EUCAST Procedure for Harmonising and Defining Breakpoints
 

Comments on this document should be sent to Dr G. Kahlmeter (Tel: +46 470587477;  Fax: +46 470587455; Email: gunnar.kahlmeter@ltkronoberg.se)

 


 

Introduction

Current breakpoints in Europe

Seven different sets of antimicrobial MIC breakpoints are used in Europe. There are 6 active European National Breakpoint Committees: BSAC (UK), CA-SFM (France), CRG (The Netherlands), DIN (Germany), NWGA (Norway) and SRGA (Sweden) and, since many of the other countries, in the absence of a national system, subscribe to breakpoints published by the CLSI (formerly NCCLS), USA, the divergence in interpretation is prominent. So far there has been no active co-ordination between the European National Committees or between Europe and the USA. To achieve harmonization of antimicrobial breakpoints, the six National Committees have now organised themselves in EUCAST (European Committee on Antimicrobial Susceptibility Testing), convened and financed by ESCMID (European Society for Clinical Microbiology and Infectious Diseases).

EUCAST

EUCAST is a standing committee of ESCMID and consists of a body of experts appointed by national societies of clinical microbiology and/or infectious diseases and national breakpoint committees. EUCAST will act with the support of national breakpoint committees to harmonize breakpoints for existing antimicrobials and set breakpoints for new antimicrobials. In this professional consensus process EUCAST will liaise with other professional groups and organisations.

The EUCAST General Committee consists of a representative from each European country and from ISC and FESCI. All pharmaceutical companies and manufacturers of susceptibility testing devices can be part of the EUCAST consultation process by participation in established email consultation groups.

The EUCAST Steering Committee is the more active part of EUCAST. Apart from the Chairman, Scientific Secretary, Clinical Data Co-ordinator and two country representatives from the EUCAST General Committee (all appointed by the ESCMID board), each of the 6 National Breakpoint Committees are represented on the steering committee. The national committees consist of 10 - 20 experts in their respective fields. This means that the consultation process beween EUCAST and the national breakpoint committees is of major importance, not only to seek the joint approval of steering committee decisions but to seek scientific answers to difficult questions. Following the internal consultation process between the steering committee and the national breakpoint committees, tentative decisions made by the steering committee are submitted to the EUCAST General Committee for comments and suggestions. The final decision rests with the EUCAST Steering committee. The described decision process is valid for all decisions taken by EUCAST, including decisions on breakpoints.

For further information on the structure of EUCAST, see the EUCAST website http://www.eucast.org.

National determination of breakpoints

Each National Breakpoint Committee consists of 10 – 20 experts within the fields of clinical microbiology, infectious diseases and pharmacology. Some have additional experts within the fields of community medicine, pediatrics and otorhinolaryngology. Each Committee has an academic process for setting national breakpoints for new drugs and for the revision of breakpoints for existing drugs. These processes vary. Some emphasize the pharmacokinetic/pharmacodynamic aspects while others emphasize microbiological factors. Several committees have representation from the pharmaceutical and antimicrobial susceptibility testing industry while others do not.

EUCAST determination of clinical breakpoints and epidemiological cut-off values.

EUCAST will make use of existing national processes for determining clinical breakpoints for new antimicrobials and for revising and harmonising breakpoints for existing drugs. The work has started with the revision of breakpoints for fluoroquinolones, aminoglycosides, glycopeptides and linezolid.  EUCAST will try a co-ordinated process for setting breakpoints for new antimicrobials (see below).

In addition to clinical breakpoints, EUCAST will define epidemiological cut-off values, which are related to the distribution of MICs of wild type susceptible populations and are of value in detecting the development of microbiological resistance to antimicrobial agents.


Breakpoints for new antimicrobials

The procedure through which EMEA, EUCAST and Pharmaceutical industry interact in the approval process for new drugs is defined in an SOP (SOP /H/3043, 14 February 2005).

The national committees (BSAC, CA-SFM, CRG, DIN, NWGA, SRGA) have agreed to notify each other when one or several are approached to set breakpoints for a new antimicrobial drug outside of the EMEA procedure.

The advantages of the agreed procedure are that it results in common European clinical breakpoints for new antimicrobials, the procedure has a time limit,  the expertise within the system is fully utilized and it is cost effective for the drug companies (one file, one presentation of the drug, a common European breakpoint).

The procedure for defining breakpoints for new antimicrobials and for harmonizing breakpoints for existing antimicrobials are described below.

 

Procedure for setting breakpoints for new antimicrobials

Data collection

Each national breakpoint committee will submit (using a form designed for this purpose):

  1. A preliminary breakpoint for the agent in question. Unless the agent belongs to a class of dugs which has been through the EUCAST harmonization process, the national clinical breakpoints of related drugs should be presented simultaneously.
  2. The nationally recommended dosages of the agent being assessed and the available formulations.
  3. The national recommended indications for the new drug.
  4. MIC distributions of relevant species.

Data collation

The EUCAST secretariat will:

  1. Collate all information in one file and other pertinent information. This file is distributed to the National Committees for ratification.
  2. Enter the MIC-distributions into the “EUCAST antimicrobial wild-type software”, thereby making all MIC distributions available to all National Committees on the internet.
  3. Suggest preliminary epidemiological cut-off values for discussion by the Steering Committee members.
  4. Point out breakpoint discrepancies for further discussions.
  5. Distribute the complete material to the Steering Committee members and the EMEA assessor if one has been appointed.
  6. Set a date for a discussion at a Steering Committee meeting and invite the pharmaceutical company and the EMEA assessor to the meeting.

Relevant factors in setting breakpoints for new antimicrobials and assessment of data:

  1. The national similarities and differences regarding maximum and minimum dosing, available formulations (oral, iv), clinical indications and practices, and target organisms.
  2. Multiple MIC distributions of relevant species, collected in the EUCAST wild type distribution program (www.eucast.org), are assessed and epidemiological cut-off values (defined as WT≤X mg/L) determined.
  3. Dose-effect relationships obtained in in vitro studies, animal studies and humans (PK/PD data) is evaluated.
  4. Modelling processes, such as Monte Carlo simulation, may be used to assist the process of breakpoint setting.
  5. Clinical data relating outcome to MIC-values
  6. Breakpoints suggested by the national breakpoint committees are compared and discussed.
  7. Consensus breakpoints are sought.
  8. Resulting breakpoints are tested against each of the major target species MIC-distributions. This is to make sure that the suggested EUCAST breakpoints do not divide the wild-type distributions of major target species. This would obviate a reproducible S, I & R- categorisation in the laboratory. The ensuing breakpoints may therefore differ between species.
  9. The committee may refrain from setting breakpoints if the species is considered a poor target for the drug (marked by in breakpoint tables) or there is insufficient evidence that the species is a good target for the drug (marked by IE in breakpoint tables)

Consultation on preliminary breakpoints

Preliminary EUCAST breakpoints on new drugs are presented to national breakpoint committees for comments. Significant points arising will be discussed in the Steering Committee and any adjustments agreed.

The tentative EUCAST breakpoints are then submitted for comments to the EUCAST General Committee members, the EMEA and the drug companies and again to national breakpoint committees.

Presentation of breakpoints

EUCAST breakpoints are presented as "tentative breakpoints for comments" in tables freely accessible on the EUCAST website. Major groups of organisms each have a breakpoint column. Current groups are Enterobacteriaceae, Pseudomonas, Acinetobacter, staphylococci, Streptococcus pneumoniae, streptococci, enterococci, Haemophilus, Moraxella, Neisseria gonorrhoeae, Neisseria meningitidis and anaerobes (Bacteroides spp/clostridia). In addition, a column of non-species related breakpoints determined mainly on the basis of PK/PD data and independent of MIC distributions of specific species are presented. These are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended. See examples on the EUCAST website.

The EUCAST General Committee and the manufacturer´s network are notified of the "tentative breakpoints for comments".

Finalisation of EUCAST breakpoints

Comments received in writing during the consultation period are made available (published on the steering committee website) to the national committees and to the steering committee members. Comments are discussed at the following EUCAST Steering Committee meeting and a consensus decision reached. In the case of a dissenting National Committee, they will submit their reasoning in writing, and this will be published with the breakpoint agreed on by the rest of the Steering Committee.

Publication of breakpoints

Breakpoints will be published on the EUCAST website, on the National Committee websites and in publications. A document will be prepared for publication in CMI.

 


Harmonizing breakpoints for existing antimicrobials

Each of the existing groups of antimicrobials will be addressed in turn. The work has started with the fluoroquinolones, aminoglycosides, glycopeptides and linezolid and is now continuing with carbapenems and cephalosporins. For existing drugs the process will be a revision exercise, involving an element of compromise to achieve harmonization of breakpoints. Decisions in the Steering Committee are taken by consensus agreement. The process involves consultation with the EUCAST General Committee, pharmaceutical industry, antimicrobial susceptibility testing industry and EMEA.

Data collection

Each national breakpoint committee will submit (using a form designed for this purpose):

  1. The current breakpoint(s) for the relevant agent(s). Those that have been recently re-evaluated will be indicated. It is important that each National Committee representative informs their National Committee of the forthcoming re-evaluation of the respective breakpoints. Ideally the National Committee should give the Steering Committee representative an “acceptable” MIC range for breakpoints to allow for compromise if necessary.
  2. The national maximum and minimum dosages of the agents being assessed and the available formulations.
  3. The nationally accepted clinical indications and the microbial targets for each of the agents being assessed.
  4. MIC distributions of relevant species, preferably those that were used in the national process of breakpoint setting.

Data collation

The EUCAST secretariat will

  1. Collate all information in one file (see enclosed example of the fluoroquinolones) and other pertinent information. This file is distributed to the National Committees for ratification.
  2. Enter the MIC-distributions into the “EUCAST antimicrobial wild-type software”, thereby making all MIC distributions available to all National Committees on the internet.
  3. Suggest tentative species-specific epidemiological cut-off values for discussion by the Steering Committee members.
  4. Point out breakpoint or other discrepancies for further discussions.
  5. Distribute the complete material to the Steering Committee members.
  6. Set a date for a discussion at a Steering Committee meeting.

Relevant factors in harmonizing clinical MIC breakpoints for existing drugs and assessment of data:

  1. The national similarities and differences regarding maximum and minimum dosing, available formulations (oral, iv), clinical indications and practices, and target organisms.
  2. Multiple MIC distributions of relevant species, collected in the EUCAST wild type distribution program (www.eucast.org).
  3. Dose-effect relationships obtained in vitro studies and animal studies (PK/PD data) are evaluated.
  4. Modelling processes, such as Monte Carlo simulation, may be used to assist the process of breakpoint setting.
  5. Clinical data relating outcome to MIC-values
  6. Existing national breakpoints are compared.
  7. Consensus breakpoints are sought.
  8. Resulting breakpoints are tested against each of the major target species MIC-distributions. This is to make sure that the suggested EUCAST breakpoints do not divide the wild-type distributions of major target species. This would obviate a reproducible S, I & R- categorisation in the laboratory. The ensuing breakpoints may therefore differ between species.
  9. The committee may refrain from setting breakpoints if the species is considered a poor target for the drug (marked by in breakpoint tables) or there is insufficient evidence that the species is a good target for the drug (marked by IE in breakpoint tables)

Consultation on preliminary breakpoints

Tentative EUCAST breakpoints are presented to national breakpoint committees for comments. Significant points arising will be discussed in the Steering Committee and any adjustments agreed.

The tentative EUCAST breakpoints are then submitted for comments to the EUCAST General Committee members, the EMEA and the drug companies and again to national breakpoint committees for comments.

Presentation of breakpoints

EUCAST breakpoints are presented as "tentative breakpoints for comments" in tables freely accessible on the EUCAST website. Major groups of organisms each have a breakpoint column. Current groups are Enterobacteriaceae, Pseudomonas, Acinetobacter, staphylococci, Streptococcus pneumoniae, streptococci, enterococci, Haemophilus, Moraxella, Neisseria gonorrhoeae, Neisseria meningitidis and anaerobes (Bacteroides spp/clostridia). In addition, a column of non-species related breakpoints determined mainly on the basis of PK/PD data and independent of MIC distributions of specific species are presented. These are for use only for species that have not been given a species-specific breakpoint and not for those species where susceptibility testing is not recommended. See examples on the EUCAST website.

The EUCAST General Committee and the manufacturer´s network are notified of the "tentative breakpoints for comments".

Finalisation of EUCAST breakpoints

Comments received in writing during the two-month consultation period are made available to the national committees and to the steering committee members. Comments are discussed at the following EUCAST Steering Committee and a consensus decision reached. If one of the National Committees cannot agree with the consensus decision, their reasoning will be submitted in writing, and this will be published with the breakpoint agreed by the rest of the Steering Committee.

Publication of breakpoints

Breakpoints will be published on the EUCAST website, on the National Breakpoint Committee websites and in publications. A document will be prepared for publication in CMI.