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.

Epidemiological and PK/PD cutoff values determination and PK/PD-based dose assessment of gamithromycin against Haemophilus parasuis in piglets

“…CBP is used to define susceptibility and resistance. In general, the determination of CBP should take into account the ECOFF, CO PD and clinical cutoff values [24,25]. Under the clinically recommended dose, the gamithromycin CO PD value (0.25 mg/L) against H. parasuis was lower than the ECOFF value (1.0 mg/L) in HTM broth.…”

“…In fact, our calculated accurate dose of gamithromycin for a PTA ≥ 90% was 6.55 mg/kg in this study, although slightly larger than the current dose. However, owing to the paucity of relevant data to bridge the relationship between MIC and clinical cure, it is practically difficult to determine a clinical cutoff in veterinary medicine [24,26]. In this case, VetCAST will not establish a CBP dividing the wild-type MIC distributions, and the ECOFF (1.0 mg/L) will therefore be recommended as surrogate [24].…”

Pharmacokinetics of marbofloxacin in Green sea turtles (Chelonia mydas) following intravenous and intramuscular administration at two dosage rates

“…Fluoroquinolones are concentration-dependent antimicrobials and the use of PK/PD surrogates can help to predict the efficacy of the drug given by its plasma concentrations. Use of the PK/ PD parameter Cmax/MIC ratio has recently been discontinued by EUCAST and VetCAST (Toutain et al, 2017) instead, the AUC/MIC is now considered the best index to predict antibacterial success (Nielsen & Friberg, 2013). Early studies agreed that an AUC 0-24 / MIC ratio > 100-125 can be used as a target for the efficacy of the antibacterial dug (Toutain, Bousquet-Mélou, & Martinez, 2007).…”

<p>Monitoring Antimicrobial Resistance and Drug Usage in the Human and Livestock Sector and Foodborne Antimicrobial Resistance in Six European Countries</p>

“…Differences between ECOFFs and CBPs are frequently underlined in literature. 91,92 ECOFFs identify the wild-type (those assumed to have no acquired/mutational resistance) from non-wild-type populations (those that show a degree of acquired/mutational resistance) while CBPs define clinically a microorganism as "sensitive", "intermediate" or "resistant" in relation to the likelihood of therapeutic success. CBPs take into account information such as the infection site, ability of the antimicrobial to reach the infection site, dosage regimens and formulations available to determine the effectiveness against the pathogen.…”