The Role and Achievements of Antimicrobial Susceptibility Testing In

EUCAST Library The European Committee on Antimicrobial Susceptibility Testing September 2010 Lecture author OnlineGunnarby Kahlmeter Chairman© of EUCAST

ESCMID Terms and acronyms Library • AST – Antimicrobial Susceptibility Testing • MIC – Minimum Inhibitory Concentration

• EU – European Union Lecture • EUCAST – European Committee on Antimicrobial Susceptibility Testing • ESCMID – The European Society of Clinicalauthor Microbiology and Infectious Diseases Onlineby • ECDC – The European Centre for Disease prevention and Control • EMA (EMEA) – The European© Medicines Agency • CLSI – Clinical Laboratory Standards Institute (USA) (formerly NCCLS) • SPC – Summary of Product Characteristics ESCMID Library Formed in 1996 and reorganised in 2001

Financed by ESCMID,Lecture EU and ECDC and National Breakpoint Committees (BSAC, CA-SFM, CRG, DIN,author NWGA, SRGA). Onlineby All European ©countries represented.

ESCMID Breakpoint committees 2001 for determining clinical MIC breakpoints Library Committee Country Disk test?

BSAC United Kingdom Yes CA-SFM France Lecture Yes CLSI USA author Yes CRG TheOnline Netherlandsby No DIN Germany© Yes NWGA Norway No SRGA Sweden Yes ESCMID Breakpoint committees 2010 for determining clinical MIC breakpoints Library Committee Country Disk test? EUCAST* Europe Yes Lecture CLSI USA Yes author *For national breakpoint committees BSAC, CA-SFM, CRG, DIN, NWGA & SRGA Onlineby ©

ESCMID Library

National Breakpoint Committees D, F, N, NL, S, UK, Lecture

EUCAST General Committee All European Countries + ISC/FESCIauthor

EUCAST SteeringOnline Committeeby BSAC, CA-SFM, CRG, DIN, NWGA, SRGA And 2 reps from the General© Committee*

Subcommittees Antifungals Expert groups Anaerobes ESCMIDExpert Rules *Currently: Estonia and Austria Library

Wild type Clinical resistance Lecture Clinical resistance Clinical resistance author Clinical resistance OnlinePhenotypicallyby detectable resistance © Genetically detectable resistance

Susceptible Resistant ESCMID Breakpoints may fail in several ways!

• Fail to predict failure (undercall Libraryresistance) – CLSI piperacillintazobactam breakpoints in Pseudomonas

• Fail to predict success Lecture(overcall resistance) – Penicillin breakpoints in S.pneumoniae in pneumonia author • Generally fail toOnline be usefulby (lack of correlation with either success© or failure) – Erythromycin breakpoints in H.influenzae (dividing a WT population in three SIR-categories) ESCMID Breakpoints that failed to predict failures! Classical cases. Library • Carbapenem breakpoints in MRSA (70ies) • Chloramphenicol breakpoints in H.influenzae (70ies) • Cephalosporin breakpoints (CLSI) in Enterobacteriaceae • Erythromycin breakpoints in S.pneumoniaeLecture • Piperacillintazobactam breakpoints in Pseudomonas • Vancomycin breakpoints in S.aureusauthor • Fluoroquinolone breakpointsOnlineby in critical (Salmonella) infections • …….. ©

With few exceptions, all revisions of breakpoints have brought breakpointsESCMID down! Tools for determining CLINICAL BREAKPOINTS

1. Dose or doses Library 2. Target organisms 3. Individual MIC-distributions for target organisms - breakpoints must not divide MIC-distributions of WT target organisms - ECOFFs determined for each Lecturespecies 4. Resistance mechanisms in target organisms 5. Clinical indications author 6. PharmacokineticsOnline (Cmax, AUC,by T½, Protein binding, Vd..) 7. Pharmacodynamic properties© (peak conc/MIC, AUC/MIC, TA, MCs) 8. Clinical outcome (clinical outcome/MIC) 9. Epidemiological cutoffs, Pk/Pd-breakpoints and clinical data togetherESCMID determine the CLINICAL BREAKPOINT Setting breakpoints • For existing drugs Library – harmonisation of Euopean brekpoints (finalised) – review of existing breakpoints • Altered indications Lecture • Change in target organisms • New resistance mechanismsauthor • New drug in class • New clinicalOnline experienceby • Change in dosing© or administration

• For new drugs (with EMA) ESCMID EUCAST and existing antimicrobials • Aminoglycosides √ • Carbapenems & aztreonam √ Library • Cephalosporins iv √ • Cephalosporins oral √ • Fluoroquinolones √ Lecture • Glycopetides √ • Macrolides and lincosamides √ author • Penicillins √ Onlineby • Tetracyclines √ © • Miscellaneous antimicrobials √

• Antifungal drugs (flu- and voriconzole) √ ESCMID Setting breakpoints • For existing drugs Library – harmonisation of Euopean brekpoints (finalised) – review of existing breakpoints • Altered indications Lecture • Change in target organisms • New resistance mechanismsauthor • New drug in class • New clinicalOnline experienceby • Change in dosing© or administration

• For new drugs (with EMA) ESCMID Review of breakpoints 2009 - 2010 Library EUCAST CLSI Change +/No change - Change/No change Cephalosporins +Lecture + Aztreonam + NE* Carbapenems - author + Vanco/Teico Onlineby+/+ +/NE* Colistin (Pseud) 2© to 4 mg/L NE*

*NotESCMID Evaluated Setting breakpoints • For existing drugs Library – harmonisation of Euopean brekpoints (finalised) – review of existing breakpoints • Altered indications Lecture • Change in target organisms • New resistance mechanismsauthor • New drug in class • New clinicalOnline experienceby • Change in dosing© or administration

• For new drugs (with EMA) ESCMID EUCAST - breakpoints for new drugs with EMA* • Daptomycin √ Library • Tigecycline √ • Doripenem √ • Glycopeptides (ongoing) Lecture • Cefalosporin (withdrawn) author • Fluoroquinolone (withdrawn) • Onlineby Diaminopyrimidine (withdrawn)© • Extensions of indications (currently none) ESCMID *EMA = European Medicines Agency Topicals and less commonly used drugs

Library 1. Mupirocin (Topical) √ 11.Cefoperazone 2. Polymyxin B (Topical) 12.Pefloxacin 3. Bacitracin (Topical) 13.Cefradine 4. Streptomycin (hlr for Lecture14.Cefamandole enterococci) 15.Sulfisoxazole 5. Neomycin (Topical) author16.Pipemidic acid 6. Sulfamethoxazole (UTI) 17.Kanamycin 7. Cephalothin (expertOnline rules?)by 18.Ceftizoxime 8. Sulfadiazine © 19.Cefprozil 9. Spiramycin 10.Nalidixic acid (screening) ESCMID + 45 others Microorganisms to be evaluated for breakpoints

Define relevant drugs, breakpoints, methodology and MIC-distributions. Library • Helicobacter spp √ • Campylobacter spp √ • Clostridium difficileLecture √ • Legionella spp • Pasteurella multocidaauthor • ListeriaOnline monocytogenesby • Burkholderia© cepacia • Corynebacterium spp • … ESCMID EUCAST web-pages Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID EUCAST Rationale Documents Library • Summarize available data on the drug at the time the breakpoint was determined or revised Lecture • Available on EUCAST website author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

Lecture author Onlineby ©

ESCMID Library

ESCMID EUCAST expert rules v1.0 → v2.0 (2010)Library • Intrinsic resistance Lecture • Exceptional phenotypes – Exceptional resistance author – Exceptional susceptibilityOnlineby © • Interpretive reading – IF - THEN ESCMID EUCAST and CLSI are different EUCAST CLSI Library

• Profession together with regulatory • Industry, the profession authorities • Funded by ESCMID, ECDC and Lecture• Funded by industry and sales of national breakpoint committees. output. • Industry consultative role. • Industry part of decision process • Decision by consensus. •authorDecision by vote. • Five meetings per year. Onlineby • Two meetings per year. • EUCAST=EMEA brpt committee.© • CLSI technical standing with FDA. • Clinical breakpoints and ECOFFs • Clinical breakpoints • Rationale for decisions published • Rationale for decisions not published. • Documents in public domain and • Documents for sale free ofESCMID charge Library

Web-links to MIC-distributions Web-links to Zone diameter distributions ESCMIDWeb-links to EUCAST Rationale Documents EUCAST disk diffusion Library

ESCMID NAC Remit: Library • A NAC is a committee which deals with questions related to antimicrobial susceptibility testing at a national level. Membership: – representatives of clinical microbiological diagnostic services – national experts on susceptibilityLecture testing of bacteria (and fungi) – representatives of reference clinical microbiology laboratories, – government author – professional organisations/societies,Onlineby – Represntatives of other antibiotic© committees Structure – Chairperson, scientific secretary, educational officer and representatives of laboratories, societies, reference laboratories (5 – 6 reps) FundingESCMID– national level NAC

• Tasks and objectives Library – Strategy for AST on national level – Implementation of breakpoints and methods – Quality assurance on a national level – Education of laboratory staff and Lectureclinical colleagues – Liaison and consultation with EUCAST (GC rep) – Liaison with groups involved in AMR-authorsurveillance (ECDC, EARSS, ….). – …. Onlineby • Antimicrobial Policies© • Antimicrobial Resistance Surveillance • Antimicrobial Consumption and Policies ESCMID EUCAST breakpoints and NACs EUCAST/NABC: NAC 2010/11: LibraryDiscussion:

France Austria Croatia Germany Belgium Greece Norway Denmark Lecture Israel Sweden Estonia Poland The Netherlands Finland Russia The UK Hungary author Turkey OnlineIreland by Italy © Lithuania Spain Latvia Switzerland ESCMID Portugal, Poland, Czeck republic, Slovakia,, Slovenia, Serbia, Rumania Library Thank you!