Carbapenemases in practice - lessons learnt from
spread in our patch, prophylaxis and
first/second line treatments
Dr Andrew Dodgson
Consultant Microbiologist and Infection Control Doctor
Health Protection Agency & Central Manchester University
Hospitals NHS Foundation Trust
Carbapenemases
• Phenotypically similar enzymes
• Genotypically diverse
• Epidemiologically Diverse
Classification
• Class A (serine based)
• KPC, GES, SME, NMC, IMI
• Class B (metallo-enzymes)
• NDM, IMP, VIM, GIM, SIM, SMP, L1, BCII, Ccra
• Class D (serine)
• OXA
From Queenan and Bush, CMR 2007
Classification
• Chromosomal
– Class A
• SME, NMC, IMI
– Class B
• BCII, L1, Ccra
• Plasmid
– Class A
• KPC, GES
– Class B
• NDM, IMP
– Class D
• OXA
From Queenan and Bush, CMR 2007
“Transmission” of Resistance
• Clonal spread (particularly ST258 K. pneumo
for KPC)
• Transmission of plasmid
• Other enterobacteriaceae implicated, e.g.
Enterobacter, E.coli
Therapy
• Need to know local epidemiology
• i.e. clonal spread
– all isolates have the same antibiogram
• or polyclonal, transmission of plasmid
– sensitivities vary depending on the background of
the strain carrying the plasmid
Local situation?
• Many different strains
• Same plasmid
E. coli
Enterobacter
KPC producer
from a nearby
hospital
Courtesy N. Woodford
Carbapenems?
• Some carbapenemase producers will have
MIC’s below the breakpoint for resistance
Carmeli et al. CMI 2010
Erta
S
I
R
≤0.5
1
>1
0.5->64
Imi
≤2
4-8
>8
0.5->64
Mero
≤2
4-8
1-64
Miriagou et al. CMI 2010.
>8
Carbapenems?
• Some carbapenemase producers will have
MIC’s below the breakpoint for resistance
• Carbapenems show some activity in animal
models against these strains
• Strong inoculum effect noted in in-vitro
models
• MIC ≤8 Mortality 29%, MIC>8 75%
Carmeli et al. CMI 2010; Daikos et al, AAC 2009
Other options
• Again, depends on susceptibility results.
• Many strains multi (or almost pan-) resistant
Other options
– Quinolones
– Aminoglycosides
– Tigecycline
– Colistin
– Trimethoprim
– Fosfomycin
– Temocillin
– Combinations (which ones?)
What should we do?
• Review of 298 published cases (244 BSI)
Treatment
Failure rate
2 drugs, inc carbapenem (MIC<8)
8%
2 drugs, no carbapenem
29%
Aminoglycoside alone
24%
Carbapenem alone(MIC<8)
25%
Tigecycline alone
36%
Colistin alone
47%
Inappropriate Rx
54%
Tzouvelekis et al, CMR 2011
Sensitivities
• Data from 30 Blood cultures
Sensitive (%)
Intermediate( %)
Resistant (%)
Colistin
92
Amikacin
77
10
13
Tigecycline
74
13
13
Gentamicin
58
3
39
Temocillin
57
43
Ciprofloxacin
52
48
Trimethoprim
48
52
Meropenem
3
8
10
87
What do we do?
• Plasmid mediated resistance
• Necessitates individual patient approach
• Usually based on sensitivities of previous
screening or clinical isolates
• Some broad principles:
–
–
–
–
2 agents
B-lactam (if poss)
Aminoglycoside if possible
Colistin never alone
Prophylaxis
• Difficult to generalise due to variable
susceptibilities
– GI Surgery
• Tigecycline
– Urology
• Aminoglycoside or Cipro
Empiric Rx
• Paeds neutropenic sepsis:
– Pip/Taz and Amikacin 1st line
– Close scrutiny of sens of all BC’s
– And sens of CPC screening isolates
– No Amik resistance (yet)
Empiric Rx
• GNR in blood culture, pt known to be
colonised
• Depends on sens and site of primary infection
• Toxicity often less of a concern (due to lack of
options)
• Almost always add suitable aminoglycoside
• Tige/Colistin not used alone
Empiric Rx
• What have we done?
– 30 bacteraemic adult pt’s
– 18 different regimes used
– 11 received monotherapy (cip 4, gent 4, tige, col,
mero)
– 15 had 2 Abx, 1 had 3 and 1 4.
– 16 of 19 with 2 or more abx had an aminoglycoside
Summary
• Carbapenemase producing enterobacteriaceae
are heterogenous
• Know your local epidemiology
• Take MIC’s into account (esp. Carb’s)
• Be prepared to think laterally
Acknowledgements
•
•
•
•
Dr Louise Sweeney
Dr Barry Neish
All the Micro staff at CMFT
Prof Neil Woodford