EUCAST The European Committee on Antimicrobial Susceptibility Testing September 2010 Gunnar Kahlmeter Chairman of EUCAST
Terms and acronyms AST Antimicrobial Susceptibility Testing MIC Minimum Inhibitory Concentration EU European Union EUCAST European Committee on Antimicrobial Susceptibility Testing ESCMID The European Society of Clinical Microbiology and Infectious Diseases 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
Formed in 1996 and reorganised in 2001 Financed by ESCMID, EU and ECDC and National Breakpoint Committees (BSAC, CA-SFM, CRG, DIN, NWGA, SRGA). All European countries represented.
Breakpoint committees 2001 for determining clinical MIC breakpoints Committee Country Disk test? BSAC United Kingdom Yes CA-SFM France Yes CLSI USA Yes CRG The Netherlands No DIN Germany Yes NWGA Norway No SRGA Sweden Yes
Breakpoint committees 2010 for determining clinical MIC breakpoints Committee Country Disk test? EUCAST* Europe Yes CLSI USA Yes *For national breakpoint committees BSAC, CA-SFM, CRG, DIN, NWGA & SRGA
EUCAST General Committee All European Countries + ISC/FESCI EUCAST Steering Committee BSAC, CA-SFM, CRG, DIN, NWGA, SRGA And 2 reps from the General Committee* Subcommittees Antifungals Anaerobes Expert Rules *Currently: Estonia and Austria National Breakpoint Committees D, F, N, NL, S, UK, Expert groups
Wild type Clinical resistance Clinical resistance Clinical resistance Clinical resistance Susceptible Phenotypically detectable resistance Genetically detectable resistance Resistant
Breakpoints may fail in several ways! Fail to predict failure (undercall resistance) CLSI piperacillintazobactam breakpoints in Pseudomonas Fail to predict success (overcall resistance) Penicillin breakpoints in S.pneumoniae in pneumonia Generally fail to be useful (lack of correlation with either success or failure) Erythromycin breakpoints in H.influenzae (dividing a WT population in three SIR-categories)
Breakpoints that failed to predict failures! Classical cases. Carbapenem breakpoints in MRSA (70ies) Chloramphenicol breakpoints in H.influenzae (70ies) Cephalosporin breakpoints (CLSI) in Enterobacteriaceae Erythromycin breakpoints in S.pneumoniae Piperacillintazobactam breakpoints in Pseudomonas Vancomycin breakpoints in S.aureus Fluoroquinolone breakpoints in critical (Salmonella) infections.. With few exceptions, all revisions of breakpoints have brought breakpoints down!
Tools for determining CLINICAL BREAKPOINTS 1. Dose or doses 2. Target organisms 3. Individual MIC-distributions for target organisms - breakpoints must not divide MIC-distributions of WT target organisms - ECOFFs determined for each species 4. Resistance mechanisms in target organisms 5. Clinical indications 6. Pharmacokinetics (Cmax, AUC, 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 together determine the CLINICAL BREAKPOINT
Setting breakpoints For existing drugs harmonisation of Euopean brekpoints (finalised) review of existing breakpoints Altered indications Change in target organisms New resistance mechanisms New drug in class New clinical experience Change in dosing or administration For new drugs (with EMA)
EUCAST and existing antimicrobials Aminoglycosides Carbapenems & aztreonam Cephalosporins iv Cephalosporins oral Fluoroquinolones Glycopetides Macrolides and lincosamides Penicillins Tetracyclines Miscellaneous antimicrobials Antifungal drugs (flu- and voriconzole)
Setting breakpoints For existing drugs harmonisation of Euopean brekpoints (finalised) review of existing breakpoints Altered indications Change in target organisms New resistance mechanisms New drug in class New clinical experience Change in dosing or administration For new drugs (with EMA)
Review of breakpoints 2009-2010 EUCAST Change +/No change - CLSI Change/No change Cephalosporins + + Aztreonam + NE* Carbapenems - + Vanco/Teico +/+ +/NE* Colistin (Pseud) 2 to 4 mg/l NE* * Not Evaluated
Setting breakpoints For existing drugs harmonisation of Euopean brekpoints (finalised) review of existing breakpoints Altered indications Change in target organisms New resistance mechanisms New drug in class New clinical experience Change in dosing or administration For new drugs (with EMA)
EUCAST - breakpoints for new drugs with EMA* Daptomycin Tigecycline Doripenem Glycopeptides (ongoing) Cefalosporin (withdrawn) Fluoroquinolone (withdrawn) Diaminopyrimidine (withdrawn) Extensions of indications (currently none) *EMA = European Medicines Agency
Topicals and less commonly used drugs 1. Mupirocin (Topical) 2. Polymyxin B (Topical) 3. Bacitracin (Topical) 4. Streptomycin (hlr for enterococci) 5. Neomycin (Topical) 6. Sulfamethoxazole (UTI) 7. Cephalothin (expert rules?) 8. Sulfadiazine 9. Spiramycin 10.Nalidixic acid (screening) 11.Cefoperazone 12.Pefloxacin 13.Cefradine 14.Cefamandole 15.Sulfisoxazole 16.Pipemidic acid 17.Kanamycin 18.Ceftizoxime 19.Cefprozil + 45 others
Microorganisms to be evaluated for breakpoints Define relevant drugs, breakpoints, methodology and MIC-distributions. Helicobacter spp Campylobacter spp Clostridium difficile Legionella spp Pasteurella multocida Listeria monocytogenes Burkholderia cepacia Corynebacterium spp
EUCAST web-pages
EUCAST Rationale Documents Summarize available data on the drug at the time the breakpoint was determined or revised Available on EUCAST website
Intrinsic resistance EUCAST expert rules v1.0 v2.0 (2010) Exceptional phenotypes Exceptional resistance Exceptional susceptibility Interpretive reading IF - THEN
EUCAST and CLSI are different EUCAST Profession together with regulatory authorities Funded by ESCMID, ECDC and national breakpoint committees. Industry consultative role. Decision by consensus. Five meetings per year. EUCAST=EMEA brpt committee. Clinical breakpoints and ECOFFs Rationale for decisions published Documents in public domain and free of charge CLSI Industry, the profession Funded by industry and sales of output. Industry part of decision process Decision by vote. Two meetings per year. CLSI technical standing with FDA. Clinical breakpoints Rationale for decisions not published. Documents for sale
Web-links to MIC-distributions Web-links to Zone diameter distributions Web-links to EUCAST Rationale Documents
EUCAST disk diffusion
NAC National Antimicrobial susceptibility testing Committee
Remit: NAC 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 susceptibility testing of bacteria (and fungi) representatives of reference clinical microbiology laboratories, government professional organisations/societies, Represntatives of other antibiotic committees Structure Chairperson, scientific secretary, educational officer and representatives of laboratories, societies, reference laboratories (5 6 reps) Funding national level
Tasks and objectives NAC Strategy for AST on national level Implementation of breakpoints and methods Quality assurance on a national level Education of laboratory staff and clinical colleagues Liaison and consultation with EUCAST (GC rep) Liaison with groups involved in AMR-surveillance (ECDC, EARSS,.).. Antimicrobial Policies Antimicrobial Resistance Surveillance Antimicrobial Consumption and Policies
EUCAST/NABC: France Germany Norway Sweden The Netherlands The UK EUCAST breakpoints and NACs NAC 2010/11: Austria Belgium Denmark Estonia Finland Hungary Ireland Italy Spain Switzerland Discussion: Croatia Greece Israel Poland Russia Turkey Lithuania Latvia Portugal, Poland, Czeck republic, Slovakia,, Slovenia, Serbia, Rumania
Thank you! www.eucast.org