Carbapenem Resistance in Enterobacteriace ae

Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team

Division of Healthcare Quality Promotion

Carbapenems
Drug Imipenem Meropenem Ertapenem Doripenem Route of Administration IV IV IM, IV IV FDA Status Cleared Cleared Cleared Application Submitted

Spectrum of Activity
Drug Imipenem Meropenem Ertapenem Doripenem Strep spp. & MSSA Enterobacteriaeae Nonfermentors Anaerobes

+ + + +

+ + + +

+ +
Limited activity

+ + + +

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

Reference: Sanford Guide

Mogenella spp. Serratia spp. Enterobacter spp. Citrobacter spp. ESBL or AmpC + E. coli and Klebsiella spp.

Emerging Carbapenem Resistance in GramNegative Bacilli

Significantly limits treatment options for lifethreatening 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

Carbapenem Resistance: Mechanisms

Enterobacteriaceae Cephalosporinase + porin loss Carbapenemase P. aeruginosa Porin loss Up-regulated efflux Carbapenemase Acinetobacter spp. Cephalosporinase + porin loss Carbapenemase

Carbapenemases
Classification Class A Enzyme KPC, SME, IMI, NMC, GES IMP, VIM, GIM, SPM Most Common Bacteria Enterobacteriaceae
(rare reports in P. aeruginosa)

Class B (metallo--lactamse)

P. aeruginosa Enterobacteriacea Acinetobacter spp. Acinetobacter spp.

Class D

OXA

Carbapenemases in the U.S.

Enzyme KPC Metallo--lactamase OXA SME Bacteria Enterobacteriaceae P. aeruginosa Acinetobacter spp. Serratia marcesens

Klebsiella Pneumoniae Carbapenemase

KPC is a class A -lactamase

Confers resistance to all -lactams including extendedspectrum 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)

Susceptibility Profile of KPC-Producing K. pneumoniae Antimicrobial Interpretation Antimicrobial Interpretation

Amikacin Amox/clav Ampicillin Aztreonam Cefazolin Cefpodoxime Cefotaxime Cetotetan Cefoxitin Ceftazidime I R R R R R R R R R Chloramphenicol R Ciprofloxacin Ertapenem Gentamicin Imipenem Meropenem Pipercillin/Tazo Tobramycin Trimeth/Sulfa Polymyxin B R R R R R R R R MIC >4g/ml

KPC Enzymes

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

KPCs in Enterobacteriaceae
Species Klebsiella spp. Enterobacter spp. Escherichia coli Salmonella spp. Citrobacter freundii Serratia spp. Pseudomonas aeruginosa Columbia & Puerto Rico Comments K. pneumoniae-cause of outbreaks K. oxytoca-sporadic occurrence Sporadic occurrence

Geographical Distribution of KPCProducers

Frequent Occurrence Sporadic Isolate(s)

Geographical Distribution of KPCProducers in New Jersey

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)

Inter-Institutional & InterState Spread of KPCProducing K. pneumoniae

Intra-institution, Interspecies KPC Plasmid Transfer

Cf Ko Cf Ko

Laboratory Detection of KPC-Producers

Problems: 1) Some isolates demonstrate low-level carbapenem resistance 2) Some automated systems fail to detect lowlevel resistance

eptibility of KPC-Producers to Imipen

S* I R

*12% of isolates test susceptible to imipenem

eptibility of KPC-Producers to Merope

S* I R

*9% of isolates test susceptible to meropenem

eptibility of KPC-Producers to Ertape

60 50 No. of Isolates 40 30 20 10 0 2 4 8 MIC ( g/m l) 16 >16

None of the isolates test susceptible to ertapenem

Method

Can Carbapenem Susceptibility of I or R Detect KPC-Producers?

Sens/Spec (%) for Detection of KPC-mediated R* Imipenem Meropenem 94/98 71/96 58/96 52/98 48/96 84/98 61/98 Ertapenem 97/89 97/82 90/84 N/A 94/93 100/89 N/A 94/93 42/96 55/96 55/96 71/98 74/96 81/96

Ref BMD Disk Diffusion Etest Vitek Legacy Vitek 2 MicroScan Phoenix

*N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

CAP Results (D-05)

KPC-producing Klebsiella pneumoniae

Susceptible Results MIC Method Imipenem Meropenem Ertapenem 63 63 0 Disk Method 57 18 0

Carbapenem MIC 2 g/ml to Detect KPCproducers

Method Ref BMD Etest Vitek Legacy Vitek 2 MicroScan Phoenix Sens/Spec (%) for Detection of KPC-mediated R* Imipenem 100/93 84/89 NA 71/91 100/93 74/96 Meropenem 100/93 90/87 NA 93/89 100/93 87/93 Ertapenem 100/89 100/82 NA 93/89 NA NA

*N = 76 K. pneum, K. oxy, E. coli; 31 KPC-producers & 45 non-KPC producers

When to Suspect a KPCProducer

Enterobacteriaceae especially Klebsiella pneumoniae that are resistant to extendedspectrum cephalosporins:

MIC range for 151 KPC-producing isolates

Ceftazidime32 Ceftriaxone Cefotaxime

to >64 g/ml 64 g/ml 64 g/ml

Variable susceptibility to cefoxitin and cefepime

Reading Disk Diffusion & Etest

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.

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.

Modified Hodge Test

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

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 blaKPC PCR if KPC-producers not previously identified in hospitals isolate population Alert clinician and infection control practitioner to possibility of mobile carbapenemase in isolate

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

Testing Other Drugs

Tigecycline:

Test by Etest if possible disk diffusion tends to overcall resistance No CLSI breakpoint, but there are FDA breakpoint
2 g/ml Intermediate = 4 g/ml Resistant 8 g/ml
Susceptible

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

2 g/ml, normal MIC range MIC 4 g/ml indicates increased resistance

MIC

Acknowledgements

Fred Tenover Roberta Carey Kamile Rasheed Kitty Anderson Brandon Kitchel Linda McDougal David Lonsway Jana Swenson

Arjun Srinivasan Susan Mikorski