isolates Imipenem disk Described by Lee et al. CMI, 7, 88-102. 2001.

29. Modified Hodge Test • Preliminary results suggest that any of the three carbapenem disks work in the Modified Hodge Test

30. What Labs Should Do Now • Look for isolates of Enterobacteriaceae (especially K. pneumoniae), with carbapenem MIC ≥ 2 mg/ml or nonsusceptible to ertapenem by disk diffusion • Consider confirmation by Modified Hodge Test • Can submit initial isolate to CDC via NJ State Lab for confirmation by blaKPC PCR if KPC-producers not previously identified in hospital’s isolate population • Alert clinician and infection control practitioner to possibility of mobile carbapenemase in isolate

31. KPC – Questions • If I have detect KPC-production, should I change susceptible carbapenem results to resistant? • Not enough data to make a clear recommendation • Clinical outcomes data will be necessary

32. Testing Other Drugs • Tigecycline: • Test by Etest if possible – disk diffusion tends to overcall resistance • No CLSI breakpoint, but there are FDA breakpoint • Susceptible ≤ 2 mg/ml • Intermediate = 4 mg/ml • Resistant ≥ 8 mg/ml

33. Testing Other Drugs • Polymixin B or Colistin • Could test either, but colistin used clinically • Disk diffusion test does not work – don’t use! • Etest – works well, but not FDA cleared • Broth microdilution – reference labs • Breakpoints - none • MIC ≤ 2 mg/ml, normal MIC range • MIC ≥ 4 mg/ml indicates increased resistance

34. Acknowledgements • Fred Tenover • Roberta Carey • Kamile Rasheed • Kitty Anderson • Brandon Kitchel • Linda McDougal • David Lonsway • Jana Swenson • Arjun Srinivasan • Susan Mikorski