Antimicrobial susceptibility testing breakpoints and

J Antimicrob Chemother 2016; 71: 3– 5 doi:10.1093/jac/dkv287 Advance Access publication 16 September 2015

Antimicrobial susceptibility testing breakpoints and methods from BSAC to EUCAST Derek F. J. Brown1*, Mandy Wootton2 and Robin A. Howe2 1

EUCAST, Peterborough, UK; 2Public Health Wales, University Hospital of Wales, Cardiff, UK *Corresponding author. Tel: +44-1223-349396; E-mail: [email protected]

Introduction At an international level, the wide variation in breakpoints for antimicrobial susceptibility testing has long been recognized as an issue in need of action, as different breakpoints lead to different reports of susceptibility for some isolates and make comparison of resistance rates in surveillance studies in different countries unsound.1 In the 1990s there were several European national committees, including the BSAC Standing Committee on Antimicrobial Susceptibility Testing in the UK, each setting their own MIC breakpoints, and some also supported their own disc diffusion method calibrated to their own breakpoints. Those countries without a national committee most commonly followed the US CLSI (formerly NCCLS) recommendations. In the late 1990s the BSAC standardized disc diffusion susceptibility testing method, with zone diameter breakpoints correlated with BSAC MIC breakpoints, was developed as a replacement for the Stokes’ comparative method. Background information and other papers on various aspects of antimicrobial susceptibility testing were published in the Journal of Antimicrobial Chemotherapy Supplement that also included a description of the disc diffusion method.2,3

Organization of EUCAST EUCAST was established in 1997 with the support of ESCMID and with the principal objective of harmonizing susceptibility testing in Europe. However, in the following few years there was little engagement with established national breakpoint committees such as the BSAC and there was little progress on harmonization of breakpoints. In 2002 EUCAST was reorganized with the central involvement of all the active European national breakpoint

committees, including the BSAC Standing Committee on Antimicrobial Susceptibility Testing. The other European national susceptibility testing committees were the Comite´ de l’Antibiogramme de la Socie´te´ Franc¸aise de Microbiologie, France (CA-SFM); the Commissie Richtlijnen Gevoeligheidsbepalingen, the Netherlands (CRG); the Deutsches Institut fu¨r Normung, Germany (DIN); the Norwegian Working Group on Antimicrobials, Norway (NWGA); and the Swedish Reference Group of Antibiotics, Sweden (SRGA). All the committees agreed to work towards harmonization of breakpoints for established antimicrobial agents and to set harmonized breakpoints for new agents by a process agreed upon with the EMA.4,5 The work has been funded by ESCMID, the European Union [later through the European Centre for Disease Prevention and Control (ECDC)] and the national breakpoint committees, including the BSAC.

Harmonization of breakpoints by EUCAST Each of the national breakpoint committees has a seat on the EUCAST Steering Committee, which coordinates the work on harmonization. The breakpoint setting and review process has included the application of more recent techniques, such as pharmacodynamic analysis, and current data, where available, on MIC distributions, resistance mechanisms and clinical outcomes related to MIC values. In this process, there has been extensive discussion between the EUCAST Steering Committee and the national committees, and wide consultation on proposals.6,7 In the interests of international standardization of susceptibility testing and the need to review older breakpoints, these developments were strongly supported by the BSAC.

# The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]

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The BSAC Standing Committee on Antimicrobial Susceptibility Testing is one of several European national breakpoint committees that agreed in 2002 to harmonize clinical MIC breakpoints. The process of harmonization has since been completed for commonly used agents, and breakpoints for new agents have been set by EUCAST in accordance with a procedure defined by the EMA. EUCAST breakpoints have now been adopted by a large majority of laboratories in Europe. BSAC implemented the EUCAST breakpoints in its own disc diffusion susceptibility testing method as harmonized breakpoints were agreed to over the years. Since the development of the EUCAST disc diffusion method, several countries with their own disc diffusion methods have switched to the EUCAST method, and BSAC will replace support of its own disc diffusion method with support for the EUCAST method from January 2016. The EUCAST breakpoints are also available in automated systems. The harmonized breakpoints and methods will help to avoid different reports of susceptibility for the same isolate in different countries and enable more reliable comparison of resistance rates in surveillance studies in different countries.

Leading article

Between 2002 and 2008 the EUCAST Steering Committee worked through and agreed on harmonized breakpoints for all commonly used agents. As the breakpoints were agreed upon, they were adopted by the BSAC and other national committees, and each national committee calibrated its disc diffusion method to the harmonized MIC breakpoints. Hence, by 2008, when the first comprehensive version of the EUCAST breakpoint tables was published, the BSAC had already incorporated most of the harmonized breakpoints into its breakpoint tables, which are updated annually.8 As a consequence of the harmonization process, some MIC breakpoints have changed over time; these changes have been reflected, where necessary, in corresponding changes to zone diameter breakpoints in the BSAC disc diffusion method.9 The EUCAST breakpoints have also been incorporated into automated systems.

Although it was not originally intended that EUCAST would develop its own disc diffusion method, there was strong demand for this development, and in several countries this step was seen as a requirement for adopting EUCAST breakpoints. In response, EUCAST developed a method based on the widely used Kirby – Bauer method, but with different disc contents for some agents and a new medium for fastidious organisms based on that used by the BSAC and several Scandinavian countries. In 2009 the disc diffusion method was published,10 and there has been extensive uptake of the method, including by laboratories in countries formerly supporting their own methods.11 The arguments in favour of BSAC adopting the EUCAST disc diffusion method are strong. The EUCAST method is correlated with MICs, which were determined according to the international standard method for testing antimicrobial susceptibility.12 The EUCAST disc diffusion method has been developed to cover more antimicrobial agent/organism combinations than the BSAC disc diffusion method, although a few gaps remain (e.g. Neisseria gonorrhoeae). Many laboratories in the UK have already changed to using the EUCAST disc diffusion method. The fact that both BSAC and EUCAST methods are now used across the UK raises issues for delivery of support and educational activities. The EUCAST disc diffusion method is now the standard method used in most European countries, including all other countries with national committees that formerley supported their own methods. It is also increasingly used outside Europe. This means that EUCAST can draw on a wide international pool of experts and laboratories (including those in the UK) for development and support, whereas the expertise to support the BSAC method is more limited. The international support also means that the development costs are spread more widely. EUCAST is recognized by the EMA for the setting of MIC breakpoints for new agents and is increasingly seen by drug developers as the standard-setting organization for MIC breakpoints and disc diffusion testing.

Conclusions EUCAST MIC breakpoints for antimicrobial susceptibility testing are now used by a large majority of laboratories in Europe and by an increasing number outside Europe. By 2016 a large majority of laboratories using disc diffusion methods will also be following EUCAST guidelines for disc diffusion. These changes will lead to more consistent susceptibility reports across Europe and beyond.

Acknowledgements The work on harmonization of antimicrobial breakpoints and susceptibility testing methods by the BSAC Standing Committee on Antimicrobial Susceptibility Testing together with the EUCAST Steering Committee and all affiliated groups is gratefully acknowledged.

Funding EUCAST is funded by ESCMID and ECDC. The BSAC Standing Committee on Antimicrobial Susceptibility Testing is funded by the BSAC.

Transparency declarations D. F. J. B. is Scientific Secretary of EUCASTand a member of the BSAC Standing Committee on Antimicrobial Susceptibility Testing. M. W. is Secretary of the BSAC Standing Committee on Antimicrobial Susceptibility Testing. R. A. H. is the Chair of the BSAC Standing Committee on Antimicrobial Susceptibility Testing and periodically sits as a member of the EUCAST Steering Committee.

References 1 Kahlmeter G, Brown DF. Resistance surveillance studies—comparability of results and quality assurance of methods. J Antimicrob Chemother 2002; 50: 775–7. 2 Andrews JM. The development of the BSAC standardized method of disc diffusion testing. J Antimicrob Chemother 2001; 48 Suppl 1: 29– 42. 3 Andrews JM. BSAC standardized disc susceptibility testing method. J Antimicrob Chemother 2001; 48 Suppl 1: 43– 58.

The future of the BSAC disc diffusion method

4 Kahlmeter G, Brown DF, Goldstein FW et al. European harmonization of MIC breakpoints for antimicrobial susceptibility testing of bacteria. J Antimicrob Chemother 2003; 52: 145–8.

For the above reasons, the BSAC Standing Committee for Antimicrobial Susceptibility Testing, with the support of BSAC Council, will cease active support, maintenance and development of the BSAC disc diffusion method from January 2016 and will

5 EMA. Harmonisation of European Antimicrobial Susceptibility Testing Breakpoints Determined by EMA/CHMP and EUCAST (revised 2007 and reviewed without changes 2009). http://www.ema.europa.eu/docs/ en_GB/document_library/Standard_Operating_Procedure_-_SOP/2009/ 09/WC500002942.pdf.

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A EUCAST disc diffusion method

recommend and support the implementation and use of the EUCAST method. Educational activities including user days and workshops have been changed to reflect this policy. EUCAST will be supported by BSAC in the further development and maintenance of the EUCAST susceptibility testing methods. Concern has been expressed that BSAC is being replaced by EUCAST and that local expertise will be lost. This is not the case, as EUCAST depends on BSAC and other national committees for their expertise. The national committees are an integral part of EUCAST and are central to all aspects of breakpoint setting and susceptibility testing.

Leading article

6 EUCAST. Setting Breakpoints for New Antimicrobial Agents. http:// www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/EUCAST_SOPs/ EUCAST_SOP_1._1_Setting_breakpoints_new_agents_1_June_2013.pdf. 7 EUCAST. Harmonization of Breakpoints for Existing Antimicrobial Agents. http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/EUCAST_ SOPs/EUCAST_SOP_2_1_Setting_breakpoints_existing_agents_20130720f. pdf. 8 EUCAST. Clinical Breakpoints. http://www.eucast.org/clinical_ breakpoints. 9 BSAC. BSAC Methods for Antimicrobial Susceptibility Testing. http://www. bsac.org.uk/wp-content/uploads/2012/02/BSAC-disc-susceptibilitytesting-methods-Jan-2015.pdf.

JAC 10 EUCAST. EUCAST Disk Diffusion Test Methodology. http://www.eucast. org/ast_of_bacteria/disk_diffusion_methodology. 11 Brown DFJ, Canton R, Dubreuil L et al. Widespread implementation of EUCAST breakpoints for antibacterial susceptibility testing in Europe. Euro Surveill 2015; 20: pii¼21008. 12 International Organization for Standardization (ISO). Clinical Laboratory Testing and In Vitro Diagnostic Test Systems. Susceptibility Testing of Infectious Agents and Evaluation of Performance of Antimicrobial Susceptibility Test Devices. Part 1: Reference Method for Testing the In Vitro Activity of Antimicrobial Agents Against Rapidly Growing Aerobic Bacteria Involved in Infectious Diseases. International Standard 20776-1. ISO, Geneva, Switzerland, 2006.


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