carbapenem resistance in enterobacteriaceae jean b. patel, phd, (d)abmm leader, antimicrobial...
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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
DrugRoute of Administration
FDA Status
Imipenem IV Cleared
Meropenem IV Cleared
Ertapenem IM, IV Cleared
Doripenem IV Application Submitted
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Spectrum of ActivityDrug
Strep spp. &
MSSAEntero-
bacteriaeaeNon-
fermentorsAnaerobes
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: MechanismsEnterobacteriaceae 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--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--lactamase P. aeruginosa
OXA Acinetobacter spp.
SME Serratia marcesens
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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)
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Susceptibility Profile of KPC-Producing K. pneumoniaeAntimicrobial 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 >4g/ml
Ceftriaxone R Colistin MIC >4g/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 -lactamases Extended spectrum -lactamases Aminoglycoside resistance
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KPC’s in EnterobacteriaceaeSpecies Comments
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
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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 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)
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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-ProducersProblems:
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
0
10
20
30
40
50
60
2 4 8 16 >16
MIC (g/ml)
No.
of I
sola
tes
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?
MethodSens/Spec (%) for Detection of KPC-mediated R*
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
MIC Method Disk Method
Imipenem 63 57
Meropenem 63 18
Ertapenem 0 0
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Carbapenem MIC ≥ 2 g/ml to Detect KPC-producers
MethodSens/Spec (%) for Detection of KPC-mediated R*
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 >64 g/ml Ceftriaxone ≥ 64 g/ml Cefotaxime ≥ 64 g/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 1:10 dilution of a 0.5 McFarland suspension
Imipenem disk
Test isolates
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 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 hospital’s 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 g/ml Intermediate = 4 g/ml Resistant ≥ 8 g/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 – don’t 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
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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