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Carbapenem Resistance in Enterobacteriaceae
Jean B. Patel, PhD, (D)ABMM
Leader, Antimicrobial Resistance Team
Division of Healthcare Quality Promotion
Carbapenems
DrugRoute of Administration
FDA Status
Imipenem IV Cleared
Meropenem IV Cleared
Ertapenem IM, IV Cleared
Doripenem IV Application Submitted
Spectrum of ActivityDrug
Strep spp. &
MSSAEntero-
bacteriaeaeNon-
fermentorsAnaerobes
Imipenem + + + +
Meropenem + + + +
Ertapenem + +Limited activity +
Doripenem + + + +
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
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
Carbapenem Resistance: MechanismsEnterobacteriaceae Cephalosporinase + porin loss
Carbapenemase
P. aeruginosa Porin loss
Up-regulated efflux
Carbapenemase
Acinetobacter spp. Cephalosporinase + porin loss
Carbapenemase
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.
Carbapenemases in the U.S.
Enzyme Bacteria
KPC Enterobacteriaceae
Metallo--lactamase P. aeruginosa
OXA Acinetobacter spp.
SME Serratia marcesens
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)
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
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
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
Geographical Distribution of KPC-Producers
Frequent Occurrence
Sporadic Isolate(s)
Geographical Distribution of KPC-Producers 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 & Inter-State Spread of KPC-Producing K. pneumoniae
Intra-institution, Interspecies KPC Plasmid Transfer
Cf Ko Cf Ko
Laboratory Detection of KPC-ProducersProblems:
1) Some isolates demonstrate low-level carbapenem resistance
2) Some automated systems fail to detect low-level resistance
Susceptibility of KPC-Producers to Imipenem
S* I R
*12% of isolates test susceptible to imipenem
Susceptibility of KPC-Producers to Meropenem
S* I R
*9% of isolates test susceptible to meropenem
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
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
CAP Results (D-05)KPC-producing Klebsiella pneumoniae
Susceptible Results
MIC Method Disk Method
Imipenem 63 57
Meropenem 63 18
Ertapenem 0 0
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
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
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
Imipenem disk
Test isolates
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 hospital’s 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 Susceptible ≤ 2 g/ml Intermediate = 4 g/ml Resistant ≥ 8 g/ml
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
Acknowledgements
Fred Tenover Roberta Carey Kamile Rasheed Kitty Anderson Brandon Kitchel Linda McDougal David Lonsway Jana Swenson
Arjun Srinivasan Susan Mikorski