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1 EUCAST and susceptibility testing Europe and beyond Gunnar Kahlmeter EUCAST, ESCMID

2 Antimicrobial susceptibility testing To guide therapy and predict clinical outcome in individual patients (clinical breakpoints) To obtain a basis for empirical therapy (clinical breakpoints) To screen for organisms with exceptional resistance (ECOFFs) for intervention in health care and community MRSA, VRE, ESBL, KPC, NDM, MDRTB etc To determine the rate of resistance development (ECOFF and clinical breakpoints) To understand and predict resistance development To form strategies to counteract resistance development Measure success and failure of strategies

3 Methods for susceptibility testing Phenotypic test methods based on antimicrobial activity (MIC) and breakpoints MIC, disk diffusion, automated systems like Phoenix, Vitek2, Microscan Predict susceptibility and resistance Quantifiable Genotypic test methods based on the detection of a resistance gene or its product (PCR, WGS) meca, vana, vanb,.pbp2, betalactamase detection (enzyme detection, Maldi Tof) Predict resistance, not sensitivity Not quantifiable Useful for epidemiological purposes. By deduction expert rules If MRSA then report all betalactam antibiotics R or soon not? If ESBL-positive, then report betalactam antibiotics R but not any longer! If erythromycin-resistant, then report all macrolide antibiotics as R; Some rules predict susceptibility, others resistance. Not quantifiable. Unreliable!

4 Phenotypic susceptibility testing is based on

5 MIC MIC MIC MIC

6 MIC MIC is a relative measure, influenced by inoculum, ph, cations, incubation time, temperature, and more - which can be standardised to the extent where we start believing it is absolute!

7 Methods for MIC determination Broth dilution MIC is 0.5 mg/l Broth microdilution (BMD) C

8 Disk diffusion Surrogate MIC determination Agar dilution Gradient MIC test Several manufacturers: biomerieux (Etest) Oxoid (M.I.C.E.) Liofilchem (MIC-strip)

9 Breakpoints Accepting that the basis for phenotypic AST is the MIC (and surrogate quantitative measurements) and that the ambition is to report not only the MIC but also an interpretation (recommendation), phenotypic tests require breakpoints.

10 Clinical breakpoints

11 Susceptibility Testing Categorisation Epidemiological cutoff values (ECOFF) WT X mg/l NWT>Y mg/l WT X mm NWT<Y mm Clinical breakpoints (EUCAST): S X mg/l R>Ymg/L (CLSI R> ) S X mm R<Y mm (CLSI < )

12 Clinical breakpoints - MIC-concentrations defined to distinguish treatable from non-treatable organisms by rendering organisms Susceptible (S X mg/l), Intermediate (I) or Resistant (R >Y mg/l) ECOFF

13 Susceptibility Testing Categorisation Epidemiological cutoff values (ECOFF) WT X mg/l NWT>Y mg/l WT X mm NWT<Y mm Clinical breakpoints (EUCAST): S X mg/l R>Ymg/L (CLSI R> ) S X mm R<Y mm (CLSI < )

14 Clinical breakpoints - MIC-concentrations defined to distinguish treatable from non-treatable organisms by rendering organisms Susceptible (S X mg/l), Intermediate (I) or Resistant (R >Y mg/l)

15 In the beginning there was one table for everything One MIC breakpoint and one zone diameter breakpoint to fit all

16 CLSI S1 (First Supplement, 1981) NCCLS First Supplement, useful for anything that would grow

17 Tools for determining clinical breakpoints Dose and mode of administration Clinical targets Target organisms MIC distributions of target organisms Resistance mechanisms of clinical importance in target organisms Pharmacokinetics of agent in target patients Pharmacodynamics of agent in relation to target organism Clinical outcome data for target infections

18 Breakpoints are determined by: 1. Medicines agencies (EMA, FDA) 2. Breakpoint committees Pharmaceutical companies AST companies Colleagues who know better

19 1. Breakpoints by Medicines agencies (as part of the process for the approval of new drugs) Evaluation is based of the claims of the company Evaluation performed by different experts/rapporteurs for different agents. Agents within a group are dealt with individually and in sequence with years in between. No corporate memory. No systematic review process.

20 2. Breakpoints by Breakpoint committees Committee members with many competences - in EUCAST there are 60 experts in national groups + many external expert committees. When a new agent is evaluated, existing related agents are reviewed as part of the process. Consistency over time corporate memory. Breakpoint committees can decide to review, and when relevant, revise breakpoints independantly of pharmaceutical companies or agencies.

21 Breakpoint committees Committee Country Disk diffusion BSAC United Kingdom Yes CA-SFM France Yes CRG The Netherlands No DIN Germany Yes NWGA Norway No SRGA Sweden Yes NCCLS (CLSI) USA Yes

22 Enterobacteriaceae Committee Amoxicillin Cefotaxime Piperacillin-tazob. BSAC (UK) 8 / 16 2 / 2 16 / 16 CA-SFM (F) 4 / 16 4 / 32 8 / 64 CRG (NL) 2 / 16 4 / / 4 DIN (D) 2 / 8 2 / / 1 NCCLS (USA) 8 / 16 8 / / 64 NWGA (N) 0.5 / 8 1 / 2 8 / 16 SRGA (S) 1 / / 1 16 / 16 All of us managed to come up with different breakpoints.

23 The breakpoint committees did not agree not because we disagreed but we were out of sync and did not communicate with each other and we all knew best

24 EUCAST General Committee All European Countries + Australia + USA EUCAST Steering Committee BSAC, CA-SFM, CRG, DIN NWGA, SRGA And 2 reps from the General Committee* Subcommittees Antifungals Anaerobes Expert Rules Detection of resistance mechanisms National Breakpoint Committees D, F, N, NL, S, UK Expert groups

25 We decided to find another role model. NCCLS/CLSI in session

26 a steering committee with reps from national breakpoint committees was formed

27 To determine clinical breakpoints for existing and new agents for bacteria and fungi together with EMA and National breakpoint committees. To determine epidemiological cut-off values (ECOFFs) for bacteria and fungi To develop and standardise AST in Europe (methods, QC, education) To act as an expert committee for EMA, ECDC, EFSA and ESCMID. To act as an umbrella organisation for national breakpoint committees

28 EUCAST Subcommittees Antifungal susceptibility testing (Current chair Maiken Arendrup) Candida species, Aspergillus species Amfotericin, conazoles, fungins Methods for MIC-testing of Candidae and Aspergillus Anaerobe susceptibility testing Expert rules and intrinsic resistance The detection of resistance mechanisms of clinical and/or public health importance Antimycobacterial susceptibility testing (AMST) (in collaboration with ESGMYC)

29 Decision process Steering Committee evaluates available data and propose breakpoints (2 3 meetings) Consultation with national breakpoint committees on proposed breakpoints (Revision of proposal) Open consultation via EUCAST webpage (Revision of proposal and further consultation) Final decision and rationale document (4 5 meetings = 1 year)

30 Breakpoints in EUCAST Existing agents - harmonization of European breakpoints ( ) for antibiotics commonly used and available in most countries: Penicillins, cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, tetracyclines, glycopeptides, macrolides etc New agents - together with EMA ( ) Daptomycin Tigecycline Doripenem Telavancin Ceftaroline Ceftobiprole Bedaquiline, Delaminid New glycopeptides, cefalosporineinhibitor agents, and more Review of established breakpoints ( ): Glycopeptides, Carbapenems, Colistin, Doripenem

31 Why regular review of breakpoints? New resistance mechanisms New agent in class New clinical data Extended indications Change in dosing or administration Change in target organisms

32 EUCAST General website EUCAST Websites free access Both available at The EUCAST MIC and zone diameter distribution website

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34 The rationale for breakpoint decisions is published

35 EUCAST encourages countries to form a National AST Committee (NAC). NAC A document describing a prototype NAC is available on website.

36 NAC Antimicrobial susceptibility testing Coherent strategy at national level Implementation of breakpoints and methods Education (national workshops, websites) Translation of documents Liaison and consultation with EUCAST via the General Committee and open consultations Liaison with other national groups involved in antimicrobial stewardship or surveillance of resistance. QA (Antimicrobial Policies) (Antimicrobial Resistance Surveillance) (Antimicrobial Consumption and Stewardship)

37 Yes Portugal Ireland Spain National AST Committees (NACs), August 2014 In the process of forming a NAC No No information Great Britain France Netherlands Belgium Luxembourg Norway Denmark Germany Switzerland Sweden Czech Republic Poland Finland Estonia Latvia Lithuania Slovakia Greece Belarus Moldova Austria Hungary Romania Slovenia Croatia Bosnia- Serbia Herzegovina Monte- Bulgaria Italy negro Macedonia Albania Ukraine Turkey Russia Malta Countries not on this map: Australia Iceland Israel South Africa USA Brazil Morocco

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39 Percent participants Trends in antimicrobial susceptibility testing guidelines in EARS-Net EUCAST CLSI

40 % Laboratories >50% 10-50% <10% No information Implementation of EUCAST breakpoints, August 2014 Ireland Great Britain France Netherlands Belgium Luxembourg Norway Denmark Switzerland Germany Sweden Czech Republic Austria Slovenia Poland Hungary Finland Estonia Latvia Lithuania Slovakia Greece Belarus Romania Moldova Croatia Serbia Bosnia- Herze- Monte- Bulgaria govina Portugal Italy negro Macedonia Spain Albania Ukraine Turkey Russia Malta Countries not on this map: Australia Iceland Israel South Africa USA Brazil Morocco

41 Adoption of the EUCAST disk diffusion method, August 2014 % Laboratories >50% 10-50% <10% No information Ireland Great Britain France Netherlands Norway Denmark Germany Belgium Luxembourg Switzerland Sweden Czech Republic Austria Slovenia Poland Hungary Finland Estonia Latvia Lithuania Slovakia Belarus Romania Moldova Croatia Serbia Bosnia- Herze- Monte- Bulgaria govina Portugal Italy negro Macedonia Spain Albania Greece Ukraine Turkey Russia Malta Countries not on this map: Australia Iceland Israel South Africa USA Brazil Morocco

42 EUCAST in summary Tasked to determine clinical breakpoints and ECOFFs and to standardise methodology in Europe. External expert committee with regulatory agreements (ECDC, EMA and EFSA) Steering committee and a General Committee with European and across-oceans representation. Financed by ESCMID and ECDC. 5 two-day meetings per year. Decisions taken by Steering Committee following open consultation. No membership fees, No charge for documents, Openly and freely available on internet. Results of consultation published. Rationale for decisions published.

43 Are we in need of even more standardisation/harmonisation? Medicine and health care is international patients move across borders. Comparable resistance data (surveillance) resistance moves across borders. Comparable evaluation of efficacy. Simplify and make procedure less costly (determining breakpoints, AST manufacturing, package inserts, education, etc) Less confusion.

44 Organisms Needs for Breakpoint Harmonization (Summary of agreement between CLSI and EUCAST breakpoint criteria for 2013) No. assessed Same breakpoints Overall Compoun ds Criteria Susceptible Resistant agreement (%) Enterobacteriaceae % P. aeruginosa % Acinetobacter spp % Staphylococci % Enterococci % S. pneumoniae % All results % 70 % disagreement between EUCAST and CLSI Ron Jones, IDSA 2013

45 Breakpoint Harmonization Needs in USA (Summary of agreement between CLSI and USA-FDA PI criteria for 2013) Fluoroquinolone a 82 breakpoints across 13 organism groups and six drugs Agreement 33.3% (moxifloxacin) to 100.0% (NA) by drug 54.3% for Gram-positive cocci 61.7% for Gram-negative pathogens 40 % disagreement between CLSI and FDA a. Most commonly used agents (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ofloxacin and nalidixic acid [NA]). Ron Jones, IDSA 2013

46 International standardisation? 1. Clinical breakpoints 2. MIC distributions and ECOFFs 3. Methodology

47 1. Clinical breakpoints - international standardisation If as a concerted action who takes the initiative? WHO, UN, ISO? EUCAST or CLSI? Financing? Business model? If by evolution and survival of the fittest is it then EUCAST or CLSI when judged on Science/credibility? Decision model? Influence/transparence? Availability to the international community?

48 2. Wild type MIC distributions and ECOFFs international standardisation MIC- (and zone diameter) distribution database is based on large quantities of MIC (and zone) data > MIC distributions isolates per distribution Data from all parts of the world Standardisation and inclusion criteria for how to define distribution and ECOFF under development The EUCAST database is being transformed to the International MIC- and Zone diameter distribution database and ECOFFs.

49 3. Methodology - international standardisation ISO-standard MIC broth microdilution ISO ; EUCAST and CLSI recommendations for disk diffusion are now almost identical. + Medium (MH), Inoculum, incubation MH-F, a few disk potencies

50 Conclusion We are well on our way to international standardisation. Thank you