AUTHOR=Pelligand Ludovic , Lees Peter , Sidhu Pritam Kaur , Toutain Pierre-Louis 

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

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01237

DOI=10.3389/fmicb.2019.01237

ISSN=1664-302X

ABSTRACT=<p>An important application of time-kill curve (TKC) assays is determination of the nature of the best PK/PD index (<italic>f</italic>AUC/MIC or <italic>f</italic>T% &gt; MIC) and its target value for predicting clinical efficacy <italic>in vivo</italic>. 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 (<italic>Pasteurella multocida</italic> and <italic>Mannheimia haemolytica</italic>) to support justification of its PK/PD<sub>breakpoint</sub> and clinical breakpoint. Individual TKC assays were performed with 6 field strains of each pathogen (initial inoculum 10<sup>7</sup> 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 (K<sub>GROWTH</sub>, natural growth rate; K<sub>DEATH</sub>, death rate; B<sub>MAX</sub>, maximum possible culture size) and florfenicol pharmacodynamic parameters (E<sub>MAX</sub>, efficacy additive to K<sub>DEATH</sub>; EC<sub>50</sub>, 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 <italic>in silico</italic> 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 10<sup>5</sup> and 10<sup>7</sup> CFU/mL. Regression analysis (I<sub>max</sub> model) demonstrated that i) <italic>f</italic>AUC/MIC outperformed <italic>f</italic>T% &gt; MIC as PK/PD index and ii) maximum efficacy (IC<sub>90%</sub>) was obtained when the average free plasma concentration over 96 h was equal to 1.2 to 1.4 times the MIC of <italic>Pasteurella multocida</italic> and <italic>Mannheimia haemolytica</italic>, respectively.</p>