Standardisation of testing for Carbapenemase Producing Organisms (CPO) in Scotland

Transcription

1 Standardisation of testing for Carbapenemase Producing Organisms (CPO) in Scotland Version June 2017 Revision Date June 2018 Scottish Microbiology and Virology Network (SMVN) SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 1 of 15

2 SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 2 of 15

3 INDEX 1. Background 3 2. UK Standards for Microbiology Investigations (SMI) 4 3. SMI flowchart to summarise methods for screening and detection of carbapenemases 5 4. Cultured isolates of Enterobacteriaceae 6 5 Cultured isolates of non-fermenters 7 6. CPE screening 7 7. Confirmatory tests for carbapenemases 8 8. Controls for carbapenemase tests 9 9. Reporting Reference Laboratory referrals References 11 Appendix 1 Satellite AMR Reference Laboratory Request Form 12 Appendix 2 Satellite AMR Reference Laboratory processing flow diagram 13 SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 3 of 15

4 1. Background 2010 CMO letter on AMR 1 Highlighted that WHO had identified AMR as one of the greatest threats to human health and that multidrug resistant Gram negative bacteria pose the greatest microbiological risk to public health. The emergence of carbapenemase producing Enterobacteriaceae (CPE) was flagged as a concern for the UK 2013 CMO, CNO, CPO letter on AMR 2 Highlighted the spread of CPEs within Europe noting that some countries were moving towards an endemic situation and that numbers in the Scotland / the UK had risen. Stated that each Scottish Health Board should have a CPE action plan in place by December Clinical Microbiology labs were expected to work towards the current Public Health England SMI Mandatory HAI and AMR policy requirements 3 Stated the following: HPS are currently supporting NHS Boards to implement CPE screening. It is the expectation that NHS Boards will inform HPS of confirmed cases as per the current guidance SMVN produced an options papers on rapid screening for CPOs 4 Recommended either a one-step real-time PCR test or a two-step combination of chromagar and real-time PCR HPS Toolkit for CPE screening in acute care 5 States that Testing should be undertaken according to the methods currently recommended by the Scottish Microbiology and Virology Network (SMVN) HIS Evidence note / Advice statement 6 In November 2016 these documents concluded that Based on current evidence of diagnostic accuracy, it is not possible to identify the most effective rectal-swab based screening test to identify patients colonised with CPE SMVN AST Group At the November 2016 meeting, the group endorsed use of the SMI (B60), in particular the flow diagram on page 31 as well as methods of reporting both positives and negatives, 2017 CPE Policy Requirement 7 NHS Boards to implement screening requirements immediately 2017 Letter from J. Reilly, HPS 8 Laboratories to use methods endorsed by SMVN AST Group: PHE SMI B 60, issue no 2.1, NHS Boards to return enhanced surveillance forms to HPS to inform national epidemiology of CPOs. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 4 of 15

5 2. UK Standards for Microbiology Investigations (SMI) The SMVN AST Group has endorsed use of the following SMI: UK Standards for Microbiology Investigations, Detection of bacteria with carbapenem-hydrolysing beta-lactamases (carbapenemases) methodology. Bacteriology B 60 Issue no: 2.1 Issue date w w.gov.uk/government/uploads/system/uploads/attachment_data/file/554654/b_60i2.1.pdf The SMI document is 41 pages in length. The purpose of this SMVN document is to highlight the most salient points of the SMI and recommend standardisation where appropriate. SMVN standardisation requirements are highlighted in pink boxes, as above SMI B60 provides recommendations on screening for / detection of carbapenemases (carbapenem-hydrolysing beta-lactamases) focusing solely on acquired carbapenemases. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 5 of 15

6 3. The SMI has created the following flowchart to summarise methods for screening and detection of carbapenemases (Copied from page 31 of SMI B60) NB: The branch with the dotted lines in this flowchart is optional but useful for diagnostic laboratories that have advanced into using molecular methods. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 6 of 15

7 4. Cultured isolates of Enterobacteriaceae Ideally all clinically significant isolates of Enterobacteriaceae should be tested against a carbapenem as the UK seeks to increase the knowledge of the national distribution of carbapenemase producers. Minimum testing should include: a) Isolates from high-risk patients and settings in accordance with current national guidance 5, when the relevant information has been provided to the laboratory on the request accompanying the sample; and b) Any isolates found grossly resistant to co-amoxiclav (>32 mg/l), if not screened with a carbapenem. This SMI supports the recommendation of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) to use meropenem as the indicator carbapenem as it offers the best compromise between sensitivity and specificity. Although ertapenem has greater sensitivity, it is not recommended because it has poor specificity for carbapenemase producers. Perform carbapenemase confirmatory tests on isolates found resistant or to have reduced susceptibility to the indicator carbapenem (see table below). Identification to genus/species level is highly desirable for the interpretation of resistance patterns. Identify all isolates found resistant to the indicator carbapenem to ensure that reduced susceptibility or resistance to the tested carbapenem is not an intrinsic trait. Consider whether the isolate should be submitted to a reference laboratory. TABLE: Recommended EUCAST screening cut-off values to detect possible CPE 9 Carbapenem MIC (mg/l) Zone diameter (mm) Meropenem a >0.12 <25 b,c Imipenem d >1 <23 Ertapenem e >0.12 <25 a b c d e Meropenem offers the best compromise between sensitivity and specificity in terms of detecting carbapenemase producers In some cases zone diameters for OXA-48-producers are up to 26mm, so <27mm may be used as a screening cut-off in countries where OXA-48 is endemic, but at the expense of lower specificity CPE with OXA-48-like enzymes are encountered sufficiently often by UK laboratories to warrant use of the <27mm criterion for meropenem Imipenem is not recommended for use as a stand-alone screening test compound because it is relatively poor at separating wild-type organisms and carbapenemase producers. Ertapenem shows high sensitivity but low specificity in terms of detecting carbapenemase producers, and so is not recommended for routine use. However, ertapenem can be used for detection in specific incidents such as in investigating of an outbreak known to have been caused by an organism that is ertapenem resistant but appears to be susceptible to meropenem on screening test method used, or where increased sensitivity is required. Another drawback with the SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 7 of 15

8 use of ertapenem is the cost implications (if the screening test is too sensitive, it will result in the excess testing of non-carbapenemase producing isolates. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 8 of 15

9 5. Cultured isolates of non-fermenters Acquired carbapenemases are also encountered in Acinetobacter species, Pseudomonas species (most commonly P. aeruginosa) and in other non-fermenters. The SMI recommends testing meropenem, imipenem or doripenem against all clinicallysignificant isolates. Ertapenem should not be tested as these species are intrinsically resistant to this carbapenem. Identification to genus / species level is highly desirable for the interpretation of resistance patterns. Identify at least to genus level all isolates found resistant to any of the indicator carbapenems, to ensure that reduced susceptibility or resistance is not an intrinsic trait. Identify to species level if the genus is not known to produce intrinsic carbapene mases. 6. CPE Screening There is no gold standard method for detection of CPE in stool samples and rectal swabs. The SMI provides details on the range of culture media available. In light of the limited available evidence the SMI recommends using commercial selective chromogenic agar. A combination of two chromogenic agars may be needed to offer maximum sensitivity. For reasons of costs, if an alternative method is chosen locally, for example, MacConkey or CLED agar with a carbapenem disc, it should have been validated locally and the medium and interpretative criteria applied should have demonstrated performance at least equivalent to plating on to a commercially-prepared agar specifically recommended for this purpose. It is essential that suspect colonies are then subjected to confirmatory tests described. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 9 of 15

10 7. Confirmatory tests for carbapenemases Laboratories should carry out confirmatory tests if: The MICs / zone diameters for indicator carbapenems indicates non-susceptibility. Colonies of an appropriate colour are obtained on any commercially-available agar for detecting carbapenem-resistant bacteria. Automated systems flag non-susceptibility to any carbapenem, irrespective of the expert interpretation given (unless it s explained by intrinsic resistance). In-house or commercial phenotypic or molecular tests yield a positive. Isolates resistant to co-amoxiclav if testing against carbapenems has not been performed. Enterobacteriaceae isolates resistant to the indicator carbapenem by clinical breakpoint or positive by the EUCAST screening criteria should be subjected to confirmatory tests There is an increasing need for molecular methods to detect and identify any carbapenemase present. Synergy tests are most effective for members of the Enterobacteriaceae but give a high proportion of false-positive results for non-fermenters. Synergy testing may be carried out using in-house or commercially-available methods (including combination disc tests, gradient tests or automated systems) and is defined by a significant (>5mm) expansion of the carbapenem zone size or significant ( 8-fold) reduction in carbapenem MIC in the presence of an inhibitor. The SMI details classic synergy phenotypic patterns, but notes that Gram negative clinical isolates are becoming more complex and co-resident mechanisms lead to exceptions. The Modified Hodge Test is not recommend. Acidometric tests may be used. They work well for well for both Enterobacteriaceae and Pseudomonas species and commercial versions of the tests are available. The acidometric test has been validated with bacterial colonies grown on Mueller -Hinton agar plates, blood agar plates, trypticase soy agar plates, and most selective media used in screening for carbapenemase producers. However, this test cannot be performed with bacterial colonies grown on Drigalski or MacConkey agar plates. MALDI-ToF is being increasingly used to detect carbapenemase production but is not yet commercially available. Molecular tests (both in-house and commercial) vary in their scope. Many are suitable for screening for colonisation and for confirmation of carbapenemases in bacterial colonies. Advantages of using molecular testing include greater speed of detection and higher sensitivity than culture. Some commercial tests gave a yes/no result and others identify the specific carbapenemase type. They cannot identify rare / new carbapenemases. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 10 of 15

11 8. Controls for carbapenemase tests The SMI states that standard EUCAST (or BSAC or CLSI) recommendations should be followed. Full details may be found in the SMI. 9. Reporting The SMVN requires all laboratories to standardise reporting as per the SMI and as follows: SCREENING SAMPLES FOR CULTURE Negatives Carbapenem-resistant organism not isolated Positives Carbapenem-resistant organism isolated. It may produce a carbapenemase; further investigations are being undertaken Positives conformed by Reference Laboratory Carbapenem resistant organism isolated. Carbapenemase production confirmed Interim / preliminary results should be issued on detection of potentially clinically significant isolates as soon as growth is detected, unless specific alternative arrangements have been made with the requestors. Urgent results should be telephoned or transmitted electronically in accordance with local policies. Final written or computer generated reports should follow preliminary and verbal reports as soon as possible. Antimicrobial susceptibility testing Report susceptibilities as clinically indicated. Prudent use of antimicrobials according to local and national protocols is recommended. Recently, EUCAST and CLSI have taken the view that, with the low breakpoints now adopted by both organisations, carbapenem susceptibility results can be taken at face value, and that carbapenems can be used as therapy so long as carbapenemase producers appear susceptible in vitro. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 11 of 15

12 10. Reference Laboratory referrals A. All organisms suspected or newly confirmed to produce a carbapenemase must be referred to the Satellite AMR Reference Laboratory, Glasgow (operational from 3 July 2017) B. Referring laboratories MUST comply with the criteria and requirements stipulated in the referral form (please see appendix) to ensure appropriate processing of referred isolates. When referring isolates please consider the following: i. Do NOT send isolates of Enterobacter that have borderline resistance to ertapenem, but remain fully susceptible to other carbapenems. ii. iii. iv. Do NOT send isolates of Serratia, Morganella or Proteus spp. that are borderline resistant to imipenem, but susceptible to other carbapenems. Do send all Pseudomonas spp. suspected to produce a carbapenemase, i.e. isolates resistant to carbapenems, ceftazidime, ceftolozane / tazobactam and piperacillin-tazobactam. Do NOT send isolates of Pseudomonas spp. resistant only to carbapenems with good susceptibility to other β-lactams. Do NOT send isolates of Pseudomonas spp. that are resistant to ertapenem, but susceptible to other carbapenems. Ertapenem resistance is inherent in the genus. v. DO send Acinetobacter spp. suspected to produce a metallo-carbapenemase, i.e. with an MIC above the EUCAST clinical breakpoint (ie MIC >8mg/l for meropenem.) vi. vii. Do NOT send isolates of Acinetobacter that are resistant to ertapenem, but susceptible to other carbapenems. Ertapenem resistance is inherent in the genus. Despite all of the above, microbiology laboratories are encouraged to have a high index of suspicion, and it is accepted that the Satellite AMR Reference Laboratory will not find a carbapenemase in all referred carbapenem-resistant isolates. There is no penalty charge when the Satellite AMR Reference Laboratorywe doesn t detect a carbapenemase (unless isolates turn out to be fully susceptible or of a wild type). viii. Do NOT send isolates of Stenotrophomonas maltophilia, Aeromonas spp., Myroides spp., Elizabethkingia meningoseptica and chryseobacteria for investigation of carbapenem resistance (though note final criterion below), because metallo-carbapenemase production is an intrinsic characteristic of these bacteria. ix. In addition, the Satellite AMR Reference Laboratory seeks representatives of any carbapenem-resistant strains (irrespective of suspected mechanism, and including species with intrinsic carbapenem resistance) that are associated with clusters or outbreaks of infection or colonization. Please see appendices 1 & 2 for Satellite AMR Reference Laboratory request form and processing flow diagram. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 12 of 15

13 11. References 1. SGHD / CMO (2010) 24 Antimicrobial Resistance 2. CMO / SGHD (2013) 14 Antimicrobial Resistance 3. DL (2015) 19 Healthcare Associated Infection (HAI) and Antimicrobial Resistance (AMR) Policy Requirements 4. SMVN 5 November 2015 Rapid screening for Carbapenemase Producing Organisms (CPO): Commercial diagnostic methods: an options paper , 31 May Health Protection Scotland Toolkit for the early detection, management and control of carbapenemaseproducing Enterobacteriaceae in Scottish acute settings. v , 2 December Healthcare Improvement Scotland Evidence note 62 Advice Statement 005/16 What is the published evidence on the accuracy, turnaround time and cost/cost effectiveness of tests to identify carbapenemase-producing Enterobacteriaceae (CPE) in hospital screening samples obtained from patients identified as at risk of CPE colonisation during clinical risk assessment? 7. DL (2017) 2 Carbapenemase-producing Enterobacteriaceae (CPE) Policy Requirement 8. J. Reilly (HPS), Letter dated 20 March 2017 to ICMs, ICDs, ICNs, HAI Executive Leads Prevention of CPE infections and containing AMR , December. European Committee on Antimicrobial Susceptibility Testing (EUCAST) The EUCAST guideline on detection of resistance mechanisms v 1.0 SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 13 of 15

14 APPENDIX 1 Satellite AMR Reference Laboratory Request Form Scottish Microbiology Reference Laboratories, Glasgow Carbapenemase Confirmation Please note that a hard copy of this form should accompany all samples submitted for analysis. CONTACT INFORMATION Sending Laboratory Address Sample Information Specimen type (Organism isolated from): Sender s Reference Number: Organism identified: Meropenem e-test result: Patient Details Name Address Please send samples to: SMiRL, Glasgow, Level 5 New Lister Building, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, G31 2ER Telephone: Date of Birth Chi Number Hospital Name and Ward Age Sex Date Sample Taken Other relevant details: Please attach Vitek (or other Method), sensitivities and MIC results to this request form before submission Reference Lab Use Only: Carbapenemase Negative for Genes Tested This isolate has been sent to PHE Colindale for confirmation Carbapenemase Positive KPC NDM VIM OXA-48 IMP Tick as Appropriat e Interpretation SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 14 of 15

15 Appendix 2 Satellite AMR Reference Laboratory, Glasgow. Processing flow diagram Presumptive Carbapenemase Positive As per AMR referral criteria / SMVN guidelines Submit Agar Slope & AMR Request Form * PCR against Big 5 Carbapenemase Genes (KPC, NDM, VIM, OXA-48, IMP) Negative Report Electronically (Generic - Interim) Positive Report Electronically (Generic - Final) mcim Modified Carbapenemase Inhibition Test Negative Positive mcim Positive Evidence of carbapenemase activity detected using the in-house carbapenem inactivation method (CIM) [Pierce et al. JCM ]. Forward to AMRHAI mcim Negative (CPE) We found no evidence of carbapenemase activity using the inhouse carbapenem inactivation method (CIM) [Pierce et al. JCM ]. This is a final report on this isolate. mcim Negative (Non-CPE) No evidence of carbapenemase activity using the in-house carbapenem inactivation method (CIM) [Pierce et al. JCM ]. How ever, in non-cpe organisms this may not reliably exclude such activity. Forward to AMRHAI * Isolates received by 12:00 noon will be reported by 17:00. N.B. Request form requires ID and sensitivity information. Failure to complete the request form may result in delays in processing this isolate. SMVN Standardisation of testing for CPO in Scotland, v1.0 Page 15 of 15