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Semi-Mechanistic Modeling of Florfenicol Time-Kill Curves and in silico Dose Fractionation for Calf Respiratory Pathogens

Pelligand, L; Lees, P; Sidhu, P K; Toutain, P-L

Authors

L Pelligand

P Lees

P K Sidhu

P-L Toutain



Abstract

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 TKC modeling for florfenicol, a long acting (96 h) veterinary antimicrobial drug licensed against calf pneumonia organisms (Pasteurella multocida and Mannheimia haemolytica) to support justification of its PK/PDbreakpoint 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 modeling (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 the present TKC model and parameters of a florfenicol population pharmacokinetic model) predicted the time-course of bacterial counts under different exposures. Of two licensed dosage regimens, 40 mg/kg administered once was predicted to be superior to 20 mg/kg administered at 48 h intervals. Furthermore, we performed in silico dose fractionation with doses 0 – 80 mg/kg administered in 1, 2 or 4 administrations over 96 h 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 PK/PD 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.

Citation

Pelligand, L., Lees, P., Sidhu, P. K., & Toutain, P. (2019). Semi-Mechanistic Modeling of Florfenicol Time-Kill Curves and in silico Dose Fractionation for Calf Respiratory Pathogens. Frontiers in Microbiology, 10, https://doi.org/10.3389/fmicb.2019.01237

Journal Article Type Article
Acceptance Date May 17, 2019
Publication Date Jun 11, 2019
Deposit Date Jun 15, 2019
Publicly Available Date Jun 17, 2019
Journal Frontiers in Microbiology
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 10
DOI https://doi.org/10.3389/fmicb.2019.01237
Public URL https://rvc-repository.worktribe.com/output/1381858

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