EUCAST proposes to change the definition and usefulness of the susceptibility category ‘Intermediate’

Author: 

G. Kahlmeter, on behalf of the EUCAST Steering Committee
Clinical Microbiology and Infection 23 (2017) 894e895

Abstract: 

The European Committee on Antimicrobial Susceptibility Testing, EUCAST, aims to change the definition of the ‘Intermediate’ susceptibility category. In 2015 EUCAST consulted on a proposed change and received many comments. Comments and EUCAST responses were published on the EUCAST website in 2016 [1]. The proposalwas modified and this is now open for public consultation. The consultation period ends on 15 September 2017. The current definition of the Intermediate category is as follows (the EUCAST steering committee has introduced the numbering to highlight the many meanings embedded in the definition): Intermediate e current definition: A microorganism is defined as intermediate by a level of (1) antimicrobial agent activity associated with uncertain therapeutic effect. It implies that an infection due to the isolate (2) may be appropriately treated in body sites where the drugs are physiologically concentrated or (3) when a high dosage of drug can be used; it also indicates (4) a buffer zone that should prevent small, uncontrolled, technical factors from causing major discrepancies in interpretations. The definition includes several meanings but there is no system to indicate which of the four meanings was intended in the individual susceptibility report. A closer look at the different meanings makes it clear that some put the responsibility for action on the recipient of the report (increase exposure of the organism to the agent), whereas others are clearly the responsibility of the laboratory (produce an unequivocal result or admit failure). Thus, in the report an intermediate result which represents a need from the laboratory to warn the clinician not to trust the efficacy of the agent, either because the activity of the agent is in doubt (number 1) and/or because the method will not allow a clear recommendation (number 4), cannot be distinguished from a result which is meant to signal the need for an increased dose (number 3) unless the agent is concentrated at the site of infection in such a way that the exposure of the organism to the agent is already guaranteed at the standard dose (number 2). It is the responsibility of the laboratory to distribute reproducible, unequivocal results which the clinicians can understand and on which to act. With the current definition of intermediate this is not possible. It is not surprising that most recipients of an intermediate result have either chosen to ignore the result as impossible to interpret or interpreted an intermediate result as a surrogate for resistant and proceeded to look for an agent for which the result was sensitive. However, the numbers of sensitive antimicrobial alternatives in susceptibility testing reports are diminishing because of the rapid development of antimicrobial resistance and the lack of available new agents. To always search for an agent categorized as sensitive drives therapy towards our most potent agents. This is unwanted. We must identify strategies to prolong the life of currently available agents. An intermediate category with an unequivocal interpretation and which is perceived as a viable option for therapy may help to achieve that. The EUCAST breakpoint system was developed in such a way that the intermediate category most frequently signals the need for a dose higher than the standard dose. During the harmonization process, it was natural to identify the dosage regimens used in the various European countries to ensure that the breakpoints would be valid everywhere [2]. Once the dosage regimens had been identified it was natural to relate breakpoints to these. Both standard and higher doses were thus defined and are now available in rationale documents and summarized in the last tab of the breakpoints table. In this way, the organism is mostly categorized as intermediate when there is a need for a higher dose, either because the sensitivity of the organism is decreased because of acquired resistance (e.g. Streptococcus pneumoniae with benzylpenicillin MICs of 0.12e2 mg/L) or because even wild-type organisms of a species are intrinsically less than fully susceptible (e.g. Pseudomonas aeruginosa vs. aztreonam). EUCAST has never used the intermediate category because there was a need for a buffer zone.In 2015 we proposed to modify the definition of the intermediate category as follows. Intermediate e 2015 proposal: A microorganism is defined as intermediate by a level of antimicrobial activity associated with a high likelihood of therapeutic success but only when a higher dosage of the agent than normal can be used or when the agent is physiologically concentrated at the site of infection. After the public consultation in 2015e16, we now propose to modify the definition of the intermediate category as follows. Intermediate e 2017 proposal: A microorganism is categorized as intermediate when there is a high likelihood of therapeutic success because exposure* is enhanced (1) by adjusting the dosing regimen, or (2) because the antimicrobial agent is concentrated at the site of infection. *Exposure refers to concentration-time profiles found in the pharmacokinetic-pharmacodynamic indices that are relevant to the drug class: that is, the area-under-the-curve of the unbound agent, divided by the MIC (fAUC/MIC ratio), or the percentage of the dosing interval that the unbound agent is above the MIC (%fT>MIC). Only agents where alternative dose regimens (standard and high) are formally accepted or where the agent is significantly concentrated locally (predominantly agents used for treating urinary tract infections) will be assigned an intermediate category. We have identified 15-20 situations in which the susceptibility testing of an organism against an agent is so problematic that a buffer zone is needed to achieve accurate and reproducible susceptibility categorization. It is for the laboratory to solve. For these EUCAST will provide guidance to laboratories. Table 1 lists some of these situations. Some can be resolved by revising a breakpoint; others need a traditional buffer zone in the laboratory where the laboratory is prompted to perform further testing to produce an unequivocal categorization. We hope to hereby increase the usefulness of the intermediate category. Colleagues are invited to take part in the public consultation as published on the EUCAST website [3].