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Carbapenem Resistance in Enterobacteriaceae. Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team Division of Healthcare Quality Promotion. Carbapenems. Spectrum of Activity . How are Carbapenems Used?. Use by Clinical Isolate Acinetobacter spp. Pseudomonas aeruginosa

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Carbapenem Resistance in Enterobacteriaceae

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carbapenem resistance in enterobacteriaceae
Carbapenem Resistance in Enterobacteriaceae

Jean B. Patel, PhD, (D)ABMM

Leader, Antimicrobial Resistance Team

Division of Healthcare Quality Promotion

how are carbapenems used
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

emerging carbapenem resistance in gram negative bacilli
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
k lebsiella p neumoniae c arbapenemase
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)
kpc enzymes
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
kpc s in enterobacteriaceae
KPC’s in Enterobacteriaceae

Pseudomonas aeruginosa – Columbia & Puerto Rico


Geographical Distribution of KPC-Producers

Frequent Occurrence

Sporadic Isolate(s)

kpc outside of united states
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)
laboratory detection of kpc producers
Laboratory Detection of KPC-Producers


1) Some isolates demonstrate low-level carbapenem resistance

2) Some automated systems fail to detect low-level resistance


Susceptibility of KPC-Producers to Imipenem




*12% of isolates test susceptible to imipenem


Susceptibility of KPC-Producers to Meropenem




*9% of isolates test susceptible to meropenem


Susceptibility of KPC-Producers to Ertapenem




None of the isolates test susceptible to ertapenem

can carbapenem susceptibility of i or r detect kpc producers
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

carbapenem mic 2 m g ml to detect kpc producers
Carbapenem MIC ≥ 2 mg/ml to Detect KPC-producers

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

when to suspect a kpc producer
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
phenotypic tests for carbapenemase activity
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
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 test29
Modified Hodge Test
  • Preliminary results suggest that any of the three carbapenem disks work in the Modified Hodge Test
what labs should do now
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
kpc questions
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
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
testing other drugs33
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
  • Fred Tenover
  • Roberta Carey
  • Kamile Rasheed
  • Kitty Anderson
  • Brandon Kitchel
  • Linda McDougal
  • David Lonsway
  • Jana Swenson
  • Arjun Srinivasan
  • Susan Mikorski