The PHE CPE Toolkit and the need to detect Carbapenemase...

The PHE CPE Toolkit and the need to detect Carbapenemase-Producing Enterobacteriaceae

Professor Neil Woodford

Antimicrobial Resistance & Healthcare Associated Infections (AMRHAI) Reference Unit

© Crown copyright

2 BSAC, 8th July 2014 © Crown Copyright

International Consensus: CarbapenemResistance is a CriticalAMR Threat

The resistance ratchet keeps turning

Pathogen Established problems Emerging threatsE. faecium VRE, HLGR, Amp-R Lin-R, Dap-R, Tig-RS. aureus MRSA (ha/ca) Van-R, Lin-R, Dap-RKlebsiella ESBLs Carbapenemases, Col-RAcinetobacter MDR, Carbapenemases Tig-R, Col-RPseudomonas MDR, except Col Carbapenemases, Col-REnterobacter AmpC, ESBLs Carba-R, CarbapenemasesE. coli Cip-R, ESBLs Carbapenemases

• 5 of 7 ESKAPEEs are Gram-negative• Increasing reliance on carbapenems• The resistance issue for the next 5-10 years


KPC

OXA-48NDM

VIM IMP

The “Big 5” carbapenemases


Carbapenem Resistance in Blood Culture Isolates, England

Pathogen % carbapenem resistance2008 2009 2010 2011 2012 2013

E. coli 0.08 0.09 0.11 0.18 0.25 0.22K. pneumoniae 0.7 0.4 0.6 1.2 1.1 1.6

5 BSAC, 8th July 2014 © Crown Copyright Courtesy, Prof Alan Johnson

Carbapenem non-susceptibility, EARS-Net 2012


K. pneumoniaeE. coli• data risk giving a false sense of security to non-experts• only 9% of UK carbapenemase producers are from blood cultures

Carbapenemase-producing Enterobacteriaceae in the UK (n = 2794)

Early cases often imported

Imported & ‘home grown’

Klebsiella spp. 79%; E. coli 12%, Enterobacter spp., 7%; others 2%

7 AMRHAI, Unpublished dataBSAC, 8th July 2014 © Crown Copyright

The spread of CPE in the UK

8 AMRHAI, Unpublished dataBSAC, 8th July 2014 © Crown Copyright

Limiting the impact of carbapenemases

• Detecting resistance in the clinical laboratory is essential for identifying infected / colonized patients:

1. appropriate patient management

2. rapid implementation of infection control procedures

3. Prevent onwards transmission

• But how ?


BSAC, 8th July 2014 © Crown Copyright

What laboratory tests do we need ?

Group to be defined Acronym Suitable lab tests

Carbapenem-resistant Enterobacteriaceae / organisms

CRE(or CRO)

Must identify resistance:

• Susceptibility tests vs. carbapenems• Growth on media with carbapenems

Carbapenemase-producing Enterobacteriaceae / organisms

CPE (or CPO)

Must detect (or infer) carbapenemaseproduction:

• Detect carbapenem hydrolysis• Detect carbapenemase genes• Beta-lactamase inhibitor tests


• Suitable for use on isolated bacteria• Suitable for use on isolated bacteria or directly on clinical specimens

The problem with spotting the carbapenemase producers

Carbapenem MIC

N

0.25 16

Wild-type Carbapenemase

ESBL / AmpC + porin lossor true carbapenemase ?

• Human experts, subjective : computer algorithms, poor specificity• ‘relative ease’: E. coli > Klebsiella spp. >> Enterobacter spp.• High index of suspicion; supplemental tests, locally or in Ref. Lab.


EUCAST algorithm for carbapenemase detection


APBA = aminophenyl boronic acid; PBA = phenyl boronic acid; DPA = dipicolinic acid; EDTA = ethylenediaminetetraacetic acid (all β-lactamase inhibitors added to discs or tablets containing meropenem in combination disc assays)1Combination of KPC + VIM may not show synergy but isolates are normally highly resistant to carbapenems – easiest to detect withmolecular assays.2High-level temocillin resistance [MIC > 32 mg/L, zone diameter <11 mm with temocillin 30 μg disc] are indicators of OXA-48 production, which should be considered in the absence of synergy with inhibitors

Limiting the impact of carbapenemases

• Detecting resistance in the clinical laboratory is too slow if using traditional AST methods and supplemental tests

• RAPID diagnostics are essential for identifying infected / colonized patients:

1. appropriate patient management

2. rapid implementation of infection control procedures

3. Prevent onwards transmission


Commercial systems

• Increasing numbers of products for a growing market

• Phenotypic detection of hydrolysis• Colorimetric e.g. Rosco Diagnostica Rapid CARB Screen kit;

bioMerieux Rapidec• MALDI-ToF

• Molecular detection of resistance genes • Coverage of ‘big five’ carbapenemases varies • Range from ‘yes/no’ tests to ‘full’ group differentiation• None will find novel carbapenemases

15BSAC, 8th July 2014 © Crown Copyright

Examples of commercial ‘real time’ solutionsCompany Kit Basis Isolates Samples Family

Coverage * Platform Time

Amplex

eazyplex SuperBug complete or

eazyplex SuperBugCRE

(CE-marked)

LAMP Yes “screening swabs”KPC, OXA-

48, VIM, NDM

Proprietary

15 mins(isolates) or

30 min (swabs)

Becton Dickinson

BD MAX CRE (RUO) RT PCR Yes “clinical samples”,

screening swabsKPC, OXA-

48, NDMProprietary

(Open) 2 h

bioMerieuxNucliSENS

EasyQ KPC(RUO)

NASBA Yes stool samples, rectal swabs KPC Proprietary 3-4 h

Cepheid GenXpert Carba-R(RUO) RT PCR Yes rectal swabs

KPC, NDM, OXA-48, VIM,

IMPProprietary 50 min

Check-Points

Check-Direct CPE(CE-marked) RT PCR Yes rectal/perianal

swabs

KPC, OXA-48, VIM,

NDM

Multiple RT machines 2 h


N.B. Coverage of alleles within the IMP, VIM and OXA-48 families varies between kits

Rapid Diagnostics to Guide Empiric Therapy

• Rapid tests for mechanisms = surrogates for rapid AST

• Absence of a resistance mechanism doesn’t confirm susceptibility• cannot indicate appropriate empiric therapy

• Presence of a resistance mechanism used to infer likely resistance• indicates potentially inappropriate empiric therapy

• Carbapenemase detected: carbapenem NOT suitable as sole agent

• (Confirming susceptibility = prime criterion for appropriate therapy)


There isn’t a single ‘best’ detection method…

• because of the diversity of carbapenemases

• their different molecular classes

• the variation between genes within major families

• all hydrolyze carbapenems, but have no other shared properties

• because of the diversity of host strains

• level of resistance is contigent on e.g. porin status etc.


Better use of resources for better patient care


• Local AST results analysed regionally on daily basis (e.g. AMWEB)*

• Daily request for MDR bacteria• Regional testing in specialist lab• Timely feedback to local lab• Better IPC / patient management

• Positive isolates sent to national reference lab for further study

*Ironmonger et al. JAC 2013 doi: 10.1093/jac/dkt181

Hawkey, Woodford & Ironmonger


• Revision in 2014

• Gathering evidence

• Comparison of commercial assays

• Evaluations of media

• Seek to make it a NICE-approved

guideline

SMI v. 2.0

The PHE CPE Toolkit and the need to detect Carbapenemase...

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