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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Microbiol. | doi: 10.3389/fmicb.2019.01237

Semi-mechanistic modelling of florfenicol time-kill curves and in silico dose fractionation for calf respiratory pathogens

  • 1Royal Veterinary College (RVC), United Kingdom
  • 2Kansas State University, United States
  • 3Ecole Nationale Vétérinaire de Toulouse, France

An important application of time-kill curve (TKC) assays is determination of the nature of the best PK/PD index (fAUC/MIC or fT%>MIC) and its target value for predicting clinical efficacy in vivo. VetCAST (the veterinary subcommittee of EUCAST) herein presents semi-mechanistic TCK modeling for florfenicol, a long acting (96h) veterinary antimicrobial licensed against calf pneumonia organisms (Pasteurella multocida and Mannheimia haemolytica) to support justification of its PK/PDcut-off and clinical breakpoint.
Individual TKC assays were performed with 6 field strains of each pathogen (initial inoculum 107 CFU/ml with sampling at times at 0, 1, 2, 4, 8 and 24 h). Semi-mechanistic modelling (Phoenix NLME) allowed precise estimation of bacteria growth system (KGROWTH, natural growth rate; KDEATH, death rate; BMAX, maximum possible culture size) and florfenicol pharmacodynamic parameters (EMAX, efficacy additive to KDEATH; EC50, potency; Gamma, sensitivity).
PK/PD simulations (using present TKC model and parameters of a florfenicol population pharmacokinetic model) predicted the time-course of bacterial counts under different exposures. Out of two licensed dosage regimen, 40 mg/kg administered once was predicted to be superior to 20 mg/kg administered at 48h intervals. Furthermore, we performed in silico dose fractionation with doses 0 – 80 mg/kg administered in 1, 2 or 4 administrations over 96h and for MICs of 0.5, 1, 2, 4 mg/L with 2 inoculum sizes 105 and 107 CFU/mL. Regression analysis (Imax model) demonstrated that i) fAUC/MIC outperformed fT%>MIC as PKPD index and ii) maximum efficacy (IC90%) was obtained when the average free plasma concentration over 96 h was equal to 1.2 to 1.4 times the MIC of Pasteurella multocida and Mannheimia haemolytica respectively.

Keywords: PK/PD, Modeling and simulation (M and S), Time-kill assay, Antimicrobial susceptibility testing (AST), Pasteurella multocida, Mannheimia haemolytica, VetCast, bovine respiratory disease

Received: 11 Apr 2019; Accepted: 17 May 2019.

Edited by:

Ghassan M. Matar, American University of Beirut, Lebanon

Reviewed by:

Cengiz Gokbulut, Balıkesir University, Turkey
Lena Friberg, Uppsala University, Sweden  

Copyright: © 2019 Pelligand, Lees, Sidhu and TOUTAIN. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Ludovic Pelligand, Royal Veterinary College (RVC), London, United Kingdom, lpelligand@rvc.ac.uk