Carbapenemases in practice - lessons learnt from spread in our patch, prophylaxis and

first/second line treatments

Dr Andrew DodgsonConsultant 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

Enterobacter

E. coli

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

S I R

Erta ≤0.5 1 >1

0.5->64

Imi ≤2 4-8 >8

0.5->64

Mero ≤2 4-8 >8

1-64

Miriagou et al. CMI 2010.

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)

Tzouvelekis et al, CMR 2011

Treatment Failure rate2 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%

Sensitivities

• Data from 30 Blood culturesSensitive (%) Intermediate( %) Resistant (%)

Colistin 92 8

Amikacin 77 10 13

Tigecycline 74 13 13

Gentamicin 58 3 39

Temocillin 57 43

Ciprofloxacin 52 48

Trimethoprim 48 52

Meropenem 3 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