Educational Workshop

Transcription

1 Educational Workshop EW10: Antimicrobial susceptibility testing with EUCAST breakpoints and methods Arranged with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Convenors: Rafael Canton Moreno (Madrid, ES) Derek F.J. Brown (Peterborough, UK) Faculty: Derek F.J. Brown (Peterborough, United Kingdom) Rafael Canton Moreno (Madrid, ES) Gunnar Kahlmeter (Växjö, Sweden) no handout available Robert L. Skov (Copenhagen, Denmark) no handout available Alasdair P. MacGowan (Bristol, United Kingdom) no handout available John D. Turnidge (Adelaide, Australia) Robin Howe (Cardiff, United Kingdom) no handout available Luis Martinez-Martinez (Santander, Spain) no handout available 1

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3 Canton Moreno - Update on EUCAST UPDATE ON EUCAST 2014 Departamento de Microbiología II Universidad Complutense. Madrid 2 new SOPS 3 new versions 39 documents Mostly describes EUCAST organization and relationship of EUCAST-SC with NACs 3

4 Canton Moreno - Update on EUCAST National Breakpoint Committees F, N, NL, S, UK Contract EUCAST General Committee (GC) All European Countries + Countries from outside EUCAST Steering Committee BSAC, CA SFM, CRG, NWGA, SRGA + 3 reps from the GC ±2 visiting members from the GC NACs = National Antimicrobial Susceptibility Testing Committees Subcommittees Antifungals Resistance mechanisms Experts (ECDC Networks, ESCMID Study Groups) Industry EUCAST general organization National breakpoint committees and NACs - Nearly all countries in Europe have an active NAC and some non-european countries also have a NAC (Australia, US, Russia) - Non-EU countries interested in forming a NAC (South Africa, Brazil,..) EUCAST General Committee - representing 36 countries EUCAST Steering committee (11 members) - Chairman, scientific secretary, clinical data coordinator - National breakpoint committee representatives: - BSAC (UK), CA-SFM (France), SRGA (Sweden) - CRG (The Netherlands), NWGA (Norway), - EUCAST General Committee representatives: - Spain and Denmark ( ), Germany ( ) - Visiting members ( 2) and observers (EMA, ECDC) at each meeting National AST Committees (NACs), 2013 Yes In the process of forming a NAC No No information Norway Sweden Denmark Finland Estonia Latvia Lithuania Russia Ireland Great Britain Netherlands Poland Germany Belgium Luxembourg Czech Republic Slovakia Belarus Moldova Ukraine Portugal Spain France Switzerland Austria Hungary Romania Slovenia Croatia Serbia Bosnia- Herzegovina Montenegro Mace- Bulgaria Italy donia Albania Turkey Greece Malta Countries not on the map: Australia Iceland Israel 4

5 Canton Moreno - Update on EUCAST 2014 EUCAST translations Implementation of EUCAST breakpoints, 2013 % Laboratories >50% 10-50% <10% No information Sweden Countries not on the map: Australia Iceland Israel EUCAST-related publications Yearly evolution of publications in PubMed including EUCAST in the title and/or abstract No. of publications *January-April,

6 Canton Moreno - Update on EUCAST visits (Q4, 2013) Top Countries % of visits Unknown 12.1 United States 10.0 Germany 7.6 Sweden 6.7 Netherlands 5.9 UK 5.5 Itally 4.5 Denmark 4.1 Switzerland 3.5 Belgium 3.3 France 2.5 Norway 2.4 Spain 2.0 Finland 2.0 Poland 1.9 Austria October December ,000 visitors/month (60% from Europe) Pages more visited (each visitor may see each page more than once) - home 46.5% - clinical breakpoints 50.9% - MIC/zone distributions 8.7% - expert rules 5.8% - publications 2.9% - disk diffusion methods 2.2% EUCAST breakpoints, 2014 (version 4.0) EUCAST breakpoints, 2014 (version 4.0) New and revised breakpoints Enterobaceriaceae Amox/clav (uncomplicated UTI only) Ciprofloxacin and Salmonella spp. Doripenem P. aeruginosa Doripenem S. lugdunensis Benzylpenicillin Enterococcus spp. Ciprofloxacin, levofloxacin (uncomplicated UTI) H. influenzae Cefaclor (removed) M. catarrhalis Cefaclor (removed) Corynebacterium spp. Different antimicrobials New screen tests Rewording of supplementary tables and notes and new notes 6

7 % of inhibited strains CMI (mg/l) % of inhibited strains CMI (mg/l) Canton Moreno - Update on EUCAST 2014 EUCAST breakpoints, 2014 (version 4.0) Amoxicillin-clavulanate and UTI new breakpoints An isolate reported as S in urine might be R in a systemic infection The laboratory might not know if the isolates is from uncomplicated or a complicated UTI EUCAST recommends reporting isolates using both uncomplicated UTI only and systemic breakpoints: MIC (mg/l) Uncomplicated ITU Systemic use 8 S S S R >32 R R EUCAST breakpoints, 2014 (version 4.0) Rationale for amox-clav and UTI new breakpoint High concentration of amoxicillin-clavulanic acid in urine 2:1 fixed ratio produce lower MICs than a 2 mg/l fixed concentration Fixed ratio (2:1) Fixed concentration (2 µg) ESßl C-P S TL TI TH-IRT BLEA C-P S TL TI TH-IRT > >256 Oliver et al. AAC 1999; 43:862-7 No intermediate category in systemic breakpoint to allocate urine isolates Clinical results support higher breakpoints in UTI - an MIC of 32 mg/l predicts clinical cure Todd and Benfield Drugs 1990; 39: ; Ball IJAA 2007; 305: EUCAST breakpoints, 2014 (version 4.0) Rationale for revised doripenem breakpoints Reduction of doripenem R breakpoint from >4 mg/l to >2 mg/l for Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter spp. New clinical data on doripenem in VAP when using high dose (1g/8h) in extended infusion (4 h) Kollef et al. Critical Care 2012; 16:R218 EMA recommendation of a high dose in patients with augmented renal clearance and/or infections due to NFGNB Reassessment of PK /PD Monte Carlo simulation using ft>mic=40-50% and confidence limits of 95-99% for target attainment 7

8 Canton Moreno - Update on EUCAST 2014 EUCAST breakpoints, 2014 (version 4.0) Revised breakpoints: Doripenem Probabilities of Target Attainment for doripenem (40-50%) 0.5 g x 3 IV ft >MIC doripenem 500 mg x 3 iv MIC mg/l 95% percentile 99% percentile Mean Volume of Distribution (Vd): 18 L, CV 20% Elimination half-life : 1.05 h, CV 20% Fraction unbound (Fu): 92% Infusion time 1.0 h Doripenem RD, v1.0, 2009 A high dose 1 g x 3 IV over 4 h would correspond to breakpoint of 2 mg/l Extended infusion improves the PK/PD performance but does not justify previous R breakpoint of >4 mg/l EUCAST subcommittees EUCAST subcommittee on resistance mechanisms Carbapenemase producing Enterobacteriaceae Susceptible (S) Intermediate (I) Clinical response to carbapenems Resistant (R) 8

9 Canton Moreno - Update on EUCAST 2014 EUCAST subcommittee on resistance mechanisms Screening cut-off for carbapenemase producing Enterobacteriaceae 1 Best balance of sensitivity and specificity ; 2 In some cases zone diameters for OXA-48-producers are up to 26 mm, so <27 mm may be used as a screening cut-off in countries where OXA-48 is endemic, but at the expense of lower. Algorithm for phenotypic detection of carbapenemases Meropenem<25 mm with diskdiffusion or MIC >0.12 mg/l in all Enterobacteriaceae Synergy with APBA/PBA only Synergy with APBA/ PBA AND cloxacillin Synergy with DPA/EDTA only No synergy KPC (or other class A carbapenemase) AmpC (chromosomal and plasmid-acquired) AmpC plus porin loss Metallo-betalactamase (MBL) ESBL plus porin loss AND OXA-48 New EUCAST guidance documents Burkholderia cepacia complex guidance document Currently, it is not possible to recommend susceptibility testing of B. cepacia isolates to guide patient therapy Susceptibility testing is problematic: - unlike gradient MIC or disk diffusion, ISO broth microdilution gives reproducible MIC results - poor correlation between different methods Difficult to establish correlations of MICs and clinical outcomes - no evidence to describe a relationship between MIC and outcomes - B. cepacia is frequently part of a mixed infection - MIC distributions are wide and encompass the PK/PD breakpoints 9

10 Canton Moreno - Update on EUCAST 2014 Topical agents guidance document Superficial skin and external eye and ear infections but not for bowel decontamination or inhaled agents EUCAST has not found a consensus to resolve different opinions - use ECOFFs for agents when used topically - use clinical breakpoints when available and ECOFF when there are not clinical breakpoints Acceptable distributions are not available for all topical agents Only specific breakpoints for nasal decolonisation of S. aureus with mupirocin is supported with clinical data If tissue is involved the use of systemic treatment and systemic breakpoints should be considered Topical agents guidance document ECOFFs and systemic clinical breakpoints for antimicrobial agents that are used topically - = inappropriate combination; IE = insufficient evidence to set a clinical breakpoint; ND = No ECOFF defined on EUCAST MIC distribution website 1Agents also available for systemic use 2Breakpoints for nasal decontamination S 1, R>256 mg/l. EUCAST: What is coming for ? New and ongoing breakpoints (BP) with - EMA ceftobiprole, β-lactam-β-lactamase inhibitor combinations macrolides, tetracyclines, glycopeptides, oxazolidinones delamanid and other antimicobacterial agent - CLSI colistin (under TATFAR initiative) - NACs temocillin, nitroxoline, spiramycin, tigecycline, aztreonam - Ciprofloxacin and N. meningitidis - N. gonorrhoeae and various antimicrobials - Daptomycin and enterococci - Organisms-agent combinations lacking clinical data supporting BP New RD documents (new agents and new RD due to revised BP) New documents, technical notes / guidance documents - new version of expert rules (v3) - dissociated clindamycin resistance (staphylococci and streptococci) - SOPs (format and revision of EUCAST documents, ) 10

11 Canton Moreno - Update on EUCAST EUCAST website changes Acknowledgements More information: - Next lecturers at this workshop! - Monday 12 May, Hall D Meet the Experts: EUCAST frequently asked questions - Monday 12 May, CCIB/Room 122/123 EUCAST General Committee meeting - Monday 12 May, :00, CCIB/Room 122/123 EUCAST Subcommittee on Antifungal Susceptibility Testing (ASFT) General Committee meeting - Saturday 10 May Tuesday 13 May EUCAST at the ESCMID Booth. EUCAST presentations EUCAST Laboratory for AST and collaborative centers 11

12 Brown - External quality assessment Antimicrobial susceptibility testing with EUCAST breakpoints and methods External quality assessment Derek Brown EUCAST Scientific Secretary Chairman, UK NEQAS Specialist Advisory Group on AST External Quality Assessment (EQA, proficiency testing) The challenge of laboratory procedures with specimens of known but undisclosed content The EQA process (UK NEQAS) Prepare samples Participants Examine samples Report results Analyse results Prepare report Participants Evaluate performance 12

13 Brown - External quality assessment Benefits of EQA in antimicrobial susceptibility testing For the individual laboratory: Independent assessment of performance Assessment of performance over time Comparison with other laboratories Highlights problem areas Performance indicator for accreditation Gives practical experience of difficult tests and uncommon resistances Benefits of EQA in antimicrobial susceptibility testing Wider benefits: Provides background information and discussion of problem tests Performance related to guidelines and methods (International differences highlighted) Limitations of EQA in antimicrobial susceptibility testing Number of specimens distributed is small May be considered inappropriate to send some organisms Specimens do not reflect routine isolates Laboratories may not treat specimens as routine 13

14 Brown - External quality assessment Results may be affected by breakpoint guidelines used E. faecalis specimen 0138 (Jan 2011) vancomycin MIC 8-16 mg/l (vanb) Guideline Breakpoints (mg/l) Percent reporting S R> S I R EUCAST (n=316) CLSI (n=314) Enterobacter cloacae 1797 piperacillin-tazobactam MIC 64 mg/l Breakpoints Percent reporting Guideline (mg/l) S R> S I R EUCAST (n=502) CLSI (n=115)

15 Brown - External quality assessment Guidelines are not always followed Guideline S. aureus specimen 0185 mupirocin MIC 4-16 mg/l Breakpoints (mg/l) Percent reporting S R> S I R EUCAST (n=248) CLSI (n=208) % of 93 labs reporting R and using CLSI breakpoints with automated systems reported MICs >8 or 8 mg/l and therefore cannot distinguish high and low-level resistance CLSI disk diffusion method requires 200µg disk 22 used 5µg disk and 20 reported R BSAC disk diffusion method requires MIC if resistant with 5µg disk 56/69 using 5µg disk reported R, suggesting MIC was not tested S. aureus specimen 1495 fusidic acid MIC 16 mg/l Breakpoints Percent reporting Guideline (mg/l) S R> S I R EUCAST (n=459) CLSI (n=119)

16 Brown - External quality assessment S. pneumoniae specimen 1887 penicillin MIC mg/l Interpretation Percent reporting Reporting EUCAST CLSI S I R Oxacillin (n=385) R R Performance may be affected by the method used E. faecalis specimen 0138 vancomycin MIC 8-16 mg/l (vanb) Method EUCAST resistant, CLSI intermediate Percent reporting S I R Automated (n=333) MIC (n=71) Disk diffusion (n=262)

17 Brown - External quality assessment E. coli specimen 1842 piperacillin-tazobactam MIC 32->128 mg/l Method EUCAST resistant, CLSI intermediate-resistant Percent reporting S I R Automated (n=283) MIC (n=44) Disk diffusion (n=211) Borderline susceptibility reduces the reliability of results E. coli specimen 1842 amikacin MIC 8-16 mg/l Breakpoints Percent reporting Guideline (mg/l) S R> S I R EUCAST (n=356) CLSI (n=100)

18 Brown - External quality assessment Uncertainty in guidelines leads to variable reporting Uncertainty in reporting S. pneumoniae specimen 1887 benzylpenicillin MIC mg/l Intermediate to penicillin Susceptible if from pneumonia Resistant if from meningitis Reporting Percent reporting S I R Pneumonia (n=531) Meningitis (n=525) Uncertainty in reporting dissociated (MLSB-inducible) resistance to clindamycin in S. aureus Clindamycin MIC mg/l (S) Resistance induced by erythromycin Year Specimen Percent reporting S I R (n=606) (n=601)

19 Brown - External quality assessment Agent Uncertainty in reporting E. cloacae specimen 9581 Inducible AmpC Expected test result % reporting S I R Cefotaxime S Ceftazidime S Inducible AmpC typical for Enterobacter spp. (also C. freundii, Serratia spp., M. morganii and Providencia spp. May mutate to stably derepressed state during treatment. Reporting inducible AmpC in Enterobacteriaceae EUCAST Expert rule 9.2. for Enterobacter spp. (also C. freundii, Serratia spp., M. morganii and Providencia spp. If susceptible in vitro, use of cefotaxime, ceftriaxone or ceftazidime in monotherapy (or in combination with an aminoglycoside) should be discouraged owing to risk of selecting resistance. Reports should note this or results should be suppressed. CLSI Report as susceptible if they appear so in susceptibility tests, but with a warning that resistance may develop during treatment and that repeat isolates should be retested.. and some resistances are just difficult to detect 19

20 Brown - External quality assessment Guideline S. aureus specimen 1699 vancomycin MIC 4 mg/l Breakpoints (mg/l) Percent reporting S R> S I R EUCAST (n=356) CLSI (n=150) Method Percent reporting S I R Automated (n=284) MIC (n=131) Disk diffusion (n=29) Use of breakpoint guidelines is changing 90 Breakpoints used by participants in UK NEQAS Percent of laboratories CLSI All EUCAST Nov 08 Nov 09 Nov 10 Nov 11 Apr 12 Dez 12 Mrz 13 Sep 13 Feb 14 20

21 Brown - External quality assessment External quality assessment -summary EQA provides valuable data on performance for individual laboratories In general, performance is good for most organism-agent combinations Performance can be linked to guidelines and methods used for some tests Discrepancies more common when: Differences between guidelines Failure to follow guidelines Susceptibility borderline Confusion over reporting Tests are difficult There is a marked trend towards use of EUCAST breakpoints 21

22 Turnidge Susceptibility testing systems are some more equal than others? Susceptibility Testing Systems Are some more equal than others? Conflicts of Interest Voting Member of the CLSI AST Subcommittee Member of the CLSI Consensus Committee on Microbiology Voting Member of the CLSI Veterinary AST Subcommittee Observer at CLSI Antifungal AST Subcommittee Member of the EUCAST General Committee Intermittent Observer at EUCAST Steering Committee Passion about AST in all its forms! ALL ANIMALS ARE EQUAL, BUT SOME ANIMALS ARE MORE EQUAL THAN OTHERS George Orwell s Animal Farm, 1945 Four legs good, two legs better! 22

23 Turnidge Susceptibility testing systems are some more equal than others? ALL SYSTEMS ARE EQUAL, BUT SOME SYSTEMS ARE MORE EQUAL THAN OTHERS The ISO Reference Standard Desirable Features of a Susceptibility Testing System Methods Reliability Reproducibility, intra and inter laboratory Accuracy Precision International reference standard To which it has been calibrated High predictive value patient outcome Driven by breakpoint selection 23

24 Turnidge Susceptibility testing systems are some more equal than others? Broth or Disc Method? Broth methods Basis of semi automated systems More readily comparable to the reference method Can generate MIC values (if on scale) which can be directly plugged into PK PD parameters Disk methods Much more flexible Requires good correlation with MIC breakpoints. So what choices are there? System CLSI: Clinical and Laboratory Standards Institute [ EUCAST: European Committee on AST [ BSAC: British Society for Antimicrobial Chemotherapy [bsac.org.uk/susceptibility] CDS: Calibrated Dichomotous System [web.med.unsw.edu.au/cdstest/] Calibrated to ISO reference Yes Yes No No Breakpoint Setting Micro + PK/PD + Clinical Outcome Micro + PK/PD + Clinical Outcome Micro + PK/PD Wild type cutoffs So what choices are there? System CLSI: Clinical and Laboratory Standards Institute [ EUCAST: European Committee on AST [ BSAC: British Society for Antimicrobial Chemotherapy [bsac.org.uk/susceptibility] CDS: Calibrated Dichomotous System [web.med.unsw.edu.au/cdstest/] Calibrated to ISO reference Yes Yes No No Breakpoint Setting Micro + PK/PD + Clinical Outcome Micro + PK/PD + Clinical Outcome Micro + PK/PD Wild type cutoffs 24

25 Turnidge Susceptibility testing systems are some more equal than others? Compare and Contrast THIS? OR THIS? Most media the same except Species/Group EUCAST CLSI Streptococcus spp. Mueller Hinton F MH + 5% sheep (disk) MH % lysed horse (BMD) Haemophilus influenzae(+para) Mueller Hinton F Haemophilus Test Medium Listeria monocytogenes Mueller Hinton F MH % lysed horse (BMD) M. catarrhalis Mueller Hinton F MH Pasteurella multocida (spp.) Campylobacter jejuni/coli Mueller Hinton F Mueller Hinton F MH + 5% sheep (disk) MH % lysed horse (BMD) MH + 5% sheep (disk) MH % lysed horse (BMD) Most media the same except Species/Group EUCAST CLSI Corynebacterium spp. Mueller Hinton F MH % lysed horse (BMD) N. gonorrhoeae (MIC method) GC Agar + suppl. N. meningitidis (MIC method) MH + 5% sheep (disk) MH % lysed horse (BMD) Helicobacter pylori (MIC method) MH + 5% sheep aged (disk) Anaerobes (MIC method) Brucella + haemin +VitK (agar dilution, add LHB for BMD) 25

26 Turnidge Susceptibility testing systems are some more equal than others? Difference in tests available for Species EUCAST v4 CLSI M100 S4 CLSI M45 A2 Pseudomonas spp. Other Non Enterobacteriaceae S. maltophilia only 1 agent H. parainfluenzae ( ) N. gonorrhoeae disk N. meningitidis disk Gram positive anaerobes Gram negative anaerobes C. difficile specific M. catarrhalis Difference in tests available for Species EUCAST v4 CLSI M100 S4 CLSI M45 A2 H. pylori MIC L. monocytogenes P. multocida C. jejuni and coli Corynebacterium spp. Abiotrophia spp., Granulicatella spp., Aeromonas spp., P. shigelloides, Bacillus spp., E. rhusiopathiae, HACEK group, Lactobacillus spp., Leuconostoc spp., Pediococcus spp., Vibrio spp., B. anthracis, Y. pestis, B. pseudomallei, B. mallei, F. tularensis, Brucella spp. Difference in tests available for Species EUCAST v4 CLSI M100 S4 Cefazolin No Cefoperazone sulbactam No No Cephalexin ( CZL) Fosfomycin IV No Fusidic acid Maybe soon Teicoplanin Telavancin Maybe soon Tigecycline FDA only Older (uncommon) cephalosporins ( unrevised) Older (uncommon) fluoroquinolones ( unrevised) Older (uncommon) aminoglycosides ( unrevised) 26

27 Turnidge Susceptibility testing systems are some more equal than others? Documentation Feature EUCAST CLSI METHODS Disk diffusion V3: Manual, Slides, Reading Guide M2 A11 Dilution Refer ISO M7 A9 MEDIA PREPARATION Media prep document (V3) M2 A11 and M7 A9 QUALITY CONTROL TABLES QC Tables (V3.1) M100 S24 SOPs 7 documents M23 A3 ADDITIONAL TESTS Resistance Detection (V1) M100 S24 EXPERT RULES Expert Rules (V2) M100 S24 RATIONALE DOCUMENTS 39 documents 3 documents GUIDANCE DOCUMENTS 5 documents M100 S24 FOREIGN LANGUAGES 8 languages By local arrangement WILD TYPE DISTRIBUTIONS MICs and Zone diameters None Business Practices Feature EUCAST CLSI Organization Co operative between ESCMID and ECDC History Since 1999 really Started 1968 Not for profit membership based NGO Funding ESCMID and ECDC Memberships, Sales and some grant funds Professional involvement Focus Committees Clinicians, Laboratorians, Academics Antimicrobial Susceptibility Testing only Steering Committee General Committee Academics, Industry, Government (esp. FDA) Laboratory standards of all types (+ some clinical) Consensus Committee AST Subcommittee AFST Subcommittee VAST Subcommittee Frequency of meetings 5 times per year 2 times per year Business Practices Feature EUCAST CLSI Consensus process Steering Committee At the meetings, plus check by Consensus Committee Public consultation Via and NACs At the meetings Response to feedback Rapid Rapid Local representation National AST Committees None specific Relationship to regulators MOU with EMA Complex: indirect and direct involvement Relationship to industry Similar to that of the regulator Complex: indirect and direct involvement Breakpoints All based on PK PD wherever possible PK PD included only from 2003 lots await revision 27

28 Turnidge Susceptibility testing systems are some more equal than others? The most notable difference EUCAST CLSI =$= 0 Minimum $170 per year (For M100) Personal Commentary Transparency Slight advantage to EUCAST (rationale documents) Facility Slight advantage to EUCAST (single fastidious medium) Currency Slight advantage to EUCAST (more agents) Scope Slight advantage to CLSI (more organisms) Personal Commentary Responsiveness Slight advantage to EUCAST (quicker turnaround) International Applicability Slight advantage to EUCAST (more agents) 28

29 Turnidge Susceptibility testing systems are some more equal than others? E U C A S T 29