Carbapenem Resistance in Enterobacteriaceae

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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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Carbapenems
Drug Route of Administration FDA Status
Imipenem IV Cleared
Meropenem IV Cleared
Ertapenem IM, IV Cleared
Doripenem IV Application Submitted
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Spectrum of Activity
Drug Strep spp. MSSA Entero-bacteriaeae Non-fermentors Anaerobes
Imipenem
Meropenem
Ertapenem Limited activity
Doripenem
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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
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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

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Carbapenem Resistance Mechanisms
Enterobacteriaceae Cephalosporinase porin loss
Carbapenemase
P. aeruginosa Porin loss
Up-regulated efflux
Carbapenemase
Acinetobacter spp. Cephalosporinase porin loss
Carbapenemase
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Carbapenemases
Classification Enzyme Most Common Bacteria
Class A KPC, SME, IMI, NMC, GES Enterobacteriaceae (rare reports in P. aeruginosa)
Class B (metallo-b-lactamse) IMP, VIM, GIM, SPM P. aeruginosa Enterobacteriacea Acinetobacter spp.
Class D OXA Acinetobacter spp.
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Carbapenemases in the U.S.
Enzyme Bacteria
KPC Enterobacteriaceae
Metallo-b-lactamase P. aeruginosa
OXA Acinetobacter spp.
SME Serratia marcesens
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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)

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Susceptibility Profile of KPC-Producing K.
pneumoniae
Antimicrobial Interpretation Antimicrobial Interpretation
Amikacin I Chloramphenicol R
Amox/clav R Ciprofloxacin R
Ampicillin R Ertapenem R
Aztreonam R Gentamicin R
Cefazolin R Imipenem R
Cefpodoxime R Meropenem R
Cefotaxime R Pipercillin/Tazo R
Cetotetan R Tobramycin R
Cefoxitin R Trimeth/Sulfa R
Ceftazidime R Polymyxin B MIC gt4mg/ml
Ceftriaxone R Colistin MIC gt4mg/ml
Cefepime R Tigecycline S

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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

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KPCs in Enterobacteriaceae
Species Comments
Klebsiella spp. K. pneumoniae-cause of outbreaks K. oxytoca-sporadic occurrence
Enterobacter spp. Sporadic occurrence
Escherichia coli Sporadic occurrence
Salmonella spp. Sporadic occurrence
Citrobacter freundii Sporadic occurrence
Serratia spp. Sporadic occurrence
Pseudomonas aeruginosa Columbia Puerto Rico
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Geographical Distribution of KPC-Producers
Frequent Occurrence Sporadic Isolate(s)
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Geographical Distribution of KPC-Producers in New
Jersey
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KPC Outside of United States

• France (Nass et al. 2005. AAC 494423-4424)
• Singapore (report from survey)
• Puerto Rico (ICAAC 2007)
• Columbia (Villegas et al. 2006. AAC 502880-2882
  ICAAC 07)
• Brazil (ICAAC 2007)
• Israel (Navon-Venezia et al. 2006. AAC
  503098-3101)
• China (Wei Z, et al. 2007. AAC 51 763-765)

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Inter-Institutional Inter-State Spread of
KPC-Producing K. pneumoniae
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Intra-institution, Interspecies KPC Plasmid
Transfer
Cf Ko
Cf Ko
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Laboratory Detection of KPC-Producers

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

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Susceptibility of KPC-Producers to Imipenem
S
I
R
12 of isolates test susceptible to imipenem
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Susceptibility of KPC-Producers to Meropenem
S
I
R
9 of isolates test susceptible to meropenem
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Susceptibility of KPC-Producers to Ertapenem
S
I
R
None of the isolates test susceptible to ertapenem
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Can Carbapenem Susceptibility of I or R Detect
KPC-Producers?
Method Sens/Spec () for Detection of KPC-mediated R Sens/Spec () for Detection of KPC-mediated R Sens/Spec () for Detection of KPC-mediated R
Method Imipenem Meropenem Ertapenem
Ref BMD 94/93 94/98 97/89
Disk Diffusion 42/96 71/96 97/82
Etest 55/96 58/96 90/84
Vitek Legacy 55/96 52/98 N/A
Vitek 2 71/98 48/96 94/93
MicroScan 74/96 84/98 100/89
Phoenix 81/96 61/98 N/A
N 76 K. pneum, K. oxy, E. coli 31
KPC-producers 45 non-KPC producers
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CAP Results (D-05)KPC-producing Klebsiella
pneumoniae
Susceptible Results Susceptible Results
MIC Method Disk Method
Imipenem 63 57
Meropenem 63 18
Ertapenem 0 0
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Carbapenem MIC 2 mg/ml to Detect KPC-producers
Method Sens/Spec () for Detection of KPC-mediated R Sens/Spec () for Detection of KPC-mediated R Sens/Spec () for Detection of KPC-mediated R
Method Imipenem Meropenem Ertapenem
Ref BMD 100/93 100/93 100/89
Etest 84/89 90/87 100/82
Vitek Legacy NA NA NA
Vitek 2 71/91 93/89 93/89
MicroScan 100/93 100/93 NA
Phoenix 74/96 87/93 NA
N 76 K. pneum, K. oxy, E. coli 31
KPC-producers 45 non-KPC producers
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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 gt64 mg/ml
• Ceftriaxone 64 mg/ml
• Cefotaxime 64 mg/ml
• Variable susceptibility to cefoxitin and cefepime

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Reading Disk Diffusion Etest
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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.
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Modified Hodge Test
Lawn of E. coli ATCC 25922 110
dilution of a 0.5 McFarland suspension
Test isolates
Imipenem disk
Described by Lee et al. CMI, 7, 88-102. 2001.
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Modified Hodge Test

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

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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
  hospitals isolate population
• Alert clinician and infection control
  practitioner to possibility of mobile
  carbapenemase in isolate

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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

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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

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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 mg/ml, normal MIC range
• MIC 4 mg/ml indicates increased resistance

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Acknowledgements

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

• Arjun Srinivasan
• Susan Mikorski