Determination of the pharmacokinetic‐pharmacodynamic cut‐off values of marbofloxacin in horses to support the establishment of a clinical breakpoint for antimicrobial susceptibility testing

• Published in: Equine veterinary journal 2021-09, Vol.53 (5), p.1047-1055
• Main Authors: Bousquet‐Mélou, Alain, Schneider, Marc, El Garch, Farid, Broussou, Diane C., Ferran, Aude A., Lallemand, Elodie A., Triboulloy, Cyrielle, Damborg, Peter, Toutain, Pierre‐Louis
• Format: Article
• Language: English
• Subjects: Antimicrobial agents; antimicrobial susceptibility testing; horse; Life Sciences; monte carlo simulations; Pathogens; Pharmacodynamics; Pharmacokinetics; PK/PD cut‐off; population pharmacokinetic
• ISSN: 0425-1644; 2042-3306
• DOI: 10.1111/evj.13385

Background Marbofloxacin (MBX), a fluoroquinolone (FQ), is considered as a critical antibiotic requiring antimicrobial susceptibility testing (AST) for prudent use. No clinical breakpoint (CBP) currently exists to interpret the results of such tests in horses. Objectives To compute PK/PD cut‐offs (PK/PDCO) that is one of the three minimum inhibitory concentrations (MICs) considered establishing a CBP for antimicrobial susceptibility test interpretation. Study design A meta‐analysis conducted by combining five sets of previously published pharmacokinetic data, obtained in clinical and nonclinical settings. Methods Horses (n = 131) received MBX intravenously at doses of either 2 or 10 mg/kg BW. They were richly sampled (five or six samples per horse). A population model was built to generate a virtual population of 5000 MBX disposition curves by Monte Carlo simulations (MCS) over 24 hours. The selected PK/PD index was the ratio of Area Under the free plasma concentration‐time Curve divided by the MIC (fAUC/MIC). The PK/PDCO, which is the highest MIC for which 90% of horses can achieve an a priori selected critical value for the numerical value of the PK/PD index, was established for Gram‐positive and Gram‐negative bacteria for a dose of 2 mg/kg. Results The PK/PDCO of MBX in horses was 0.125 mg/L for Gram‐positive pathogens and 0.0625 mg/L for Gram‐negative pathogens. MBX MICs determined by broth microdilution for 54 Escherichia coli and 189 Streptococcus equi isolates are reported. Main limitation No clinical data are taken into account in the determination of a PK/PDco. Conclusion The computed PK/PDco predicts that MBX may be efficacious in horses to treat infections associated with Enterobacteriaceae but unlikely to those involving Staphylococcus aureus or Streptococcus equi.