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

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Presentation on theme: "Carbapenem Resistance in Enterobacteriaceae Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team Division of Healthcare Quality Promotion."— Presentation transcript:

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

2 Carbapenems Drug Route of Administration FDA Status ImipenemIVCleared MeropenemIVCleared ErtapenemIM, IVCleared DoripenemIVApplication Submitted

3 Spectrum of Activity Drug Strep spp. & MSSA Entero- bacteriaeae Non- fermentors Anaerobes Imipenem ++++ Meropenem ++++ Ertapenem ++ Limited activity + Doripenem ++++

4 How are Carbapenems Used? Uses by Clinical Syndrome Bacterial meningitis Hospital-associated sinusitis Sepsis of unknown origin Hospital-associated pneumonia 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. 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 EnterobacteriaceaeCephalosporinase + porin loss Carbapenemase P. aeruginosaPorin loss Up-regulated efflux Carbapenemase Acinetobacter spp.Cephalosporinase + porin loss Carbapenemase

7 Carbapenemases ClassificationEnzymeMost Common Bacteria Class AKPC, SME, IMI, NMC, GES Enterobacteriaceae (rare reports in P. aeruginosa) Class B (metallo- -lactamse) IMP, VIM, GIM, SPM P. aeruginosa Enterobacteriacea Acinetobacter spp. Class DOXAAcinetobacter spp.

8 Carbapenemases in the U.S. EnzymeBacteria KPCEnterobacteriaceae Metallo- -lactamase P. aeruginosa OXAAcinetobacter spp. SMESerratia marcesens

9 Klebsiella Pneumoniae Carbapenemase KPC is a class A -lactamase Confers resistance to all -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 AntimicrobialInterpretationAntimicrobialInterpretation AmikacinIChloramphenicolR Amox/clavRCiprofloxacinR AmpicillinRErtapenemR AztreonamRGentamicinR CefazolinRImipenemR CefpodoximeRMeropenemR CefotaximeRPipercillin/TazoR CetotetanRTobramycinR CefoxitinRTrimeth/SulfaR CeftazidimeRPolymyxin B MIC >4 g/ml CeftriaxoneRColistin MIC >4 g/ml CefepimeRTigecyclineS

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

12 KPCs in Enterobacteriaceae SpeciesComments Klebsiella spp.K. pneumoniae-cause of outbreaks K. oxytoca-sporadic occurrence Enterobacter spp. Sporadic occurrence Escherichia coli Salmonella spp. Citrobacter freundii Serratia spp. 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

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*IR *12% of isolates test susceptible to imipenem

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

21 Susceptibility of KPC-Producers to Ertapenem SIR None of the isolates test susceptible to ertapenem

22 Can Carbapenem Susceptibility of I or R Detect KPC-Producers? Method Sens/Spec (%) for Detection of KPC-mediated R* ImipenemMeropenemErtapenem Ref BMD94/9394/9897/89 Disk Diffusion42/9671/9697/82 Etest55/9658/9690/84 Vitek Legacy55/9652/98N/A Vitek 271/9848/9694/93 MicroScan74/9684/98100/89 Phoenix81/9661/98N/A *N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

23 CAP Results (D-05) KPC-producing Klebsiella pneumoniae Susceptible Results MIC MethodDisk Method Imipenem 6357 Meropenem 6318 Ertapenem 00

24 Carbapenem MIC 2 g/ml to Detect KPC-producers Method Sens/Spec (%) for Detection of KPC-mediated R* ImipenemMeropenemErtapenem Ref BMD100/93 100/89 Etest84/8990/87100/82 Vitek LegacyNA Vitek 271/9193/89 MicroScan100/93 NA Phoenix74/9687/93NA *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 Ceftazidime32 to >64 g/ml Ceftriaxone 64 g/ml Cefotaxime 64 g/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 Imipenem disk Test isolates 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 g/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 bla KPC PCR if KPC-producers not previously identified in hospitals 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 g/ml Intermediate = 4 g/ml Resistant 8 g/ml

33 Testing Other Drugs Polymixin B or Colistin Could test either, but colistin used clinically Disk diffusion test does not work – dont use! Etest – works well, but not FDA cleared Broth microdilution – reference labs Breakpoints- none MIC 2 g/ml, normal MIC range MIC 4 g/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

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