At the turn of this century, there was considerable variation in antimicrobial susceptibility testing (AST) breakpoints used in Europe. The UK, France, The Netherlands, Germany, Norway and Sweden had their own national breakpoint committees and each published their own set of breakpoints. Laboratories in European countries without a national committee often subscribed to the US Clinical and Laboratory Standards Institute (CLSI) breakpoints and AST methodology, as the only system that was perceived as having some international standing.
Such disparity in breakpoints meant that it was difficult for the European clinical community to communicate regarding international AST and surveillance issues. There was a strong possibility that an isolate reported as resistant to a particular antimicrobial in one country could be reported as susceptible in another.
It was clear that harmonisation of AST breakpoints and standardisation of methodology was required across Europe. This would necessitate a joint strategy – the coming together of the six strong national breakpoint committees in Europe, together with representatives from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), and later with input from the European Medicines Agency (EMEA) and the European Centre for Disease Prevention and Control (ECDC). Thus, the European Committee on Antimicrobial Susceptibility Testing (EUCAST) was formed in 1997.
The EUCAST steering committee (chairman Professor Gunnar Kahlmeter, scientific secretary Derek Brown, clinical data coordinator Rafael Canton and eight other members from different European countries) meets five times a year to make decisions on AST issues within Europe and consults with experts from within the scientific community and industry on EUCAST proposals.
The European Committee on Antimicrobial Susceptibility Testing also has subcommittees on antifungal susceptibility testing, expert rules for antimicrobial susceptibility testing, and antimicrobial susceptibility testing of anaerobes. Significantly, EUCAST also now sets breakpoints for new antimicrobial agents (and extended indications for existing agents) through EMEA.
Common language
The first year of the project was spent planning and ensuring that everyone was on board. In these initial stages, the committee agreed on definitions (eg sensitive, intermediate and resistant) and the tools that would be required. It was important that the new system was not simply a compromise of existing systems, but that the work was started afresh, ensuring that it is modern and applicable.
The main aims of EUCAST were to:
* set common European breakpoints for surveillance of antimicrobial resistance
* produce updated documents on AST technology
* promote standardisation of methods across Europe and comparability of results obtained by different technologies
* encourage national and international quality assessment schemes
* collaborate with European and international groups concerned with AST and/or epidemiology of antimicrobial resistance
* advise the European community
* work with other bodies to achieve an international consensus.
Common antimicrobial breakpoints
In 2009, EUCAST harmonised most antimicrobial breakpoints in Europe. The EUCAST wild-type minimum inhibitory concentration (MIC) distributions are available on the EUCAST website, including MICs from national and international surveillance programmes such as the British Society for Antimicrobial Chemotherapy (BSAC) resistance surveillance programme, the Norwegian Surveillance Programme for Antimicrobial Resistance (NORM), the SENTRY Antimicrobial Surveillance Programme (monitoring antimicrobial resistance on a global scale), the European Antimicrobial Resistance Surveillance System (EARSS), the Meropenem Yearly Susceptibility Test Information Collection Surveillance Programme (MYSTIC), and others, as well as MIC distributions from published articles, the pharmaceutical industry, veterinary programmes and individual laboratories.
This harmonisation offers consistency throughout Europe, but the EUCAST breakpoints are still different to those provided by CLSI. However, CLSI breakpoints for cefotaxime will, from 2010, coincide with the EUCAST breakpoints.
The EUCAST breakpoints are now in widespread use in France, Germany, Norway, Sweden, The Netherlands and the UK. However, CLSI breakpoints are still used in many other European countries.
It would be beneficial for EUCAST breakpoints to be adopted throughout Europe for a number of reasons:
* EUCAST breakpoints are set for European minimum and maximum dosages
* they are based on EMEA-approved indications and outcome evaluations, and are determined using modern tools
* EUCAST breakpoints are accepted by European regulatory authorities (EMEA and ECDC)
* they offer harmonised standards for national/European strategies
* the rationale behind EUCAST decisions are transparent and published
* EUCAST is independent of commercial interest
* EUCAST breakpoints are reviewed at regular intervals
* the information is in the public domain, free of charge.
Major milestone
The quality of this work has been recognised by various regulatory bodies, including EMEA. The EMEA has appointed EUCAST to sets breakpoints for all new antimicrobials as part of the regulatory process for the approval of new agents and extended indications for existing agents.
A standard operating procedure (SOP) has been drawn up by EMEA, EUCAST and the pharmaceutical industry to regulate the role of EUCAST for setting breakpoints, and these are now the only ones to be published in the product summary. Significantly, the US Food and Drug Administration (FDA), which is equivalent to EMEA, does not recognise CLSI breakpoints in this way.
Standardised methodology
Another function of EUCAST has been to establish a standardised European disc-diffusion test method, calibrated to EUCAST MIC breakpoints, for routine AST.
Until now, there has not been a coherent European disc test method. Different countries use different methods, adding to breakpoint variation. In 2007–2008, a survey was sent out to all European countries with a view to developing a method that would meet international requirements. The European scientific community has been involved from the outset to ensure ownership and uptake of the standardised method.
Some of the issues that have been addressed include:
* the use of Mueller-Hinton (MH) agar for non-fastidious organisms
* the use of a different medium for fastidious organisms
* reassessment of disc strengths
* reassessment of ATCC strains used.
The new EUCAST method is based on two media: MH without supplements for non-fastidious organisms (including enterococci); and MH with 5% horse blood and 20 mg beta-NAD/L (MH-F), for streptococci, Haemophilus influenzae and other fastidious organisms. A uniform agar depth of 4(±0.5) mm should be used, with an inoculum equivalent to 0.5 McFarland for all organisms. Plates should be incubated at 35ºC for 18(±2) hours. Mueller-Hinton plates should be incubated in air and MH-F plates in 5% CO2.
The advantage of the new method is that only two plates are needed, saving time and resources, and allowing laboratories to increase their capacity. It also ensures that results and breakpoints are comparable between laboratories, both nationally and internationally.
The new disc-diffusion method has now been published on the EUCAST website (www.eucast.org) and includes basic methodology, ATCC tables and provisional diameter breakpoints.
The European community now has access to European breakpoints, set using modern tools, which are relevant and harmonised across Europe. As a result, clinical laboratories in Europe can be confident that they are working in line with colleagues in other European countries, that their results are comparable, and that they are speaking the same ‘AST’ language. In EUCAST, they now have a valuable channel for communication and standardisation.
Oxoid is EUCAST-ready
Through close association with EUCAST, Oxoid has developed a comprehensive portfolio of EUCAST-ready products, including AST discs, disc dispensers and accessories; dehydrated and prepared culture media; and the Culti-Loops range of QC organisms.
Disc diffusion remains one of the simplest and most widely used methods for susceptibility testing. It is an extremely flexible technique, with a wide variety of antibiotics and concentrations available, which can be changed easily as required. The disc-diffusion test not only categorises resistant, intermediate and sensitive organisms through quantitative results but also provides a visual indication of
inoculum level, presence of contamination, resistant mutants, beta-lactamase activity, and antagonism and synergy between antibiotics.
Oxoid antimicrobial susceptibility test discs are all manufactured under BS EN ISO 9001, with extended scope to BS EN 46001, and to the DIN specifications for potency (the tightest international standards available). All the compounds recommended by the EUCAST method can be found within the standard Oxoid range.