Carbapenem Resistance in Enterobacteriaceae Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team Division of Healthcare Quality Promotion.
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Transcript Carbapenem Resistance in Enterobacteriaceae Jean B. Patel, PhD, (D)ABMM Leader, Antimicrobial Resistance Team Division of Healthcare Quality Promotion.
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