ACQUIRED
CARBAPENEMASES IN
GRAM-NEGATIVE
PATHOGENS
Mazen Kherallah, MD, FCCP
mkherallah@msn.com
www.mecriticalcare.net
Carbapenems
OH
OH
R1
Penems
Penams
O
NH
S
R2
R
R
N
S
N
N
O
O
O
-
-
-
COO
COO
COO
An exceptionally
broad antimicrobial
spectrum due to: Carbacephems
Cephems
Oxacephems
O
O
O
• High stability to b-lactamases
NH
NH affinity to
S PBPs
NH
O
• High
R1
R1
R1
• Good penetration across
the OM of Gram-negatives
N
N
• Poor substrates
forRefflux systems N
R
2
O
-
COO
O
2
O
-
O
-
COO
COO
R
NH
R
Monobactams
N
O
-
SO3
R2
Carbapenems: an exceptionally broad spectrum
Neisseria
Staphylococci (exc. MRSA)
Pneumococci (incl. PRP)
Other streptococci
Listeria
E. faecalis (Imipenem)
Moraxella
(incl. b-lactamase+)
Haemophilus
(incl. b-lactamase+)
Recommended among the drugs of choice for empiric
treatment of several types of serious infections
Enterobacteriaceae
(e.
g.
FN,
HAP/VAP,
IAIs etc.)
(incl. AmpC+ & ESBL+)
Bacteroides
other gram-negative anaerobes
most gram-positive anaerobes
Pseudomonas (exc. Ertapenem)
(incl. AmpC+ & ESBL+)
Acinetobacter (exc. Ertapenem)
Classification of β-lactamases
β-lactamases
Serine enzymes
Class A
enzymes
(Plasmid)
ESBL
Pen-Cephs-Inh-S
Class C
enzymes
(Chromosomal)
Metallo-enzymes
Class D
enzymes
(Plasmid)
AmpC
OXA
Cephs-Inh-R
Pens, esp Oxa
Inhib-R/S
Class B
enzymes
(Chromosomal)
MbL (IMP/VIM)
Carbapenems
Inh-R
Bush. Rev Inf Dis 1987;10:681; Bush et al. Antimicrob Agents Chemother 1995;39:1211–1233
Bush. Curr Opin Investig Drugs 2002;3:1284–1290
Acquired resistance to
carbapenems, an issue for:
Pseudomonas aeruginosa
++
• Impermeability/efflux
• Carbapenemases
Acinetobacter
++
• Carbapenemases
+/- (++*)
• Carbapenemases
• Impermeability +
Enterobacteriaceae
* in some geograhical areas
• Impermeability/efflux
• Modified target?
ESBL/AmpC
Carbapenemases βlactamases:
Acquired carbapenemases in Gramnegative pathogens
Enzyme family
Class
Pathogens
Serine-β-lact.
A
Enterobacteriaceae
Serine-β-lact.
D
Acinetobacter
B
Pseudomonas
Acinetobacter
Enterobacteriaceae
Metallo-β-lact.
P. aeruginosa
Enterobacteriaceae
Klebsiella Pneumoniae
Carbapenemase
• KPC is a class A b-lactamase
– Confers resistance to all b-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)
KPC carbapenemases: a very broad
spectrumMIC (μg/ml)
KPC-2
Yigit et al. AAC 2003
JAC 2007
% carbapenem-resistant
50
Klebsiella pneumoniae
40
30
Due to spread of KPC
carbapenemases
20
22% of isolates resistant to:
- Aminoglycosides
- Fluoroquonolones
- 3rd 4th gener. Cephems
- Carbapenems
XDR phenotype
10
Susceptibility only to:
- Colistin
- Tigecycline
0
1999
2001
Years
2006
Also in E. coli, C. freundii, and
E. cloacae from the same area
Jones et al – DMID 2008
Class A serine-carbapenemases in
Enterobacteriaceae
NMC/IMI-type
SME-type
KPC-type
Geographical Distribution of KPCProducers
Frequent Occurrence
Sporadic Isolate(s)
Class A serine-carbapenemases in
Enterobacteriaceae
KPC-2 in
P. aeruginosa
NMC/IMI-type
SME-type
KPC-type
Acquired carbapenemases in Gramnegative pathogens
Enzyme family
Class
Pathogens
Serine-β-lact.
A
Enterobacteriaceae
Serine-β-lact.
D
Acinetobacter
B
Pseudomonas
Acinetobacter
Enterobacteriaceae
Metallo-β-lact.
P. aeruginosa
Enterobacteriaceae
Class D Oxacillinase —
Carbapenemases
•
•
•
•
Class D enzymes
OXA-23, -24, -25, -26, -27, -28, -40, -49, -58, ….
Highly mobile (integron, plasmid)
Multi-drug resistance (penicillins and 3rd & 4th
generation cephalosporins, BL/BL-inhibitors,
aminoglycosides, SXT,…)
• Variable resistance levels to imipenem and
meropenem (4–>256 mg/mL)
Acquired class D serinecarbapenemases
A. baumannii
OXA-23-type P. mirabilis
OXA-24-type A. baumannii
OXA-58-type A. baumannii
OXA-48
K. pneumoniae
Contribution of class D serine-carbapenemases to βlactam resistance in A. baumannii
Strain
A. baumannii MAD (OXA-58+)
A. baumannii FER (OXA-23+)
A. baumannii CLA-1 (OXA-24+)
A. baumannii CIP 7010T
A. baumannii CIP 7010T (OXA-58+)
A. baumannii CIP 7010T (OXA-23+)
A. baumannii CIP 7010T (OXA-24+)
MIC (mg/ml)
TIC
IPM
MEM
>256
>256
>256
32
>32
>32
>64
>32
>32
4
0.25
0.25
>256
>256
>256
0.5
4
4
0.5
4
4
Heritier et al. – AAC 2005
Acinetobacter: wordlwide surveillance data (20012004)
(n = 2621 isolates)
% Susceptibility
100%
80%
60%
40%
20%
0%
Italy, 2002 – 2003; J Chemother 2006
Gales et al. CMI 2006
Acquired carbapenemases in Gramnegative pathogens
Enzyme family
Class
Pathogens
Serine-β-lact.
A
Enterobacteriaceae
Serine-β-lact.
D
Acinetobacter
B
Pseudomonas
Acinetobacter
Enterobacteriaceae
Metallo-β-lact.
P. aeruginosa
Enterobacteriaceae
Acquired metallo-b-lactamases
(MBLs): functional features
Penicillins
Cephalosporins (all)
good
Carbapenems
activity
no
Monobactams
Suscept. to inhibitors
(clavulanate & sulphones)
-
Class B (Metallo)-Carbapenemases
•
•
•
•
•
•
Hydrolyzing virtually all b-lactams
Mediate broad spectrum b-lactam resistance
No clinical inhibitor available
Present on large plasmids and integrons
Genes are continuously spreading
Associated (80%) with aminoglycoside
resistance
Still rare but increasing, especially in non-fermenters
In-vitro activity (%) of various antimicrobials
against MBL+ve and MBL–ve P. aeruginosa
strains
RESORT study 2002–2004
MBL +ve (n=47)
MBL –ve (n=1006)
Polymyxin B
Amikacin
Gentamicin
93.8100.0
60.7
8.5
26.4
Levofloxacin
35.3
Ciprofloxacin
36.6
Imipenem
63.8
Meropenem
61.3
Cefepime
43.2
Ceftazidime
54.6
Cefoper.-Sulb.
Cefoperazone
41.2
28.6
Piper.-Tazo.
Piperacillin
56.8
46.2
Dekhnich, et al. ICAAC 2006
MBLs and acquired MBLs in gram-negative pathogens
BlaB
KHM
GIM
IMP
EBR
ILM
IND/CGB
JOHN
MUS
TUS
SIM
SPM
SLB/SFB
B1
CAR
CcrA
B4
GOB
Bc-II
B3
B2
FEZ
POC
VIM
Sfh
L1
CVI
NOV
AIM
BJP
THIN-B
CAU
CphA
Distribution of acquired MBLs
IMP (>20 variants)
VIM (>20 variants)
SPM-1
GIM-1
SIM-1
AIM-1
KHM-1
P. aeruginosa Acinetobacter oth. GNNFs Enterics Aeromonas
P. aeruginosa Acinetobacter oth. GNNFs Enterics Aeromonas
P. aeruginosa
P. aeruginosa
Acinetobacter
P. aeruginosa
Enterics
Acquired MBLs in Gram-negative nonfermenters
P. aeruginosa and Acinetobacter are
the most common hosts, but
occasional detections also in other
species (P. putida, Achromobacter)
Wordlwide distribution (P. aeruginosa)
Overall low prevalence, but notable
regional differences and possibility of
even large outbreaks
MBL (VIM-1)-producing P. aeruginosa index strain Verona,
Italy, 1997
(now a major Italian clone – ser. O11; ST227; BG11)
GM
COL
IPM outbreak ongoing since 2000;
Very large
FEP
Multiward, even LTCFs and outpatients;
Significant increase of carbapenem resistance rates
TOB TZP CAZ MEM
ATM
PRL
AK
CIP
Lauretti et al. – AAC 1999
Cornaglia et al. - CID, 2000
Lagatolla et al. - EID 2004
Riccio et al. – AAC 2005
Giske et al. – JCM 2006
Carbapenem MICs of MBL
producers
IMI
MER
IMI
MER
128
MIC (mg/ml)
64
R
32
16
8
I
4
2
1
0.50
S
Resistance profile of ESBL+/MBL+
K. pneumoniae
Carboxy-pen.
Ureido-pen.
BLICs
Cefepime
Ceftazidime
Cefotaxime
Imipenem
Meropenem
R
R
R
R
R
R
S
MICs, 1-4 mg/L*
S
* >8 mg/L in a single isolate which had also lost k36 porin
Cagnacci et al. – JAC 2008
ESCMID Expert Meeting
on Metallo-β-Lactamases
November 14-15, 2005,
Siena, Certosa di Pontignano
MBL-producing Enterobacteriaceae
may appear still susceptible to
carbapenems according to current
breakpoints, although showing
carbapenem MICs higher than
modal values for the species
Phenotypic tests for detection of
MBLs in Enterobacteriaceae
Double-disk
Combo-disk
IPM
IPM
IPM + EDTA
EDTA
IPM
Phantom zone
Etest
IPM + EDTA
14 cases of BSIs (4 CVC-related) and 3 cases of VAP,
caused by VIM-1 MBL-producing Enterobacteriaceae (15
Klebsiella, 2 Enterobacter)
Carbapenem MICs: 1 - >32 mg/L (7/17 susceptible)
5 cases occurred under carbapenem-based regimens (in
one case the strain was carbapenem susceptible)
Success with imipenem in only one case (MIC, 8 mg/L)
CLSI 2008
b-lactamases: Summary
Broad Spectrum
TEM/
Class
Inhibition by
Clavulanic Acid
Penicillins
Oxacilin
Narrow Spectrum
Cephalosporins
Cephamycins
Oxyiminocephalosporins
Cefepime
Monobactam
Carbapenems
Polymyxin E
SHV
A
Expanded Spectrum
AmpC
OXA
TEM/SHV
CTX-M
OXA
D
A
A
D
C
Carbapenemase
KPC
MBL
OXA
A
B
D