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