EUCAST 2016/17 and what to do when there are no breakpoints and if the UK should exit EU

EUCAST 2016/17 and what to do when there are no breakpoints and if the UK should exit EU Gunnar Kahlmeter

What is new in EUCAST? New organisms breakpoints 2016 Breakpoints for exisiting agents breakpoints 2016 Temocillin, nitroxoline, Review (and revision) of breakpoints Colistin, fluoroquinolones ongoing consultations carbapenems, aminoglycosides, tigecycline 2016/17 What to do when there are no breakpoints? (SOP 2016) Redefining the intermediate category!? (2017) Instruction videos (commissioned by WHO) ASM Microbe 2016

New organisms with breakpoints Kingella kingae Aerococcus spp Aeromonas Plesiomonas Nocardia Bacillus Streptomyces Lactobacillus Leuconostoc ASM Microbe 2016

Colistin methods and breakpoints reviewed by joint EUCAST/CLSI subcommittee (Chair John Turnidge, Australia) ASM Microbe 2016

Colistin Current and suggested breakpoints Enterobacteriaceae Pseudomonas aeruginosa Acinetobacter Colistin 2016 2/2 4/4 2/2 Colistin 2017 2/2 2/2 2/2 ASM Microbe 2016

Colistin MIC distributions and ECOFFs ASM Microbe 2016

The proposal is to reduce the breakpoint from 4/4 to 2/2 mg/l. ASM Microbe 2016

Proposed new ciprofloxacin breakpoints S X / R>Y mg/l ASM Microbe 2016

ASM Microbe 2016

EUCAST Subcommittee on the role of whole genome sequencing (WGS) in antimicrobial susceptibility testing of bacteria Chair: Neil Woodford, London UK Formed immediately after 2015 ECCMID, Copenhagen 1 st report at ECCMID 2016. Report available for consultation until 25 June, 2016. 10

Phenotypic vs. Genotypic AST Phenotypic AST WGS-based AST Measures susceptibility Resistance mechanisms (limited) ECOFF (WT vs. non-wt) Clinical resistance (S vs. R) +/- (inferred) Additional data Suitable speed (most) (e.g. TB) (most) (e.g. TB) Cost South Africa 2016

Disk diffusion instruction videos EUCAST project 10 videos (5 finalised) financed by WHO. Subtitles in other languages Youtube, WHO webpage, EUCAST webpage. ASM Microbe 2016

Uptake of EUCAST guidelines All countries inside Europe have decided to adopt EUCAST guidelines. Increasing numbers of countries outside Europe are going over to EUCAST. Website hits now >50 000 per month. User questions from all over the world are increasing. France and the UK have abandoned their respective disk diffusion test. >90% of labs in Queensland, Australia, are now on EUCAST. Almost 90% of NEQAS subscribers are now on EUCAST. All competitors (except CLSI) have resigned and joined EUCAST. ASM Microbe 2016

Trends in antimicrobial susceptibility testing guidelines in EARS-Net ASM Microbe 2016

ASM Microbe 2016

Wide variation in disk quality in 16 disks from nine manufacturers. EUCAST Development Laboratory (EDL) Växjö Sweden

Results from First (1) and Second (2) Study Bio-Rad Liofilchem BD Abtek SirScan Oxoid HiMedia Bioanalyse Mast Antimicrobial disk 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 Benzylpenicillin 1 unit L H H NA NA H H Amoxicillin-clav. 30 µg H H* L H H L Piperacillin-tazo. 36 µg L L H NA NA Oxacillin 1 µg L L L H H L Mecillinam 10 µg L H H H Cefotaxime 5 µg 1 NA L NA NA Cefoxitin 30 µg 2 H* H* H H* NA L L* L* L Ceftazidime 10 µg L L L H Meropenem 10 µg 1 H H* L L H H Ciprofloxacin 5 µg 2 L L L L H H* L L Norfloxacin 10 µg L L H* H Pefloxacin 5 µg L L L NA NA NA H Gentamicin 10 µg H L NA H H Tobramycin 10 µg NA NA H H* H* Erythromycin 15 µg L L L L H H L* L Tetracycline 30 µg L L* L* L L* L L L Mean value within ± 1 mm of the target value Mean value >1 mm but within ± 2 mm of the target value Mean value >2 mm from target value but still within the QC range Mean value out of the QC range Disk included in first study, but not supplied for second study NA = Not Available H = High, mean value >1 mm above target L = Low, mean value >1 mm below target * One or more readings out of QC range 1 Data has been reanalyzed due to changes in QC criteria for H. influenzae ATCC 49766 with cefotaxime 5 µg (2015) and E. coli ATCC 25922 with meropenem 10 µg (2016). 2 For specific comments on cefoxitin and ciprofloxacin, see next slide. 17

ASM Microbe 2016

EUCAST has agreed to evaluate follow up disk lots on the request of manufacturers. We have invited manufacturers with disk problems to review production procedures and QC and to send us new lots for testing. Several manufacturers availed themselves of this offer. Here is one example: Previous results Results Antimicrobial disk Manufacturer New disk lot New disk lot tested 1 2 new lot Meropenem 10 µg Bio-Rad H 5K00E2 May 2016 Mean value within ± 1 mm of the target value Mean value >1 mm but within ± 2 mm of the target value Mean value >2 mm from target value but still within the QC range Mean value out of the QC range Disk included in first study, but not supplied for second study NA = Not Available H = High, mean value >1 mm above target L = Low, mean value >1 mm below target * One or more readings out of QC range 19

Warnings on EUCAST website South Africa May 2016

What to do when there are no breakpoints in the EUCAST table? Gunnar Kahlmeter Gunnar.kahlmeter@escmid.org

AST - when there is no breakpoint? EUCAST SOP 2016 1. The breakpoint is IE 2. The breakpoint is 3. The agent is not in the table 4. The species is not in the table 5. The MIC breakpoints lack zone diameter correlates South Africa 2016

1. Breakpoint table indicates IE IE : insufficient evidence EUCAST has evaluated the agent/species There is not enough evidence to support a clinical breakpoint in vitro data encouraging. South Africa 2016

2. Breakpoint table indicates - - : intrinsic resistance EUCAST has evaluated the agent/species available evidence suggests that the agent is clinically ineffective irrespective of dose. In vitro data not encouraging. South Africa 2016

3. The agent is not in the table Agent available only in few countries The juice is not worth the queeze (streptomycin, josamycin, spiramycin, sparfloxacin) New agent waiting for breakpoints as part of registration (EMA, FDA) process, breakpoints in semi-automated systems (biomerieux, BD, Siemens etc) waiting to be developed or approved. zone diameter correlates to MIC breakpoints (EUCAST, CLSI) waiting to be developed. Reliable AST difficult or not possible - fosfomycin (agar dilution only), caspofungin

4. The species is not in the table 1. Species/subspecies considered poor target for agent E. coli and vancomycin, Enterococci and cephalosporins, 2. Species/Subspecies considered of doubtful/low clinical importance Bacillus spp., Campylobacter laridis, Yersinia fredericksoniae 3. Rare species Erysopelothrix rusopathiae, Kingella kingae, Aerococcus spp 4. Common species but rare subspecies in human medicine Haemophilus aphrophilus 5. Clinical outcome data insufficient or not available Campylobacter laridis vs. erythromycin 6. Reliable MIC determination not possible Acinetobacter vs. cephalosporins, Stenotrophomonas vs. moxifloxacin m fl, Burkholderia spp.

There is no solution unless a reproducible MIC can be determined

Sometimes there are species and agents not mentioned in EUCAST tables but present in CLSI tables. CLSI needs to decide whether or not they take responsibility for these. Example: Chloramphenicol breakpoints for Enterococci. South Africa 2016

Where there is no breakpoint Is there a breakpoint for a related organism? Is there a PK/PD breakpoint to guide? Is there an MIC wild type distribution for the species and agent? If so, determine if the isolate is wild type (devoid of resistance mechanisms) or non-wild type (with resistance mechanisms)

Breakpoints for related organisms Find breakpoints for related organisms and interpret accordingly. Campylobacter laridis, use C.jejuni and C.coli; Haemophilus aphrophilus, use Haemophilus influenzae, Enterococcus bovis, use Enterococcus faecium, etc Proceed with caution

Isolates where there is no breakpoint Is there a breakpoint for a related organism? Is there a PK/PD breakpoint to guide? Is there an MIC wild type distribution for the species and agent? If so, determine if the isolate is wild type (devoid of resistance mechanisms) or non-wild type (with resistance mechanisms)

Exempel: Leuconostoc spp. benzylpenicillin MIC 0.25 mg/l PK/PD (Non-species related) breakpoints EUCAST Clinical Breakpoint Table v. 6.0, valid from 2016-01-01 These breakpoints are used only when there are no species-specific breakpoints or other recommendations (a dash or a note) in the speciesspecific tables. Penicillins MIC breakpoint Notes (mg/l) S R > Benzylpenicillin 0.25 2 1. For susceptibility testing purposes, the concentration of sulbactam is fixed at 4 mg/l. Ampicillin 2 8 2. For susceptibility testing purposes, the concentration of clavulanic acid is fixed at 2 mg/l. 3. For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/l. Ampicillin-sulbactam 2 1 8 1 Amoxicillin 2 8 Amoxicillin-clavulanic acid 2 2 8 2 Piperacillin 4 16 Piperacillin-tazobactam 4 3 16 3 Ticarcillin 8 16 Ticarcillin-clavulanic acid 8 2 16 2 Phenoxymethylpenicillin IE IE Oxacillin IE IE Cloxacillin IE IE Dicloxacillin IE IE Flucloxacillin IE IE Mecillinam IE IE

EUCAST PK-PD breakpoints Last tab in the breakpoint table PK/PD (Non-species related) breakpoints EUCAST Clinical Breakpoint Table v. 6.0, valid from 2016-01-01 These breakpoints are used only when there are no species-specific breakpoints or other recommendations (a dash or a note) in the species-specific tables. Penicillins Penicillin MIC breakpoint (mg/l) S R > Notes Benzylpenicillin 0.25 2 1. For susceptibility testing purposes, the concentration of sulbactam is fixed at 4 mg/l. Ampicillin 2 8 2. For susceptibility testing purposes, the concentration of clavulanic acid is fixed at 2 mg/l. 3. For susceptibility testing purposes, the concentration of tazobactam is fixed at 4 mg/l. Ampicillin-sulbactam 2 1 8 1 Amoxicillin 2 8 Amoxicillin-clavulanic acid 2 2 8 2 Piperacillin 4 16 Piperacillin-tazobactam 4 3 16 3 Ticarcillin 8 16 Ticarcillin-clavulanic acid 8 2 16 2 Phenoxymethylpenicillin IE IE Oxacillin IE IE Cloxacillin IE IE Dicloxacillin IE IE Flucloxacillin IE IE Mecillinam IE IE MIC breakpoint (mg/l) S R> Benzylpenicillin 0.25 2 Ampicillin 2 8 Ampicillin-sulbactam 2 1 8 1 Amoxicillin 2 8 Amoxicillin-clavulanic acid 2 2 8 2 Piperacillin 4 16 Piperacillin-tazobactam 4 3 16 3 Ticarcillin 8 16 Ticarcillin-clavulanic acid 8 2 16 2

Isolates where there is no breakpoint Is there a breakpoint for a related organism? Is there a PK/PD breakpoint to guide? Is there an MIC wild type distribution for the species and agent? If so, determine if the isolate is wild type (devoid of resistance mechanisms) or non-wild type (with resistance mechanisms)

Check MIC against the wild type distribution for the species (or a closely related species) If an MIC distribution is available check whether the organism is wild type e.g. Lactobacillus spp., Erythromycin MIC 0.5 mg/l

How to report?

1. Breakpoint table IE IE : insufficient evidence Compare the MIC with wild type distributions and the PK/PD breakpoint. Report the MIC (not essential) and a comment South Africa 2016

2. Breakpoint table - - : intrinsic resistance If a report is warranted, report resistant without testing. South Africa 2016

3. Agent not in table Can a surrogate agent be used for testing and categorisation? Erythromycin for macrolide (josamycin) Ciprofloxacin for gramnegatives vs. fluoroquinolone; Norfloxacin for grampositives and a fluroquinolone. Vancomycin for a glycopeptide. Colistin for polymyxin?

4. Species not in table Check MIC against breakpoints of a related species. Report the result of the comparison. Check MIC against PK/PD breakpoints. Report as below or above the PK/PD breakpoints. Check MIC against the wild type MIC distribution of the species or a related species Report as without or with resistance mechanisms. Report MIC (not essential) + comment

When there are no breakpoints Do not report S, I or R These are susceptibility categories based on evidence for or against favorable clinical outcome. Add a comment instead. South Africa 2016

Thank you! This advice will be developed into an SOP on the EUCAST Website. www.eucast.org

Alla rekommendationer bygger på att ett MIC-värde kan bestämmas. Om ett MIC-värde kan bestämmas med någon säkerhet, kan en bedömning göras mot EUCASTs PK/PD-brytpunkter (se brytpunktstabell eller rational dokument), brytpunkter för närbesläktad art mot MIC-databasen (WT/NWT) för aktuell eller närbesläktad art.

Jämför isolatets MIC-värde med MIC-fördelningen för arten eller en närbesläktad art. e.g. Arcanobacterium haemolyticum with vancomycin MIC 0.5 mg/l Gram-positive bakteriers vancomycin vildtyp är vanligen 0.25-2 mg/l

Bedömning Om det aktuella isolatets MIC-värde är >PK/PD S-brytpunkten >EUCAST-brytpunkten för en närbesläktad art >ECOFF för arten eller en närbesläktad art besvara med R (aldrig I).

Bedömning Om det aktuella isolatets MIC-värde är PK/PD S-brytpunkten EUCAST-brytpunkten för en närbesläktad art ECOFF för arten eller en närbesläktad art besvara med en kommentar: Det saknas brytpunkter varför resistensbestämning ej kan utföras. Med utgångspunkt från de undersökningar vi kunnat utföra bedömer vi att isolatet kan behandlas med antibiotikum X.