En Route towards European Clinical Breakpoints for Veterinary Antimicrobial Susceptibility Testing: A Position Paper Explaining the VetCAST Approach

Abstract

VetCAST is the EUCAST sub-committee for Veterinary Antimicrobial Susceptibility Testing. Its remit is to define clinical breakpoints (CBPs) for antimicrobial drugs (AMDs) used in veterinary medicine in Europe. This position paper outlines the procedures and reviews scientific options to solve challenges for the determination of specific CBPs for animal species, drug substances and disease conditions. VetCAST will adopt EUCAST approaches: the initial step will be data assessment; then procedures for decisions on the CBP; and finally the release of recommendations for CBP implementation. The principal challenges anticipated by VetCAST are those associated with the differing modalities of AMD administration, including mass medication, specific long-acting product formulations or local administration. Specific challenges comprise mastitis treatment in dairy cattle, the range of species and within species breed considerations and several other variable factors not relevant to human medicine. Each CBP will be based on consideration of: (i) an epidemiological cut-off value (ECOFF) - the highest MIC that defines the upper end of the wild-type MIC distribution; (ii) a PK/PD breakpoint obtained from pre-clinical pharmacokinetic data [this PK/PD break-point is the highest possible MIC for which a given percentage of animals in the target population achieves a critical value for the selected PK/PD index (fAUC/MIC or fT > MIC)] and (iii) when possible, a clinical cut-off, that is the relationship between MIC and clinical cure. For the latter, VetCAST acknowledges the paucity of such data in veterinary medicine. When a CBP cannot be established, VetCAST will recommend use of ECOFF as surrogate. For decision steps, VetCAST will follow EUCAST procedures involving transparency, consensus and independence. VetCAST will ensure freely available dissemination of information, concerning standards, guidelines, ECOFF, PK/PD breakpoints, CBPs and other relevant information for AST implementation. Finally, after establishing a CBP, VetCAST will promulgate expert comments and/or recommendations associated with CBPs to facilitate their sound implementation in a clinical setting.

Keywords: Antimicrobial Susceptibility Testing; VetCAST; antimicrobials; breakpoints; veterinary.

FIGURE 1

The successive steps in the process for establishing and implementing Clinical Breakpoints (CBPs) by VetCAST will follow three steps. The scientific assessment is a scientifically based process comprising determination of two critical MICs associated to ECOFF and PK/PD breakpoint and of clinically collected surrogates (MIC, AUC_24h/MIC…) able to predict clinical outcomes. The second step is decision (provisional for review or final for implementation) of a CBP based upon the different pieces of information determined at the previous step. This second step requires independence from all stakeholders. The final step involves communication, and includes the interactive exchange of information on standards, expert comments, guidelines, SOPs, ECOFF, PK/PD breakpoint, the CBP and any matter relating to susceptibility testing between VetCAST and its stakeholders.

FIGURE 2

Clinical breakpoints (CBP) are the values of the MIC (mg/L) selected by an ad hoc committee to be used by testing laboratories to qualitatively report the results of AST as Susceptible (S), Intermediate (I), or Resistant (R). CBPs are determined by taking into account the ECOFF, the PK/PD breakpoint and the clinical cut-off when available. CBP is established also by taking into account any aspects (scientific or not) that should be considered to ensure harmonization between countries.

FIGURE 3

The epidemiological cut-off (ECOFF) of amoxicillin for Escherichia coli; ECOFF is the MIC (8 μg/mL) that best separates the two sub-populations of the observed MICs (from 0.25 to 256 μg/mL) distribution, i.e., the wild-type population and of the non-wild-type population. ECOFF is a parameter that can be determined using simple visual inspection in the case of a clear bimodal distribution (as here) or by statistical techniques when greater certainty of the estimation is required (EUCAST raw data).

FIGURE 4

The three steps for the determination of a PK/PD breakpoint. The first step is to select one of the two PK/PD indices predictive of clinical efficacy, i.e., either the time for which plasma concentration remains above the MIC during the dosage interval (fT > MIC) or the ratio of area Under the plasma Concentration curve over the MIC (fAUC/MIC); the second step is to determine the size of the selected index required to ensure clinical and bacteriological efficacy. The third step is to determine, using Monte Carlo Simulation, the highest possible MIC for which a given percentage of animals in the target population (e.g., a prediction interval of 95%) is able to achieve the selected PK/PD index.