Shift to European (EUCAST) breakpoints – the impact on the BSAC recommendations Alasdair MacGowan Southmead Hospital BRISTOL

Topics Process what is EUCAST? what does it do? why does it do it? what are the advantages? (if any), Do I care? Definitions  clinical breakpoints and wild type cut offs  categorical results (S, R, I)  non- species specific breakpoints How a clinical breakpoint is assessed/decided Changes in BSAC breakpoints so far The future Summary

EUCAST Is - European Committee on Antimicrobial Susceptibility Testing formed in 1997, restructured into present form in 2002 convened by – European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and National Breakpoint Committees of Europe (France, CA-SFM; Germany; DIN; Netherlands, CRG; Norway, NWGA; Sweden, SRGA; UK, BSAC WP) Financed by – ESCMID National Committees DG-SANCO of the EU for 3years until May 07

EUCAST objectives  set common European antimicrobial breakpoints for surveillance  to harmonise breakpoints for existing and new drugs (all agents)  (promote standardisation of methodologies)  (encourage I and E QA)  (collaborate with other groups in AST and epidemiology)  advise EU institutions  (training)

EUCAST General Committee  one representative of each European country (n=32), ISC and FESCI (n=2)  Chair/Scientific Secretary/Clinical Co-ordinator (n=3) appointed by ECCMD Steering Committee  one representative of each European national breakpoint committee (n=6)  two representatives of the EUCAST General Committee.  Chair/Scientific Secretary/Clinical Co-ordinator (as above)

EUCAST website constitution & organisation Committees & meetings documents & MIC breakpoints MIC distributions

Impact of EUCAST on the BSAC standardised method definitions of S, R and I changed clinical breakpoints to define susceptibility introduction of “wild type cut-offs” listing of non-species specific clinical breakpoints

Advantages of the EUCAST process for BSAC users vigorous process for reviewing clinical breakpoints based on pK, pD, MIC distributions, clinical trials, medical experience. consultation with 5 other National Committees and open consultation across Europe. harmonised breakpoints for old agents improved data (pK, pD, MIC, clinical trial) for new agents - link with EMEA improved international acceptance of UK breakpoints epidemiological advantages reduced dependency on CLSI/NCCLS and FDA

Definitions Clinical breakpoints susceptible a micro organism is defined as susceptible of inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic success. Resistant a micro organism is defined as resistant if inhibited in vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic failure

Definitions – cont’d Intermediate a micro organism is defined as intermediate by a level of antimicrobial agent activity associated with uncertain effect. It implies –  infection may be treated in body sites where the drug is concentrated or, when a high dosage can be used.  it indicates a buffer zone to prevent small uncontrolled technical factors causing major discrepancies in interpretation.

The intermediate category (I)  re-introduction for BSAC users (previous M is Stoke’s methodology).  most other breakpoint committees have I category.  until now I and R combined in BSAC methodology - both called R.  usually a doubling tube dilution higher than S/I breakpoint.

What does intermediate mean? All things to all men? if drug is concentrated at a body site, can use the I/R breakpoint to define susceptibility, example urinary testing for uncomplicated UTI. Problems: definitions of tissue penetration : most bps based on blood levels for the treatment of tissue infection : little evidence to support an I/R breakpoint

Intermediate - cont’d if you can use a bigger dose, novel dosing strategy this will overcome the resistance level. Twice the dose, doubles the clinical breakpoint also could add a second agent to overcome low level resistance e.g. P. aeruginosa therapy with meropenem if MIC 2-8mg/L problems -emergence of resistance may be more common: efflux mutants and fluoroquinolones -what if the mechanism is an enzyme in contrast to efflux pump or target site mutation

Intermediate - cont’d the clinical outcome is truly indeterminate i.e. H. influenzae and macrolides problem - good quality clinical data - ethics of relevant studies

Intermediate - cont’d acts as a buffer zone to prevent major blunders related to minor methodological changes i.e. I  S mis categorisation less of a problem than R  S. helps explain day-to-day variation in results. Problems:- - difficult for epidemiological capture

Is the intermediate category a useful adjunct Yes because:- allows consideration of high dose, addition of a second agent, novel dosing. (much more data needed, i.e. MIC value) allows consideration of tissue penetration (be very careful) allows a blunder zone can continue to lump I/R together for epidemiological purposes Main problems:- understanding what I means at a clinical level coping with S/I/R in epidemiological capture of laboratory data others

Epidemiological cut of values a micro organism is defined as wild type (WT) by the absence of acquired or mutational resistance mechanisms WT is presented as WT < Xmg/L Wild type organisms may or may not respond clinically to antimicrobial treatment

Graph shown in the EUCAST program for display of MIC distributions of wild type bacteria. Values >1% show on graph!

Non species specific breakpoint (clinical breakpoint) -these are determined on the basis of Pharmacokinetic/ Pharmacodynamic data and are independent of MIC distributions of any bacterial species. They may be used only for species that have not been given a clinical breakpoint.

Relevant factors in setting clinical breakpoints national similarities and differences regarding dosing and dose size national differences in target organisms dose/concentration effect relationships in animals, in vitro and man (pK/pD data). modelling process such as Monte Carlo simulation may be used to assess breakpoints clinical outcome data related to MICs, drug exposures and pD indices breakpoints are tested against MIC distribution data to ensure wild type MIC distributions not split consensus is sought through the General Committee and National Committees

1. Data on dosing, formulations, clinical indications and target organisms are reviewed and differences which might influence breakpoints are highlighted Dosage BSAC UK CA-SFM France CRG Netherlands DIN Germany NWGA Norway SRGA Sweden Most common dose 500 x 2 oral 400 x 2 iv 500 x 2 oral 200 x 2 iv 250 x 2 oral 200 x iv 500 x 2 oral 200 x 2 iv x 2 oral 400 x 2 iv 500 x 2 oral 400 x 2 iv Maximum dose schedule 750 x 2 oral 400 x 3 iv 750 x 2 oral 400 x 3 iv 750 x 2 oral 400 x 3 iv 750 x 2 oral 400 x 2 iv data pending 750 x 2 oral 400 x 3 iv Available formulationsoral, iv EUCAST procedure for setting breakpoints

2. Multiple MIC-distributions are collected, the wild type MIC distribution is defined and tentative epidemiological cut-off values determined (WT <X mg/L) Epidemiological cut off: WT<0.064 mg/L EUCAST procedure for setting breakpoints

3. Existing national clinical breakpoints are compared Breakpoints prior to harmonisation (mg/L) S BSACCA-SFMCRGDINNWGASRGANCCLS General breakpointsND1/ /21/2 Species related breakpointsnot yetno Enterobacteriaceae1/10.12/20.12/11/2 Pseudomonas spp.1/4ND1/11/2 Acinetobacter spp.1/11/2 Staphylococci1/10.12/20.06/21/2 Streptococci1/1excluded0.12/2 excl S. pneumoniae2/2 (I)*excluded0.12/2 (I)* excl Enterococciexcluded 0.12/2 1/2 Haemophilus/Moraxella spp.1/10.12/ /0.251/- Corynebacteriaexcl N. Meningitidis1/10.06/ /0.25 N. Gonorrhoeae0.06/-0.06/10.06/ / /0.5 P. MultocidaND 0.12/0.25 AnaerobesexcludedNDexcluded Campylobacter spp.1/1 Helicobacter pylori2/2no EUCAST procedure for setting breakpoints

S = 0.5 mg/L S = 1 mg/L Pk/Pd 4. Using available Pk/Pd data, Monte Carlo simulations are performed and a Pk/Pd breakpoint calculated based on conventional dosing regimens

5. Clinical data relating outcome to MIC-values, wild type and resistance mechanisms are assessed in relation to the tentative breakpoint EUCAST procedure for setting breakpoints

6a. Tentative breakpoints are checked against target species wild type MIC distributions to avoid splitting the wild type to obtain tentative breakpoints <2 mg/L Epidemiological cut off: WT<2.0 Splitting the wild type must be avoided to permit reproducible susceptibility testing …the breakpoints were set at S≤0.125 and R>2 mg/L, rendering wild type S. pneumoniae intermediate in susceptibility to ciprofloxacin.

6b. Tentative breakpoints are checked against target species wild type MIC distributions to avoid splitting the wild type to obtain tentative breakpoints - example levofloxacin Epidemiological cut off: WT<2.0 <2 mg/L Splitting the wild type must be avoided to permit reproducible susceptibility testing! … a break-point of 2 mg/L was acceptable with a footnote that this relates to high dose therapy.

7. Tentative breakpoints proposed by the EUCAST Steering Committee are referred to the national breakpoint committees for comments. When Steering Committee and national committees agree the tentative breakpoints are subjected to the EUCAST consultation process: 9. Rationale document prepared and published on website 8. Consultation process on tentative breakpoints: - EUCAST General Committee - Expert groups (eg Neisseria, anaerobes) - Pharmaceutical industry, AST device manufacturers - Others via EUCAST website EUCAST procedure for setting breakpoints

”Dashed” – laboratories are recommended not to test against this species Click on name to directly access MIC distributions Insufficient evidence EUCAST breakpoint tables available at

Changes to BSAC breakpoints so far Agreed breakpoints for – aminoglycosides aztreonam carbapenems cephalosporins fluoroquinolones glycopeptides linezolid New agents – daptomycin tigecycline Draft/consultation breakpoints for macrolides penicillins garenoxacin

Summary of changes

Which pathogen groups have changed the most?

Impact on susceptibility rates: BSAC surveillance 2005

The future  complete set of clinical breakpoints and wild type cut offs based on European process (EUCAST)  mapping of breakpoints into standard methods (France, Norway, Sweden, UK)  ?standardised methodologies ISO/SEN standard for MIC testing  relationship with EMEA means EUCAST will set breakpoints for new agents in Europe and for new drug SPC  relationship with CLSI/NCCLS

Summary  EUCAST is a functional EU funded national collaboration!  Professionally based  improved credibility for UK clinical breakpoints  improved cross Europe epidemiology  some different concepts for BSAC users: I, wild type cut offs, non-species specific breakpoints  some different breakpoints but less direct impact than you may think  major focus for BSAC in medium term is on implementation/ education