Creating a global consensus for antimicrobial breakpoint to combat antibiotic resistance in future drugs.

The World Health Organization states that we are in “a race against time to develop new antibiotics,” with very few antibiotics in drug development. This may be because we have run out of ideas or because return on investment is considered poor. Furthermore, the speed with which bacteria develop new resistance can dampen the enthusiasm of anyone. This, coupled with the global spread of resistant bacteria between countries, means we now have a situation that demands immediate reactions from governments.

Over the last three decades no new antibiotic classes were discovered. New members in already-known groups of antimicrobials have been developed and some of these have been combined with beta-lactamase inhibitors. Central to on-going global efforts is the standardization of the definition of resistance for each relevant antimicrobial agent and species.

Antimicrobial Breakpoint

Over the past 15-years, the European community of microbiologists and infectious disease specialists have established common breakpoints for Europe. An antimicrobial breakpoint is the agreed concentration of an agent at which bacteria can, and cannot, be treated with the antimicrobial agent in question. This will be related to the dose needed to treat susceptible bacteria. Essentially, the breakpoint is a man-made or rather decided concentration, which corresponds to a dose required to inhibit bacterial growth in relevant infections.

A typical breakpoint is S≤1 and R>4 mg/L which should be interpreted as anything with a minimum inhibition concentration (MIC) less than or equal to 1 is to be categorized as “susceptible” (possible to treat with agreed standard dosing of the agent in question), and anything with an MIC above 4 is to be categorized “resistant” (not possible to treat even with the highest possible dose). Everything in-between is categorized as “intermediate” (treatable given an increase in dosage). As new resistance mechanisms develop, dosing schemes are developed, and other infections or bacteria than those originally evaluated are to be included. There is a need to review and sometimes revise these breakpoints.

Until very recently we had no census on this. Although more and more countries adopt the EUCAST (European Committee on Antimicrobial Susceptibility Testing) recommendations, there are still many countries which utilize other systems—most often, the U.S. system through CLSI (Clinical Laboratory Standards Institute). On a practical level, this means antimicrobial agents may have different breakpoints in different countries, which means an isolated bacterium could be categorized as susceptible and resistant to an agent in two countries. If we are going to tackle the problem of antibiotic resistance, we need to compare it like-for-like on a global scale. This is the remit of EUCAST. 

The History of EUCAST

Since the 1970s, breakpoint committees such as EUCAST have determined the breakpoints for phenotypic antimicrobial susceptibility testing as part of regulatory processes for the approval of new drugs. The European Medicines Agency (EMA) and EUCAST drew up a standard operating procedure (SOP) regarding the setting of antimicrobial susceptibility testing breakpoints. The SOP was introduced as part of the centralized procedure for the assessment and approval of new drugs in the European Union.

In 2008, only 20-30 percent of European nations had adopted the EUCAST guidelines. In 2015, this number has increased to 90 percent, with several non-European countries following suit. These include nations as far reaching as Australia, New Zealand, South Africa, and Morocco. Previous to EUCAST, it would have been particularly complicated to use a common system given that there were seven different systems in place.

  • EUCAST deals with breakpoints and technical aspects of phenotypic in vitro antimicrobial susceptibility testing and functions as the breakpoint committee of EMA.
  • EUCAST consists of a group of scientists, primarily from the field of clinical microbiology who develop methods and breakpoints within the field of susceptibility testing of bacteria and fungi.
  • EUCAST consists of a general committee with representatives from all countries.
  • The EUCAST steering committee, with representatives from the General Committee and with experts in the field, prepares all decisions and consults with the General Committee, EMA, ECDC, and the world at large in an open consultation process.
  • EUCAST subcommittees deal with specific areas, such as fungi, anaerobe bacteria, detection of specific resistance mechanisms, etc.
  • Funding is from ESCMID and ECDC.  

Developing Breakpoints

The process by which break points are defined is based on the work of a committee formed by individuals from different backgrounds in clinical microbiology and infectious diseases. After research into and discussions of parameters—such as antimicrobial activity, resistance mechanisms, pharmacokinetics, and pharmacodynamics—clinical outcome data will define the concentration which will serve as the breakpoint. At the end of the process, it is published as a tentative breakpoint on the EUCAST website and opened for consultation. Opinions are gathered and discussed, and final breakpoints and rebuttals are eventually published. 

Together with EMA, EUCAST has determined breakpoints for approximately 10 new agents and is currently occupied with several compounds that are still being processed. Companies in the process of developing new agents are encouraged to seek contact with EUCAST early in the development cycle to obtain advice on the procedure. We can also help pave the way for the development of AST material needed for susceptibility testing of the new agent.

Despite the recent success of EUCAST, there are still undecided countries. In many countries, laboratories take individual decisions, and it is not unusual for countries to end up with the unfortunate situation of having two systems. Since the two systems do not agree, especially on older agents, this is detrimental to both patient care and on-going programs of resistance surveillance.

In the UK, the British Society for Antimicrobial Chemotherapy (BSAC) recently recommended UK laboratories to adopt EUCAST guidelines and informed laboratories that the BSAC-recommended method will not be updated after the end of 2015. In USA, there are two sets of breakpoints, those decided by FDA as part of the registration process and those recommended by CLSI. To complicate matters further, a group of U.S. scientists now work as an integral part of EUCAST.

Everyone agrees that international unity would be beneficial to all. To perform everyday susceptibility testing, efforts to combat antimicrobial resistance and the dissemination of resistant organisms, the development of new agents and of new diagnostics would greatly benefit from having a uniform definition of breakpoints for use in phenotypic susceptibility testing.

Bacteria are fighting antibiotics globally, regardless of geographic boundaries, and we need to take the same approach in our research.

Gunnar Kahlmeter is the Communications Officer and Past President of ESCMID and Clinical Data Coordinator and Past Chairman of EUCAST.

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