Commercial assays for the detection of acquired carbapenemases

Commercial assays for the detection of acquired carbapenemases

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About Public Health England

Public Health England exists to protect and improve the nation’s health and wellbeing,

and reduce health inequalities. We do this through world-leading science, knowledge

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Prepared by: Danièle Meunier, Rachel Freeman, Katie L. Hopkins.

Contributors: Susan Hopkins, Neil Woodford, Colin Brown, Caroline Chilton, Frances Davies,

Kerry Davies, Tom Lewis, Jonathan Otter, David Richards, Rifat Soyfoo, Mark Wilcox.

For queries relating to this document, please contact: amrhai@phe.gov.uk

© Crown copyright 2019

You may re-use this information (excluding logos) free of charge in any format or

medium, under the terms of the Open Government Licence v3.0. To view this licence,

visit OGL. Where we have identified any third party copyright information you will need

to obtain permission from the copyright holders concerned.

Published May 2019

PHE publications PHE supports the UN

gateway number: GW-427 Sustainable Development Goals

Commercial assays for the detection of acquired carbapenemases

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Contents

Executive summary 4

1.0 Introduction 5

1.1 What are acquired carbapenemases? 5

1.2 Why is it important to detect carbapenemase-producing Enterobacterales? 5

1.3 What is the current guidance for the detection of CPE? 6

1.4 Who is this report for and what is its purpose? 6

2.0 Commercial assays available for detection of the ‘big 4’ carbapenemase families 7

2.1 Nucleic acid amplification technologies (NAATs) 7

Table 1: List of NAATs available for detection of the ‘big 4’ carbapenemases 9

Table 2: Performance of NAATs 14

2.2 Immuno-chromatographic assays 19

Table 3: List of immuno-chromatographic assays 19

Table 4: Performance of immuno-chromatographic assays 20

2.3 Syndromic assays 21

Table 5: List of syndromic assays 21

Table 6: Performance of syndromic assays 22

3.0 Points to consider for implementation 23

References 26

Appendix: Changes to referral and reporting of carbapenemase-producing Gram-negative

bacteria in England 29

Rationale for change 29

Summary of changes 29

Reporting of locally-confirmed carbapenemase-producing Gram-negative bacteria 31

Referral of suspected carbapenemase producers 32

PHE Field Service Information Manager or SGSS support contact details 32

Commercial assays for the detection of acquired carbapenemases

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Executive summary

Almost all NHS hospitals in England have detected carbapenemase-producing Gram-

negatives within their patient populations, either as colonisations or causing clinical

infections. The purpose of this report is to provide evidence-based guidance to enable

diagnostic laboratories to make an informed choice in their selection of one or more

commercially available methods for the detection of carbapenemase-producing Gram-

negatives when considering local business needs.

The report strongly recommends the implementation of an assay for the detection of

the ‘big 4’ carbapenemases in frontline diagnostic laboratories. Local testing with rapid

turnaround will have maximal impact on individual patient management to prevent

onward transmission and effective clinical treatment.

Commercial assays for the detection of acquired carbapenemases

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1.0 Introduction

1.1 What are acquired carbapenemases?

Resistance to carbapenem antibiotics is one of the major threats faced in antimicrobial

treatment of Gram-negative infections. Acquired carbapenem resistance, predominantly

mediated by transferable genes, is of particular importance as these genes (usually

located on mobile genetic elements such as transposons or plasmids) can move

vertically (within a strain) and horizontally (between strains, species and genera),

causing multi-species outbreaks that can be difficult to recognise or control unless the

resistance mechanism is tracked in relative real-time.

This document focusses on acquired carbapenemases, which are detected in a growing

number of Enterobacterales and are currently the most important mechanisms of

resistance to carbapenems from a public health perspective. Different families of

carbapenemases have been reported globally and nationally within the UK, of which the

KPC, OXA-48-like, NDM and VIM families (often referred to as the ‘big 4’) are the most

commonly identified.1, 2 KPC, OXA-48-like, NDM and VIM carbapenemases accounted

for 95.6% of the 4,028 CPE referred to PHE’s Antimicrobial Resistance and Healthcare

Associated Infections (AMRHAI) Reference Unit in 2018, with coverage increasing to

99.3% if IMP carbapenemases are included. However, carbapenemases belonging to

the GES, IMI, FRI, SME, SPM, GIM and DIM families have also been detected in low

numbers of UK isolates (AMRHAI, unpublished data).

1.2 Why is it important to detect carbapenemase-producing Enterobacterales?

Although still responsible for a low number of invasive infections within the UK,

carbapenemase-producing Enterobacterales (CPE) are widely scattered in the UK

population and are increasingly associated with hospital- and community-acquired

infections. Infections caused by CPE are challenging to treat, and are associated with

an increase in morbidity, attributable mortality, and increased healthcare costs resulting

from prolonged hospital stays and the care of infected and colonised patients.

Acquired carbapenemase genes are frequently located on mobile genetic elements,

which can potentially transfer resistance between different bacterial strains, species and

genera. Thus, early detection of CPE and distinction from bacteria with other

carbapenem resistance mechanisms is important to minimise their spread by the rapid

implementation of effective infection prevention and control procedures.

Differentiation between the various carbapenemase families may also be useful, not

only to inform epidemiology but also to guide patient treatment. A recent report from the

Commercial assays for the detection of acquired carbapenemases

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British Society for Antimicrobial Chemotherapy, Healthcare Infection Society and British

Infection Association Joint Working Party strongly recommended the determination of

the responsible family of carbapenemase in all meropenem or imipenem resistant

Enterobacterales.3 For example, ceftazidime/avibactam is effective for the treatment of

CPE producing a KPC or OXA-48-like non-metallo-carbapenemase, but is ineffective

against CPE producing metallo-carbapenemases such as NDM or VIM.

1.3 What is the current guidance for the detection of CPE?

In 2013, PHE published a toolkit to provide expert advice on the management of

colonisation or infection due to CPE in England, to prevent or reduce their spread into

(and within) health and residential care settings. This highlighted the role of the early

detection of CPE in preventing further spread.4

In 2016, PHE issued the UK Standards for Microbiology Investigations (SMI) ‘Detection

of bacteria with carbapenem-hydrolysing β-lactamases (carbapenemases)’.5

Whilst the SMI was not prescriptive about how laboratories should test for

carbapenemases as there is no ‘gold standard’ methodology, it did provide an overview

of methods available at the time of writing for screening and confirmation of

carbapenemase producers, with a focus on phenotypic detection of carbapenemase

activity. The advantages and disadvantages of molecular methods compared with

phenotypic methods were discussed, but no specific recommendations were made on

the suitability of particular assays. Evidence-based guidance to assist diagnostic

laboratories in their selection of an appropriate CPE detection method is therefore

needed, and this evidence has been accumulating in the period since the SMI was

published. In their recent survey, Berry and colleagues found considerable diversity in

the methods used by English diagnostic laboratories for detection of CPE and

concluded that evidence to support adoption of a CPE detection method would be

beneficial to the UK healthcare system.6

1.4 Who is this report for and what is its purpose?

The purpose of this report is to provide the evidence base for diagnostic laboratories to

facilitate an informed decision on the choice of commercial CPE detection assays to

implement, based on their local circumstances. This report focusses on molecular and

immunochromatographic assays that detect specific carbapenemase families;

phenotypic assays are outside the scope of this report.

It strongly recommends the implementation of an assay for the detection of the ‘big 4’

carbapenemases in frontline diagnostic laboratories to inform appropriate individual

patient management at a much earlier stage and accelerate infection prevention and

control decisions.

Commercial assays for the detection of acquired carbapenemases

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2.0 Commercial assays available for detection

of the ‘big 4’ carbapenemase families

We established a list of commercial assays available in the UK for detection of acquired

carbapenemases by searching the published literature and the websites of

manufacturers exhibiting at ECCMID and ASM Microbe in 2018. The literature search

was carried out between May and December 2018 using PubMed and the following

search terms: [carbapenemase], [diagnostic], [assay], [‘name of the assay’].

The assays listed are limited to those that claim to identify as a minimum the ‘big 4’

carbapenemases (KPC, OXA-48-like, NDM and VIM). Publications referring to the

assay but not including data for detection of the ‘big 4’ carbapenemases were excluded.

To our knowledge, and at the time of publication, this list should be as exhaustive as

possible and no bias is intended if any assay has been excluded from this report.

The list of assays has been divided into three categories: nucleic acid amplification

technologies (NAATs), immuno-chromatographic assays and syndromic assays. Details

of assay performance (as presented in the published literature and on company

websites) can be found in the sections that follow to assist diagnostic laboratories in

making a choice regarding which assay(s) to implement. However, performance

characteristics should not be readily compared as the evaluations were performed by

multiple groups using different sample panels with variation in the size of panel and

carbapenemase family coverage.

Pictures provided in the tables are for information only and diagnostic laboratories

should consider that the platform footprints will vary between companies. List price per

test has been included, although laboratories should be aware that costs are likely to

vary depending on sample throughput and local arrangements made between

companies and distributors.

2.1 Nucleic acid amplification technologies (NAATs)

Nucleic acid amplification technologies (NAATs) generate results within 15 minutes to 5

hours. The technology principle relies mostly on the detection of carbapenemase genes

by real-time PCR (RT-PCR), although some tests use isothermal amplification. The

required platform may be a generic RT-PCR thermocycler already available in the

diagnostic laboratory or a proprietary platform requiring capital expenditure. Sample

throughput depends on the platform and can be increased if using modular systems.

In the following tables the £ symbols relate to the costs as outlined below:

Commercial assays for the detection of acquired carbapenemases

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**Cost per isolate <£10 = £; £10-49 = ££; £50-100 = £££; >£100 = ££££; x = price not available at time of publication. ***Equipment cost <£1000 = £; £1k-<10k = ££; £10k-<50k = £££; >£50k = ££££; x = price not available at time of publication.

Commercial assays for the detection of acquired carbapenemases

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Table 1: List of NAATs available for detection of the ‘big 4’ carbapenemases

NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Additional equipment required

Workflow Cost/isolate** Equipment

cost***

eazyplex® Superbug complete A/complete B/CRE

Amplex

KPC, OXA-48-like, NDM, VIM

heating block, centrifuge

(for processing blood cultures)

sample in buffer, heating 2 min/99 °C,

processing in the GENIE®

£££ £££

CRE EU 16 well

AusDiagnostics

KPC, OXA-48-like, NDM, VIM, IMP

plate spinner

sample in sample buffer, processing in

the MT processor and RT-PCR in the MT

analyser

££

£££

BD MAX™ Check-Points CPO

BD

KPC, OXA-48-like, NDM, VIM/IMP

(VIM/IMP not differentiated by the assay)

None

add 50 µl Amies tube to Sample Buffer

Tube, processing in the BD MAX™

system

x x

Commercial assays for the detection of acquired carbapenemases

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NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Additional equipment required

Workflow Cost/isolate** Equipment

cost***

XPERT® CARBA-R

Cepheid

KPC, OXA-48-like, NDM,

VIM, IMP-1-like

none

swab/colonies in sample reagent,

transfer of sample reagent to cartridge,

processing of cartridge in GeneXpert®

££ £££-££££

CRE ELITe MGB® kit

ELITech

KPC, OXA-48-like, NDM/VIM/IMP

(NDM/VIM/IMP not differentiated by the assay)

none

DNA extraction process in cartridge

and RT-PCR in cartridge

££ ££££

Amplidiag® CarbaR + VRE

Mobidiag

KPC, OXA-48-like, NDM, VIM, IMP

cycler BioRad CFX 96

sample in buffer, processing in

Amplidiag® Easy, RT-PCR, automated

result analysis and reporting with

Amplidiag Analyzer software

££ ££££

Commercial assays for the detection of acquired carbapenemases

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NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Additional equipment required

Workflow Cost/isolate** Equipment

cost***

Novodiag® CarbaR+

Mobidiag

KPC, OXA-48-like, NDM, VIM, IMP

none

Rectal swab or colony into 2 ml eNATTM,

600µl in the cartridge, cartridge inserted in

the Novodiag® platform

££ £££

AllPlexTM Entero-DR assay

Seegene

KPC, OXA-48-like, NDM, VIM, IMP

different platforms for automated

extraction and set-up, cycler

BioRad CFX 96

DNA extraction, set-up, RT-PCR

x x

EntericBio® CPE Screen

Serosep

KPC, OXA-48-like, NDM, VIM, IMP

EntericBio® heatstation, Lightcycler

swab into Sample Preparation Solution,

heating for 30 min/103 °C,

processing in the EntericBio

workstation, load onto Lightcycler for

amplification/detection

££ ££££

Commercial assays for the detection of acquired carbapenemases

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*Coverage within carbapenemase families may vary between each assay

NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Additional equipment required

Workflow Cost/isolate** Equipment

cost***

CT102 or CT103 XL Array

Check-Points

KPC, OXA-48-like, NDM, VIM, IMP

thermocycler, heating block,

centrifuge

DNA extraction from pure culture, block-

based PCR, hybridisation of PCR products to the array

££ (CT

102)/£££ (CT103 XL)

x

Commercial assays for the detection of acquired carbapenemases

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*Coverage within carbapenemase families may vary between each assay

NAATs – PCR kits required and compatible PCR platforms

Assay Assay coverage*

Compatible platforms

Workflow Cost/isolate** Equipment

cost***

CARBAPLEX®

Bruker

KPC, OXA-48-like, NDM, VIM, IMP

ABI 7500, BioRad CFX96,

RotorGene Q, ABI QuantStudio 5

DNA extraction from rectal swab, crude extract from pure

culture, PCR using two mastermixes

££ N/A

Check-Direct CPE

Check-Points

KPC, OXA-48-like, VIM/NDM (VIM/NDM are not

differentiated by the assay)

ABI 7500, BioRad CFX96, RotorGene Q, LightCycler®

480 system I&II,

DNA extraction from rectal swab using

NucliSENS® easyMAG®, crude

extract from pure culture

£

N/A

Amplidiag® CarbaR + VRE or CarbaR+MCR

Mobidiag

KPC, OXA-48-like, NDM, VIM, IMP

ABI 7500, BioRad CFX96, RotorGene Q

DNA extraction from stool samples, rectal

swabs or pure culture, crude extract from pure

culture, automated result analysis and

reporting with Amplidiag Analyzer software

££ N/A

STRECK ARM-D® kit

Streck

KPC, OXA-48-like, NDM, VIM, IMP

ABI 7500 Fast, BioRad CFX96, RotorGene Q,

ABI QuantStudio 7 Flex, Streck

Zulu RT™

DNA extraction from pure culture, PCR using

three mastermixes ££ N/A

LightMix® Modular Carbapenemases

TibMolBiol/Roche

KPC, OXA-48-like, NDM, VIM, IMP

LightCycler® 480

DNA extraction from rectal swabs, pure

culture x N/A

AllPlexTM Entero-DR assay

Seegene

KPC, OXA-48-like, NDM, VIM, IMP

BioRad CFX96 DNA extraction from rectal swabs, pure

culture x N/A

Commercial assays for the detection of acquired carbapenemases

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Table 2: Performance of NAATs

NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Throughput per

run

Hands on time/

sample

Sample to

results#

Sample types validated by

manufacturer

Performance characteristics (sample types tested)

eazyplex® Superbug complete A/complete B/CRE

Amplex

KPC, OXA-48-like, NDM, VIM

8 to 12 samples 2 min 15 to 20

min

c, liquid swab, u, bc

from manufacturer:

Sens: 100%; Spec: 99.4% (c)a*

from published data: 7Sens 95.7% Spec 100% (c) 8Sens 100% Spec 100% (c)

CRE 16 well

AusDiagnostics

KPC, OXA-48-like, NDM, VIM, IMP

24 samples 5 min <4h c

from manufacturer: Sens 98.0-100% Spec 99.5-100% (c)a*

from published data: 9Sens 100% Spec 100% (c)

BD MAX™ Check-Points CPO assay

BD

KPC, OXA-48-like, NDM, VIM/IMP (VIM/IMP not

differentiated by the assay)

up to 24 tests <5 min <3h c, rs

from manufacturer: Sens 99.0% Spec 99.5% (c, rs)a*

from published data:

7Sens 100% Spec 100% (c)

Commercial assays for the detection of acquired carbapenemases

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NAATs integrated workflow - proprietary platform required

Assay Assay coverage*

Throughput per

run

Hands on time/

sample

Sample to

results#

Sample types validated by

manufacturer

Performance characteristics (sample types tested)

XPERT® CARBA-R Cepheid

KPC, OXA-48-like, NDM, VIM, IMP

1 to 80 samples depending on the

number of modular systems

<1 min 48 min c, rs, prs

from manufacturer: Sens 93.7% Spec 99.6% (rs, prs)a* Sens 100% Spec 97.1-98.1% (c)a*

from published data:

10Sens 100% Spec 100% (u, bc) 7Sens 94.4% Spec 100% (c)

11Sens 100% Spec 97.1-98.1% (c) 12Sens 84-100% Spec 84-100% (br) 13Sens 96.6% Spec 98.6% (rs, rs)

14Sens 97.7% Spec 97.2% (rs)

CT 102 or CT103 XL Array Check-Points

KPC, OXA-48-like, NDM, VIM, IMP

CT 102: 3 to 72 samples

CT103 XL: 1 to 24 samples

45 min 6h c

from manufacturer:

Sens 90-100% Spec 100% (c)b*

from published data:

15Sens 100% Spec100% (c) 16Sens 95-100% Spec 100% (c)

17 Sens 98.7% Spec 100% (c) 18Sens 97% Spec 100% (c)

19Sens 100% Spec 95.7% (c)

CRE ELITe MGB® kit

ELITech

KPC, OXA-48-like, NDM/VIM/IMP

(NDM/VIM/IMP not differentiated by

the assay)

1 to 12 samples <2 min <3h rs, bc

from manufacturer:

Sens 99.3% Spec 100% (rs)b*

from published data:

20Sens 100% Spec100% (c, rs, bc)

Commercial assays for the detection of acquired carbapenemases

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Novodiag® CarbaR+

Mobidiag

KPC, OXA-48-like, NDM, VIM, IMP

4-16 samples/run 35 min 1h20 rs, bc

from manufacturer:

Sens 85.7-100% Spec 84.6-100% (rs)a* Sens 100% Spec 100% (c)a*

EntericBio® CPE Screen

Serosep

KPC, OXA-48-like, NDM, VIM, IMP

1-46 samples/run <2 min 3h c, st, liquid rs

from manufacturer:

Sens 100% Spec 99.8% (rs)a* Sens 100% Spec 100% (c)a*

from published data: 21Sens 100% Spec 100% (c)

Commercial assays for the detection of acquired carbapenemases

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NAATs – – PCR kits required and compatible PCR platforms

Assay Assay coverage*

Throughput per

run

Hands on

time/

sample

Sample

to

results#

Sample types

validated by

manufacturer

Performance characteristics (sample

types tested)

CARBAPLEX®

Bruker

KPC, OXA-48-like,

NDM, VIM, IMP

Depending on the

platform 5 min <3h c, rs no data available

Check-Direct CPE

Check-Points

KPC, OXA-48-like,

VIM/NDM (VIM and

NDM are not

differentiated by the

assay)

up to 96 tests 5 min 2h c, rs, prs

from manufacturer:

Sens 100% Spec 100% (c)b*

from published data:

7Sens 100% Spec 100% (c) 22Sens 100% Spec 94% (rs)

23Sens 100% Spec 100% (c, rs) 24Sens 100% Spec 88% (rs) 25Sens 100% Spec100% (c)

Amplidiag® CarbaR + VRE or

CarbaR+MCR

Mobidiag

KPC, OXA-48-like,

NDM, VIM, IMP

up to 29 samples

48 samples with

Amplidiag® Easy

5 min <2h

c (Carba R+VRE and Carba R+

MCR) c, rs, st (Carba

R+ MCR)

from manufacturer:

Sens 91.7-100% Spec 99.4-100% (c)a* Sens 95.5-100% Spec 98.5-100% (st, rs)a*

from published data:

26Sens 100% Spec 88.9-100% (c) 27Sens 92.5-100% Spec 86-100% (c, rs)

AMRHAI (unpublished):

Sens 99% Spec 97.6% (c)

STRECK ARM-D® kit

Streck

KPC, OXA-48-like,

NDM, VIM, IMP

Depending on the

platform 5 min

22 min

to 1h c

from manufacturer:

Sens 100% Spec 97-100% (c)b*

Commercial assays for the detection of acquired carbapenemases

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#: time to result excludes the incubation time required for bacterial growth sample type: c = bacterial colonies; u = urine; bc = blood culture; rs = rectal swab, prs = peri-rectal swabs, br = bronchial specimens, st = stool samples, underlined and bold: spiked sample a*: assay performance determined from multi-centre evaluations b*: assay performance without evidence of multi-centre evaluations

NAATs – – PCR kits required and compatible PCR platforms

Assay Assay coverage*

Throughput per

run

Hands on

time/

sample

Sample

to

results#

Sample types

validated by

manufacturer

Performance characteristics (sample types tested)

LightMix® Modular Carbapenemases

TibMolBio/Roche

KPC, OXA-48-like,

NDM, VIM, IMP

Depending on the

platform 5 min <2h c, rs

from published data:

28Sens 100% Spec 89.8-93.3% (rs) 29Sens 99% Spec 100% (c, bc, bc)

AllPlexTM Entero-DR assay

Seegene

KPC, OXA-48-like,

NDM, VIM, IMP 40 samples/run 5 min 3h c, rs, u no data available

Commercial assays for the detection of acquired carbapenemases

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2.2 Immuno-chromatographic assays

Immuno-chromatographic assays (or lateral flow assays) are based on immunological detection of epitopes of the targeted

carbapenemase enzyme (rather than gene detection). These are typically formatted as cassettes with a 10-15 minute running

time and allow screening of one sample per cartridge.

Table 3: List of immuno-chromatographic assays

*Coverage within carbapenemase families may vary between each assay

Assay Assay coverage*

Additional

equipment required Workflow Cost/test**

Equipment cost***

RESIST– 4 O.K.N.V.

Coris

KPC, OXA-48-like, NDM, VIM

vortex colonies in lysis buffer,

suspensions added in the strips, two strips required

££ N/A

NG-test Carba 5

NG-Biotech

KPC, OXA-48-like, NDM, VIM, IMP

Vortex, NG-Test® Reader

colonies in lysis buffer, suspensions added in the strips

blood culture processed with the NG-Test blood culture Prep, suspension added to the strip

£-££ N/A

Commercial assays for the detection of acquired carbapenemases

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Table 4: Performance of immuno-chromatographic assays

*Coverage within carbapenemase families may vary between each assay #: time to result excludes the incubation time required for bacterial growth sample type: c = bacterial colonies; bc = blood culture; underlined and bold: spiked sample ND = not determined a*: assay performance determined from multi-centre evaluations b*: assay performance without evidence of multi-centre evaluations

Assay Assay coverage*

Throughput per

cartridge Hands on

time/sample

Sample to

results#

Sample types validated by

manufacturer

Performance characteristics (sample types tested)

RESIST– 4 O.K.N.V.

Coris

KPC, OXA-48-like, NDM, VIM

1 sample <5 min 20 min c

from the manufacturer:

Sens 97.4-100% Spec 100% (c)a*

from published data:

30Sens 97.1% Spec ND (c) 31Sens 99.2-100% Spec 100% (c) 32Sens 75-100% Spec 100% (bc)

NG-test Carba 5

NG-Biotech

KPC, OXA-48-like, NDM, VIM, IMP

1 sample <5 min 20 min c, bc

from the manufacturer:

Sens 100% Spec 100% (c)a*

from published data:

33Sens 100% Spec 95.3-100% (c) 34Sens 97.3% Spec 99.75% (c)

Commercial assays for the detection of acquired carbapenemases

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2.3 Syndromic assays

Syndromic assays combine approaches for the detection and identification of bacterial species associated with clinical

syndromes (such as bloodstream, respiratory or urinary tract infections) and selected antimicrobial resistance genes. The

technology principle relies on a combination of PCR and DNA hybridization.

Table 5: List of syndromic assays

*Coverage within carbapenemase families may vary between each assay

Assay Assay coverage* Additional

equipment required Workflow Cost/isolate**

Equipment cost***

Unyvero®

Curetis AG

KPC, OXA-48-like, NDM, VIM, IMP

none

sample in Unyvero Sample tube, sample tube inserted in the Unyvero Lysator, sample

tube and mastermix I the Unyvero cartridge, cartridge in

the Unyvero Analyzer

x x

ePlex® BCID-GN panel

GenMarkDx

KPC, OXA-48-like, NDM, VIM, IMP

none blood culture sample loaded in

cartridge ££££ £££

Verigene® Gram-negative blood culture test

Nanosphere Luminex

KPC, OXA-48-like, NDM, VIM

none blood culture sample loaded in

cartridge ££ £££

Commercial assays for the detection of acquired carbapenemases

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Table 6: Performance of syndromic assays

#: time to result excludes the incubation time required for bacterial growth sample type: u = urine; bc = blood culture; IAI = fluid samples from intra-abdominal infections; underlined and bold: spiked sample ND = not determined a*: assay performance determined from multi-centre evaluations b*: assay performance without evidence of multi-centre evaluations

Assay Assay coverage* Throughput

per run

Hands on time/

sample

Sample to

results#

Samples types

validated by manufacturer

Performance characteristics (sample types tested)

Unyvero®

Curetis AG

KPC, OXA-48-like, NDM, VIM, IMP

1 to 8 samples

2 min 5h bc, u

from published data:

35 Sens 100% Spec 100% (IAI)

ePlex® BCID-GN panel

GenMarkDx

KPC, OXA-48-like, NDM, VIM, IMP

3 to 24 samples

depending on the

number of platforms

<2min 1.5h bc

No data

Verigene® Gram-negative blood culture

test

Nanosphere -Luminex

KPC, OXA-48-like, NDM, VIM

depending on the

number of platforms

<5 min <2h bc

from manufacturer:

Sens 77.8-100% Spec 100% (bc)b*

from published data:

36Sens 92.3% Spec 100% (bc) 37Sens 100% Spec ND (bc)

38Sens 100% Spec ND (bc, bc) 39Sens 100% Spec ND (bc)

Commercial assays for the detection of acquired carbapenemases

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3.0 Points to consider for implementation

Diagnostic laboratories should consider whether carbapenemase detection is to be

performed from isolated bacterial colonies or directly from clinical specimens such as

rectal swabs/faeces; the latter will be more appropriate for rapid identification of patients

colonised with CPE. PHE’s recommendation is that diagnostic laboratories should have

methods in place for both. However, as previously highlighted by Health Improvement

Scotland, a lack of evidence of diagnostic accuracy means that it is not currently

possible to identify the most effective assay for screening using rectal swabs.40

However, diagnostic laboratories should also be aware that some assays require prior

DNA extraction from rectal swabs before further processing eg (CARBAPLEX®

(Bruker), Check-Direct CPE (Check-Points), CarbaR+MCR (Amplidiag®), AllPlexTM

Entero-DR assay (Seegene), STRECK ARM-D® kit (Streck) and LightMix® Modular

Carbapenemases (TibMolBio/Roche)). Other assays such as the CarbaR+MCR

(Amplidiag®) and the AllPlexTM Entero-DR assay (Seegene) can be run either on a

generic PCR platform following manual DNA extraction or on a proprietary platform,

which automates the DNA extraction process.

Published evaluations (including head-to-head and multi-centre evaluations) are

currently lacking for some assays, with syndromic assays being particularly under-

represented in the literature. In several studies referenced in this report, ability of the

assay to detect the ‘big 4’ carbapenemases was evaluated on spiked blood culture,

urine or bronchial samples as the prevalence of bacteria containing these

carbapenemases in such clinical samples is likely to be low in most hospital settings.12

Diagnostic laboratories wishing to test direct from clinical specimens (and bacterial

cultures) must therefore perform their own assay validation locally to conform to UKAS

requirements.

Overall, the assays presented in this report vary considerably in the amount of user

input and molecular expertise required to set up each test, ranging from assays that

require minimal staff training (eg eazyplex® Superbug complete A/complete B/CRE

(Amplex), CRE 16 well (AusDiagnostics), XPERT® CARBA-R (Cepheid) and BD

MAX™ Check-Points CPO assay or immuno-chromatographic tests) to assays that

require prior extraction of DNA from clinical specimens/bacterial isolates and/or

preparation of several reagent master mixes. Choice of an assay will therefore depend

on staff expertise and ability of an assay to fit into local workflows. Bench space

required for the installation of the platform should also be assessed prior to

implementation.

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When comparing performance characteristics, readers should be aware that

calculations of sensitivity and specificity will be based on the assumption that all isolates

of CPE will be detected by either the assay under evaluation or the comparator test.

Analytical performance of an assay may be exaggerated if it is compared against a

poorly performing alternative and will also depend on the diversity and size of the test

panel. Laboratories should therefore ensure that representatives of each

carbapenemase family circulating in their patient population, and preferably

representatives of each of the ‘big 4’ carbapenemase families, are included in local

validation exercises. To assist with local validation a panel of CPE isolates representing

common variants of KPC, OXA-48-like, NDM, VIM and IMP carbapenemases known to

be circulating in the UK can be obtained on request from AMRHAI. A lenticule®

including NCTC positive controls for the ‘big 4’ carbapenemases (also including IMP) is

also available from NCTC.

All the assays listed in this report claim to detect the ‘big 4’ carbapenemases, with some

assays having coverage extended to include detection of IMP metallo--lactamases

(MBLs) and the detection of rarer class A carbapenemase families (GES, IMI, FRI)

(Amplidiag® CarbaR+MCR, CRE 16 well (AusDiagnostics), EntericBio® CPE screen,

CT 102 or CT103 XL Array (Check-Points), LightMix® Modular Carbapenemases

(TibMolBiol/Roche)). However, some assays included here (Check-Direct CPE (Check-

Points), BD MAX™ Check-Points CPO (Check-Points), CRE ELITe MGB® kits

(ELITech)) will detect but not distinguish between all carbapenemases (see Table 1).

Whilst a ‘yes/no’ answer regarding presence of an MBL is sufficient to implement

infection prevention and control procedures and enable appropriate patient

management, the knowledge of which MBL family is present will inform local

epidemiology.

All assays in this report will be limited in that they will only detect known

carbapenemases (or closely related variants) within the families covered; newly

emerged variants may not be reliably detected and, obviously, carbapenemases

belonging to families outside of an assay’s scope will not be detected. Coverage within

a carbapenemase family may also vary from assay to assay, eg the Superbug

complete A (Amplex) does not detect two variants of OXA-48 (OXA-181 and OXA-232),

whilst the Xpert® Carba-R (Cepheid) focusses on detection of IMP-1-like

carbapenemases rather than the entire IMP family.7

In April 2018, AMRHAI introduced charging for detection of the ‘big 4’ carbapenemase

families. Extended molecular screening for IMP, GES and other rarer carbapenemase

families remains free-of-charge for any carbapenem-resistant isolates that meet

EUCAST criteria for further investigation but are negative for the ‘big 4’ families in local

tests. The CE-marked real-time PCR assay that we use screens for class A (KPC, IMI,

GES, FRI and SME), class B (GIM, IMP, NDM, SIM, SPM and VIM) and class D (OXA-

Commercial assays for the detection of acquired carbapenemases

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48-like) carbapenemases, which covers all carbapenemase families identified amongst

>16,000 CPE submitted to AMRHAI from UK laboratories since 2000.9 AMRHAI will

monitor for the emergence of novel carbapenemases not covered by our PCR assay by

more detailed investigation of PCR-negative isolates from clinical specimens.

In order that locally-confirmed isolates continue to contribute to national CPE

surveillance PHE has developed methods to collect results of local carbapenemase

detection testing via PHE’s Second Generation Surveillance System (see Appendix).

Commercial assays for the detection of acquired carbapenemases

26

References

1. Logan LK, Weinstein RA. The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace. J Infect Dis 2017; 215: S28-s36.

2. Public Health England. English Surveillance Programme for Antimicrobial Utilisation and Resistance (ESPAUR), Report 2018. In: https://www.gov.uk/government/publications/carbapenemase-producing-enterobacteriaceae-early-detection-management-and-control-toolkit-for-acute-trusts

3. Hawkey PM, Warren RE, Livermore DM et al. Treatment of infections caused by multidrug-resistant Gram-negative bacteria: report of the British Society for Antimicrobial Chemotherapy/Healthcare Infection Society/British Infection Association Joint Working Party. J Antimicrobial Chemother 2018; 73: iii2-iii78.

4. Acute trust toolkit for the early detection, management and control of carbapenemase-producing Enterobacteriaceae https://assetspublishingservicegovuk/government/uploads/system/uploads/attachment_data/file/329227/Acute_trust_toolkit_for_the_early_detectionpdf 2013.

5. UK Standards for Microbiology Investigations B 60: Detection of bacteria with carbapenem hydrolysing β lactamases (carbapenemases). https://www.gov.uk/government/consultations/uk-smi-b-60-screening-and-detection-of-bacteria-with-carbapenem-hydrolysing-lactamases-carbapenemases 2016.

6. Berry C, Davies K, Woodford N et al. Survey of screening methods, rates and policies for the detection of carbapenemase producing Enterobacteriaceae in English hospitals. J Hospital Infect 2019; 101: 158-62.

7. Findlay J, Hopkins KL, Meunier D et al. Evaluation of three commercial assays for rapid detection of genes encoding clinically relevant carbapenemases in cultured bacteria. J Antimicrobial Chemother 2015; 70: 1338-42.

8. Garcia-Fernandez S, Morosini MI, Marco F et al. Evaluation of the eazyplex® SuperBug CRE system for rapid detection of carbapenemases and ESBLs in clinical Enterobacteriaceae isolates recovered at two Spanish hospitals. J Antimicrobial Chemother 2015; 70: 1047-50.

9. Meunier D, Woodford N, Hopkins KL. Evaluation of the AusDiagnostics MT CRE EU assay for the detection of carbapenemase genes and transferable colistin resistance determinants mcr-1/-2 in MDR Gram-negative bacteria. J Antimicrobial Chemother 2018; 73: 3355-8.

10. Jaureguy F, Mansour H, Bigot J et al. Use of the Xpert CarbaR assay for direct detection of carbapenemase genes from blood cultures and urine samples. J Hospital Infect 2018; 98: 245-6.

11. Traczewski MM, Carretto E, Canton R et al. Multicenter evaluation of the Xpert® Carba-R assay for the detection of carbapenemase genes in Gram-negative isolates. J Clin Microbiol 2018; 56: doi: 10.1128/JCM.00272-18.

12. Burillo A, Marin M, Cercenado E et al. Evaluation of the Xpert Carba-R (Cepheid) assay using contrived bronchial specimens from patients with suspicion of ventilator-associated pneumonia for the detection of prevalent carbapenemases. PLoS One 2016; 11: e0168473.

13. Tato M, Ruiz-Garbajosa P, Traczewski M et al. Multisite evaluation of Cepheid Xpert Carba-R assay for detection of carbapenemase-producing organisms in rectal swabs. J Clin Microbiol 2016; 54: 1814-9.

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14. Moore NM, Canton R, Carretto E et al. Rapid identification of five classes of carbapenem resistance genes directly from rectal swabs by use of the Xpert Carba-R Assay. J Clin Microbiol 2017; 55: 2268-75.

15. Bogaerts P, Cuzon G, Evrard S et al. Evaluation of a DNA microarray for rapid detection of the most prevalent extended-spectrum beta-lactamases, plasmid-mediated cephalosporinases and carbapenemases in Enterobacteriaceae, Pseudomonas and Acinetobacter. Int J Antimicrob Agents 2016; 48: 189-93.

16. Cuzon G, Naas T, Bogaerts P et al. Evaluation of a DNA microarray for the rapid detection of extended-spectrum beta-lactamases (TEM, SHV and CTX-M), plasmid-mediated cephalosporinases (CMY-2-like, DHA, FOX, ACC-1, ACT/MIR and CMY-1-like/MOX) and carbapenemases (KPC, OXA-48, VIM, IMP and NDM). J Antimicrobial Chemother 2012; 67: 1865-9.

17. Naas T, Cuzon G, Bogaerts P et al. Evaluation of a DNA microarray (Check-MDR CT102) for rapid detection of TEM, SHV, and CTX-M extended-spectrum beta-lactamases and of KPC, OXA-48, VIM, IMP, and NDM-1 carbapenemases. J Clin Microbiol 2011; 49: 1608-13.

18. Stuart JC, Voets G, Scharringa J et al. Detection of carbapenemase-producing Enterobacteriaceae with a commercial DNA microarray. J Med Microbiol 2012; 61: 809-12.

19. Woodford N, Warner M, Pike R et al. Evaluation of a commercial microarray to detect carbapenemase-producing Enterobacteriaceae. J Antimicrobial Chemother 2011; 66: 2887-8.

20. Girlich D, Bernabeu S, Fortineau N et al. Evaluation of the CRE and ESBL ELITe MGB® kits for the accurate detection of carbapenemase- or CTX-M-producing bacteria. Diagn Microbiol Infect Dis 2018; 92: 1-7.

21. Vanstone GL, Wey E, Mack D et al. Evaluation of the EntericBio CPE assay for the detection of carbapenemase-producing organisms. J Med Microbiol 2018; 67: 1728-30.

22. Huang TD, Bogaerts P, Ghilani E et al. Multicentre evaluation of the Check-Direct CPE® assay for direct screening of carbapenemase-producing Enterobacteriaceae from rectal swabs. J Antimicrobial Chemother 2015; 70: 1669-73.

23. Nijhuis R, Samuelsen O, Savelkoul P et al. Evaluation of a new real-time PCR assay (Check-Direct CPE) for rapid detection of KPC, OXA-48, VIM, and NDM carbapenemases using spiked rectal swabs. Diagn Microbiol Infect Dis 2013; 77: 316-20.

24. Lau AF, Fahle GA, Kemp MA et al. Clinical performance of Check-Direct CPE, a multiplex PCR for direct detection of bla(KPC), bla(NDM) and/or bla(VIM), and bla(OXA)-48 from perirectal swabs. J Clin Microbiol 2015; 53: 3729-37.

25. Meunier D, Hopkins K.L., Findlay J., Woodford N. Evaluation of the Check-Direct CPE assay for detecting carbapenemase genes in multidrug-resistant Gram-negative bacteria. 25th ECCMID. Copenhagen, Denmark: eV0775, 25-28 April 2015.

26. Oueslati S, Girlich D, Dortet L et al. Evaluation of the Amplidiag CarbaR+VRE Kit for accurate detection of carbapenemase-producing bacteria. J Clin Microbiol 2018; 56: doi: 10.1128/JCM.01092-17.

27. Girlich D, Bernabeu S, Grosperrin V et al. Evaluation of the Amplidiag CarbaR + MCR kit for the accurate detection of carbapenemase-producing and colistin-resistant bacteria. J Clin Microbiol 2018.

28. Lowman W, Marais M, Ahmed K et al. Routine active surveillance for carbapenemase-producing Enterobacteriaceae from rectal swabs: diagnostic implications of multiplex polymerase chain reaction. J Hospital Infect 2014; 88: 66-71.

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29. Oviano M, Torres I, Gonzalez M et al. Evaluation of a novel procedure for rapid detection of carbapenemase-producing Enterobacteriaceae (CPE) using the LightMix® modular carbapenemase kits. J Antimicrobial Chemother 2016; 71: 3420-3.

30. Kolenda C, Benoit R, Carricajo A et al. Evaluation of the new multiplex immunochromatographic O.K.N.V K-Set assay for the rapid detection of OXA-48-like, KPC, NDM and VIM carbapenemases. J Clin Microbiol 2018; 56: doi: 10.1128/JCM.01247-18.

31. Greissl C, Saleh A, Hamprecht A. Rapid detection of OXA-48-like, KPC, NDM, and VIM carbapenemases in Enterobacterales by a new multiplex immunochromatographic test. Eur J Clin Microbiol Infect Dis 2019; 38:331-335.

32. Cointe A, Bonacorsi S, Truong J et al. Detection of carbapenemase-producing Enterobacteriaceae in positive blood culture using an immunochromatographic RESIST-4 O.K.N.V. Assay. Antimicrob Agents Chemother 2018; 62: doi: 10.1128/AAC.01828-18.

33. Boutal H, Vogel A, Bernabeu S et al. A multiplex lateral flow immunoassay for the rapid identification of NDM-, KPC-, IMP- and VIM-type and OXA-48-like carbapenemase-producing Enterobacteriaceae. J Antimicrob Chemother 2018; 73: 909-15.

34. Hopkins KL, Meunier D, Naas T et al. Evaluation of the NG-Test CARBA 5 multiplex immunochromatographic assay for the detection of KPC, OXA-48-like, NDM, VIM and IMP carbapenemases. J Antimicrob Chemother 2018; 73: 3523-6.

35. Ciesielczuk H, Wilks M, Castelain S et al. Multicenter performance evaluation of the Unyvero IAI cartridge for detection of intra-abdominal infections. Eur J Clin Microbiol Infect Dis 2018; 37: 2107-15.

36. Dodemont M, De Mendonca R, Nonhoff C et al. Performance of the Verigene Gram-negative blood culture assay for rapid detection of bacteria and resistance determinants. J Clin Microbiol 2014; 52: 3085-7.

37. Mancini N, Infurnari L, Ghidoli N et al. Potential impact of a microarray-based nucleic acid assay for rapid detection of Gram-negative bacteria and resistance markers in positive blood cultures. J Clin Microbiol 2014; 52: 1242-5.

38. Sullivan KV, Deburger B, Roundtree SS et al. Pediatric multicenter evaluation of the Verigene gram-negative blood culture test for rapid detection of inpatient bacteremia involving gram-negative organisms, extended-spectrum beta-lactamases, and carbapenemases. J Clin Microbiol 2014; 52: 2416-21.

39. Hill JT, Tran KD, Barton KL et al. Evaluation of the nanosphere Verigene BC-GN assay for direct identification of gram-negative bacilli and antibiotic resistance markers from positive blood cultures and potential impact for more-rapid antibiotic interventions. J Clin Microbiol 2014; 52: 3805-7.

40. Healthcare Improvement Scotland. Carbapenemase-producing Enterobacteriaceae (CPE) in hospital screening samples obtained from patients identified as at risk of CPE colonisation during clinical risk assessment. http://www.healthcareimprovementscotland.org/his/idoc.ashx?docid=d4087619-faf0-4fcd-9440-99f4a4e8f9be&version=-1

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Appendix: Changes to referral and reporting

of carbapenemase-producing Gram-

negative bacteria in England

Rationale for change

Since the Electronic Reporting System (ERS) for enhanced surveillance of

carbapenemase-producing Gram-negative bacteria commenced in May 2015 an

increasing number of local microbiology laboratories have implemented methods for the

detection of carbapenemases.

A survey conducted by Public Health England (PHE) found that nearly half of local

laboratories in England now perform testing that allows them to identify the presence of

some of the most prevalent carbapenemases in England. To accommodate this

advancement in testing methodologies, PHE needs to modify its surveillance approach.

A number of changes are being made to allow more efficient capture of data on

carbapenemase producers identified in England and streamline the referral of isolates

that continue to be submitted to the national reference laboratory.

Summary of changes

The Electronic Reporting System for the enhanced surveillance of carbapenemase-

producing Gram-negative bacteria was decommissioned on 30 April 2019.

Bacteria identified as carbapenemase producers at local laboratories to be reported via

PHE’s Second Generation Surveillance System (SGSS).

Specimens referred to the national reference laboratory for detection or confirmation of

carbapenemase presence should now return to being referred on paper forms and PHE

is working with vendors to develop standardised electronic requesting solutions for

laboratories. Specimens sent to the reference laboratory need to include patient

identifiers (particularly NHS number and date of birth) and specimen identifiers

(specimen type and laboratory number). PHE will then link the reference laboratory

specimens to the SGSS reports in order to allow NHS laboratories to review and

download their own data.

SGSS can be accessed the via the internet at the following location:

https://sgss.phe.org.uk/Security/Login

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As of January 1st 2019 only locally-confirmed carbapenemase producers from sterile

sites (eg blood, CSF, joint fluid) should be sent for inclusion in the national strain

archive.

In addition, the AMRHAI Reference Unit seeks:

All Enterobacterales suspected to produce a carbapenemase (meropenem MIC >0.12

mg/L):

• isolates of Enterobacter spp. that have borderline resistance to ertapenem, but

remain fully susceptible to other carbapenems should not be sent

• isolates of Serratia, Morganella or Proteus spp. that are borderline resistant to

imipenem, but susceptible to other carbapenems should not be sent

All Pseudomonas spp. suspected to produce a carbapenemase. Such isolates should

be resistant to all relevant carbapenems (imipenem, meropenem and doripenem) and

usually ceftazidime; exhibit resistance to ceftolozane/tazobactam; exhibit >4-fold

imipenem/EDTA synergy; susceptibility or resistance to aztreonam is variable because

most carbapenemase-producing pseudomonads have a metallo-carbapenemase

usually of the VIM family:

• isolates of Pseudomonas spp. resistant only to carbapenems and susceptible to

other beta-lactams should not be sent

• isolates of Pseudomonas spp. that are resistant to ertapenem, but susceptible to

other carbapenems should not be sent (ertapenem resistant is inherent in the genus)

All Acinetobacter spp. suspected to produce a metallo-carbapenemase, that is, with

strong imipenem-EDTA synergy:

• isolates of Acinetobacter that are resistant to ertapenem, but susceptible to other

carbapenems should not be sent (ertapenem resistance is inherent in the genus)

Isolates of Stenotrophomonas maltophilia, Aeromonas spp. (that are resistant to the

carbapenems but susceptible to 3rd and 4th generation cephalosporins) and

‘chryseobacteria’ for investigation of carbapenem resistance should not be sent for

confirmation of either carbapenem resistance or carbapenemase production because

metallo-carbapenemase production is an intrinsic characteristic of these bacteria.

Despite all of the above, microbiology laboratories are encouraged to have a high index

of suspicion, at least for Enterobacterales.

Submission of enhanced surveillance data is no longer required on identification of

carbapenemase presence.

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Reporting of locally-confirmed carbapenemase-producing Gram-negative

bacteria

Laboratories using one of the molecular or immunochromatographic methods described

in the main body of this report are requested to record their findings on their Laboratory

Information Management System (LIMS) and make use of ‘dummy’ antibiotic codes to

report results via SGSS.

How to set up SGSS reporting

Guidance on how to set up systems to report results via SGSS is briefly explained here.

For further information and support please contact your local PHE Field Service

Information Manager (see below for contact details).

For each carbapenemase gene you can identify, create a ‘dummy’ antibiotic code in

your LIMS: suggested codes to use are listed in Table 1. Please inform us of alternative

dummy codes being used so that we are able to translate and interpret these in SGSS.

The results (detected or not detected) need to be reported as a single character,

preferably ‘+’ for detected and ‘-‘ for not detected: systems that are only able to store

alphanumeric characters should preferably use ‘P’ for detected and ‘N’ for not detected;

however, if the system only allows ‘R’ and ‘S’ then please use ‘R’ for detected and ‘S’

for not detected.

For specimens that have not undergone culture, report organism as ‘NO ORGANISM

ISOLATED’.

These results may need to be suppressed for your reports; however, the SGSS AMR

feed should be configured to include all test results (including those suppressed for the

purpose of local reporting).

Table 1: Suggested codes and descriptions for reporting local carbapenemase

results

Code Description

IMP Imipenemase

KPC Klebsiella pneumoniae carbapenemase

NDM New Delhi metallo-β-lactamase

OXA48 Oxacillinase 48

VIM Verona integron metallo-β-lactamase

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Referral of suspected carbapenemase producers

Local laboratories that are yet to implement methods for the identification of the ‘big 4’

carbapenemase genes (KPC, OXA-48-like, NDM and VIM) should continue to refer

isolates to the national reference laboratory (or PHE Birmingham laboratory for West

Midland laboratories) until local methods for detection are in place. Isolates that are

negative for the ‘big 4’ on local testing but meet EUCAST criteria for further investigation

should be referred to the national reference laboratory to rule out presence of

uncommon carbapenemases.

Any local laboratory requiring identification or confirmation of carbapenemase presence

should refer isolates in line with the UK Standards for Microbiology Investigations:

Laboratory Detection and Reporting of Bacteria with Carbapenem-Hydrolysing β-

lactamases (Carbapenemases). Referrals should be made using the relevant

‘Healthcare Pathogens: Characterisation and resistance’ form.

PHE Field Service Information Manager or SGSS support contact details

Region Contact details

East of England daniel.west@phe.gov.uk

London donny.webley@phe.gov.uk

North East ian.fawcett@phe.gov.uk

North West richard.dunn@phe.gov.uk

South East john.kirwan@phe.gov.uk

South West koren.jones@phe.gov.uk

West Midlands dean.ironmonger@phe.gov.uk

Yorkshire and the Humber ivan.probert@phe.gov.uk