Shift to European (EUCAST)breakpoints – the impact on the

BSAC recommendations

Alasdair MacGowanSouthmead Hospital

BRISTOL

Topics

Processwhat is EUCAST? what does it do? why does it do it?what are the advantages? (if any), Do I care?

Definitionsclinical 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) andNational Breakpoint Committees of Europe (France, CA-SFM; Germany;DIN; Netherlands, CRG; Norway, NWGA; Sweden, SRGA; UK, BSAC WP)

Financed by –ESCMIDNational CommitteesDG-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

www.eucast.org

constitution & organisationCommittees & meetings

documents & MIC breakpointsMIC 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 invitro by a concentration of an antimicrobial agent that isassociated with a high likelihood of therapeutic success.

Resistant

a micro organism is defined as resistant if inhibited in vitroby a concentration of an antimicrobial agent that isassociated with a high likelihood of therapeutic failure

Definitions – cont’d

Intermediate

a micro organism is defined as intermediate by a level ofantimicrobial 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 morecommon: efflux mutants and fluoroquinolones

- what if the mechanism is an enzyme in contrastto 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 ofMIC distributions of any bacterial species. Theymay be used only for species that have not beengiven 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 BSACUK

CA-SFMFrance

CRGNetherlands

DINGermany

NWGANorway

SRGASweden

Most common dose 500 x 2 oral400 x 2 iv

500 x 2 oral200 x 2 iv

250 x 2 oral200 x iv

500 x 2 oral200 x 2 iv

200-400 x 2 oral

400 x 2 iv

500 x 2 oral400 x 2 iv

Maximum dose schedule 750 x 2 oral400 x 3 iv

750 x 2 oral400 x 3 iv

750 x 2 oral400 x 3 iv

750 x 2 oral400 x 2 iv data pending 750 x 2 oral

400 x 3 iv

Available formulations oral, iv oral, iv oral, iv oral, iv oral, iv oral, iv

EUCAST procedure for EUCAST procedure for setting breakpointssetting 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 Epidemiological cut off: WToff: WT<<0.064 mg/L0.064 mg/L

EUCAST procedure for EUCAST procedure for setting breakpointssetting breakpoints

3. Existing national clinical breakpoints are comparedBreakpoints prior to harmonisation (mg/L) S< R>

BSAC CA-SFM CRG DIN NWGA SRGA NCCLS

General breakpoints ND 1/2 1/2 1/2 0.125/2 1/2

Species related breakpoints not yet no

Enterobacteriaceae 1/1 0.12/2 0.12/1 1/2

Pseudomonas spp. 1/4 ND 1/1 1/2

Acinetobacter spp. 1/1 1/2

Staphylococci 1/1 0.12/2 0.06/2 1/2

Streptococci 1/1 excluded 0.12/2 0.12/2 excl

S. pneumoniae 2/2 (I)* excluded 0.12/2 (I)* 0.12/2 (I)* excl

Enterococci excluded excluded 0.12/2 0.12/2 1/2

Haemophilus/Moraxella spp. 1/1 0.12/0.5 0.12/0.25 1/-

Corynebacteria excl

N. Meningitidis 1/1 0.06/0.12 0.03/0.25

N. Gonorrhoeae 0.06/- 0.06/1 0.06/0.12 0.06/0.25 0.06/0.5

P. Multocida ND ND 0.12/0.25

Anaerobes excluded ND excluded

Campylobacter spp. 1/1

Helicobacter pylori 2/2 no no no no

EUCAST procedure for EUCAST procedure for setting breakpointssetting breakpoints

S = 0.5 mg/L S = 1 mg/LPk/Pd

0.25 0.5 1 2 4 80

20406080

100120140160180200

99% CI

Average

ciprofloxacin 500 mg q12h oral

MIC mg/L

fAUC

/MIC

0.25 0.5 1 2 4 80

20406080

100120140160180200

99% CI

Average

levofloxacin 500 mg q24h oral

MIC mg/LfA

UC/M

IC

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 EUCAST procedure for setting breakpointssetting 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/L2 mg/L

Epidemiological cut off: WT<2.0

Splitting the wild type must be avoidedto 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/L2 mg/L

Splitting the wild type must be avoidedto 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 EUCAST procedure for setting breakpointssetting breakpoints

”Dashed” – laboratories are recommended not to test

against this species

Click on name to directly access

MIC distributions

Insufficient evidence

EUCAST breakpoint tablesEUCAST breakpoint tablesavailable at http://www.eucast.orgavailable at http://www.eucast.org

Changes to BSAC breakpoints so far

Agreed breakpoints for –aminoglycosidesaztreonamcarbapenemscephalosporinsfluoroquinolonesglycopeptideslinezolid

New agents –daptomycintigecycline

Draft/consultation breakpoints formacrolidespenicillinsgarenoxacin

Summary of changes

EUCAST vs BSAC lower same higher 1diln

aminoglycosides aztreonam carbapenems cephalosporins fluoroquinolones glycopeptides linezolid

0 2 9 9

11 0 2

3 0 2 6 2 6 2

9 0 0 0 0 0 0

0 2 3 4 0 0 0

n=63 33 (53%)

21 (33%)

9 (14%)

9 (14%)

Which pathogen groups have changed the most?

lower same higher Enterococcus Pseudomonas Staphylococcus Enterobacteriacae B. haemolytic streps H. influenzae/ M. catarrhalis

0 3 3 8 9

10

4 4 5 5 2

1

0 3 3 3 0 0

Impact on susceptibility rates: BSAC surveillance 2005

%S gentamicin BSAC

( 1mg/L) EUCAST ( 2mg/L)

E coli (n=247) S. aureus (n=244) P. aeruginosa (n=216)

87.4 97.9 57.4

92.7 98.8 81.9

%S ciprofloxacin BSAC

( 1mg/L) EUCAST

( 0.5mg/L) E coli P. aeruginosa H. influenzae

93.5 82.4 99.8

93.5 79.2 99.8

%S entapenem BSAC

( 2mg/L) EUCAST

( 0.5mg/L) E coli K. pneumoniae Ent cloacae

100 99.5 96.5

100 99.5 86.7

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