Plan implementation Reporting options including risk communication

Appendix 1. Interpretation of antimicrobial susceptibility test results Phenotypic determination of antimicrobial susceptibility of a bacterial isolate is important to ensure appropriate therapy for infections in animals and humans and to produce monitoring data on the occurrence of acquired resistance among bacteria in different reservoirs. Semi- quantitative methods for determining the MIC of an antimicrobial agent for a given bacterial isolate are currently the gold standard for antimicrobial susceptibility testing. A MIC is defined as the lowest drug concentration that visibly inhibits bacterial growth. In routine antimicrobial susceptibility testing, MICs are usually determined by serial two-fold drug dilutions, thus implying that the actual MIC of an isolate is only approximated. Indeed, the true MIC of an isolate growing at 1 mgL, but not at 2 mgL thus, the recorded MIC is 2 mgL, lies somewhere between 1 mgL and 1.99 mgL. MIC values are interpreted using defined criteria to categorize bacterial isolates as susceptible or resistant, which is essential both for guiding appropriate clinical treatment and for comparing results from different monitoring programmes over time. However, interpretive criteria may differ among laboratories and countries, and also based on the purpose of the MIC determination. For example, MIC breakpoints appropriate for predicting clinical efficacy might differ from those used for surveillance purposes. An isolate might acquire reduced susceptibility to a given antimicrobial but still have a sufficiently low MIC to allow successful therapy. It is therefore important to differentiate between interpretative criteria used for clinical purposes clinical breakpoints and those used for monitoring epidemiological cut-off values [ECOFFs], as illustrated in the Figure A1.1 below. Fig.A1.1 MIC distribution for a hypothetical organism-antimicrobial combination. S, susceptible; I, intermediate; R, resistant 6 8 C om bi ne d A na lys is a nd Re po rt in g 3 According to clinical breakpoints, bacterial isolates are categorized as susceptible, intermediate or resistant to a given antimicrobial. Setting clinical breakpoints requires microbiological MIC data generated using standardized in vitro testing methods, pharmacokinetic and pharmacodynamic information generated from animal models and human studies, and outcome data from clinical efficacy trials. Clinical breakpoints provide guidance for antimicrobial treatment by implying that susceptible isolates are inhibited by the usually achievable concentrations of that antimicrobial agent when the recommended dosage is used for that site of infection. On the contrary, resistant isolates are not inhibited by the usually achievable concentrations of that antimicrobial with approved dosage schedules. The intermediate category provides flexibility for body sites where an antimicrobial is physiologically concentrated thus likely implying clinical efficacy or when higher-than-normal dosage of an antimicrobial can be used. In addition, it provides a buffer zone to account for day-to-day variability in in vitro antimicrobial susceptibility testing. As defined by EUCAST, the ECOFF is the highest MIC for organisms devoid of phenotypically detectable acquired resistance mechanisms. Bacterial isolates are categorized as wild-type and non-wild-type. Wild-type isolates exhibit no resistance to a given antimicrobial whereas non-wild-type isolates have some type of acquired mechanism e.g. mutations, acquisition of foreign DNA, up-regulation of an efflux pump, up-regulation of target production reducing susceptibility to a given antimicrobial. Setting ECOFFs requires determination of the MIC distribution for organism-antimicrobial combinations using a large number of bacterial isolates of different geographical origin and collection times. Thus, the epidemiological cut-off takes into account exclusively microbiological properties independent of any consideration on drug dosages, site of infection, animal species and clinical efficacy. Several national and international committees establish interpretive criteria for antimicrobial susceptibility testing. The most widely used are those provided by the Clinical and Laboratory Standards Institute CLSI, www.clsi.org, which publishes methods for antimicrobial susceptibility testing and interpretive criteria based on clinical breakpoints. In Europe, the European Committee for Antimicrobial Susceptibility Testing EUCAST, www.eucast.org provides both ECOFFs and clinical breakpoints which are freely available on the EUCAST website. It should be emphasized that interpretive criteria established by different organization may differ; therefore, it is important to specify the criteria used when reporting antimicrobial susceptibility test results. Continuous efforts to harmonize interpretive criteria for antimicrobial susceptibility test results should be pursued. Being dependent exclusively on microbiological properties, ECOFFs provide a categorization of bacteria relative to antimicrobial susceptibility that is comparable across geographical areas, animal species and over time. Therefore, for monitoring purposes, the WHO Collaborating Centre for Antimicrobial Resistance in Foodborne Pathogens recommends and uses ECOFFs provided by EUCAST, as the reference standard for all organisms and antimicrobials. 6 9