AUTHOR=Xiao Xia , Lan Weixuan , Zhao Yaqin , Li Ruichao , Liu Yuan , Liu Juan , Wang Zhiqiang 

TITLE=In vivo Pharmacokinetic and Pharmacodynamic (PK/PD) Modeling and Establishment of the PK/PD Cutoff of Florfenicol Against Pasteurella multocida in Ducks

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.616685

DOI=10.3389/fmicb.2020.616685

ISSN=1664-302X

ABSTRACT=<p><italic>Pasteurella multocida</italic> can invade and translocate through endothelial cells and result in vascular-system infection, which can cause severe economic losses in the poultry industry. Antibacterial therapy (especially florfenicol) plays an important part in controlling <italic>P. multocida</italic> infection. To preserve the effect of florfenicol, <italic>in vivo</italic> pharmacokinetic/pharmacodynamic (PK/PD) modeling of florfenicol against three <italic>P. multocida</italic> strains in duck was established. Then, the efficacy of the currently marketed dose, a rational dosage regimen for populations, and the PK/PD cutoff were predicted through Monte Carlo simulations (MCSs). The area under the concentration–time curve from 0 to 24 h/minimum inhibitory concentration (AUC<sub>0–24 <italic>h</italic></sub>/MIC) was the optimal PK/PD parameter. The PK/PD surrogate values of florfenicol against <italic>P. multocida</italic> were similar using different organs as the PD target, but varied in different strains. For the florfenicol-sensitive strain 0825Y<sub>1</sub>, when the AUC<sub>0–24 <italic>h</italic></sub>/MIC reached 117.54 and 108.19, florfenicol showed a bactericidal effect in the liver and lung, respectively. For the florfenicol-sensitive strain 0901J<sub>1</sub>, the corresponding value was 78.39 and 54.30, respectively. For the florfenicol-resistant strain JY160110, florfenicol could attain a maximum effect of 1 – log<sub>10</sub> reduction in bacteria in the liver and lung when the AUC<sub>0–24 <italic>h</italic></sub>/MIC reached 2.03 and 2.06, respectively. The PK/PD-based prediction for the population dose indicated a poor effect for the low end of the currently marketed dose (40 mg/kg body weight per day), but a robust effect for the high end of the currently marketed dose (60 mg/kg body weight per day) with a target attainment rate of 92.79% and 81.44% against <italic>P. multocida</italic> in mainland China and worldwide, respectively. The recommended dose optimized by MCSs was 52 mg/kg body weight in mainland China. The PK/PD cutoff of florfenicol against <italic>P. multocida</italic> at the low end and high end of the current daily dose (40 and 60 mg/kg body weight) and predicted daily dose in mainland China (52 mg/kg body weight) was 0.25, 4, and 0.5 μg/ml, respectively. These results suggested that more than one strain should be involved for PK/PD modeling and contributed to rational use of florfenicol in populations. We also provided fundamental data for determination of florfenicol breakpoints in poultry.</p>