Carbapenem Resistance
in Enterobacteriaceae
Jean B. Patel, PhD, (D)ABMM
Leader, Antimicrobial Resistance Team
Division of Healthcare Quality Promotion
Carbapenems
Imipenem
Route of
Administration
IV
Meropenem
IV
Cleared
Ertapenem
IM, IV
Cleared
Doripenem
IV
Application
Submitted
Drug
FDA Status
Cleared
Spectrum of Activity
Strep spp. &
MSSA
Enterobacteriaeae
Nonfermentors
Anaerobes
Imipenem
+
+
+
+
Meropenem
+
+
+
+
Ertapenem
+
+
Limited
activity
+
Doripenem
+
+
+
+
Drug
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





Reference: Sanford Guide
Mogenella spp.
Serratia spp.
Enterobacter spp.
Citrobacter spp.
ESBL or AmpC + E. coli
and Klebsiella spp.
Emerging Carbapenem Resistance
in Gram-Negative Bacilli

Significantly limits treatment options for lifethreatening 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:
Mechanisms
Enterobacteriaceae
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
IMP, VIM,
(metallo-b-lactamse) GIM, SPM
P. aeruginosa
Enterobacteriacea
Acinetobacter spp.
Class D
Acinetobacter spp.
OXA
Carbapenemases in the U.S.
Enzyme
Bacteria
KPC
Enterobacteriaceae
Metallo-b-lactamase
P. aeruginosa
OXA
Acinetobacter spp.
SME
Serratia marcesens
Klebsiella Pneumoniae Carbapenemase

KPC is a class A b-lactamase


Occurs in Enterobacteriaceae



Confers resistance to all b-lactams including extendedspectrum cephalosporins and carbapenems
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. 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 >4mg/ml
Ceftriaxone
R
Colistin
MIC >4mg/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 b-lactamases
 Extended spectrum b-lactamases
 Aminoglycoside resistance

KPC’s in Enterobacteriaceae
Species
Comments
Klebsiella spp.
K. pneumoniae-cause of outbreaks
K. oxytoca-sporadic occurrence
Enterobacter spp.
Escherichia coli
Salmonella spp.
Sporadic occurrence
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 KPCProducers
Problems:
1) Some isolates demonstrate low-level carbapenem
resistance
2) Some automated systems fail to detect low-level
resistance
Susceptibility of KPC-Producers to Imipenem
Imipenem
No. of Isolates
S*
I
R
60
40
20
0
≤1
2
4
8
16
32
>32
MIC (mg/ml)
*12% of isolates test susceptible to imipenem
Susceptibility of KPC-Producers to Meropenem
Meropenem
I
No. of Isolates
S*
R
100
50
0
2
4
8
16
>16
MIC (mg/ml)
*9% of isolates test susceptible to meropenem
Susceptibility of KPC-Producers to Ertapenem
S
I
2
4
R
No. of Isolates
60
50
40
30
20
10
0
8
16
>16
MIC (mg/ml)
None of the isolates test susceptible to ertapenem
Can Carbapenem Susceptibility of
I or R Detect KPC-Producers?
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
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 mg/ml to
Detect KPC-producers
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
NA
NA
NA
Vitek 2
71/91
93/89
93/89
MicroScan
100/93
100/93
NA
Phoenix
74/96
87/93
NA
Vitek Legacy
*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 extendedspectrum cephalosporins:

MIC range for 151 KPC-producing isolates
 Ceftazidime
 Ceftriaxone
 Cefotaxime

32 to >64 mg/ml
≥ 64 mg/ml
≥ 64 mg/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
Test isolates
Imipenem disk
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 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

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
≤ 2 mg/ml
 Intermediate = 4 mg/ml
 Resistant ≥ 8 mg/ml
 Susceptible
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

≤ 2 mg/ml, normal MIC range
 MIC ≥ 4 mg/ml indicates increased resistance
 MIC
Acknowledgements








Fred Tenover
Roberta Carey
Kamile Rasheed
Kitty Anderson
Brandon Kitchel
Linda McDougal
David Lonsway
Jana Swenson


Arjun Srinivasan
Susan Mikorski