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

Pasteurella multocida 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 P. multocida infection. To preserve the effect of florfenicol, in vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling of florfenicol against three P. multocida 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(0-24 h)/MIC) was the optimal PK/PD parameter. The PK/PD surrogate values of florfenicol against P. multocida were similar using different organs as the PD target, but varied in different strains. For the florfenicol-sensitive strain 0825Y(1), when the AUC(0-24 h)/MIC reached 117.54 and 108.19, florfenicol showed a bactericidal effect in the liver and lung, respectively. For the florfenicol-sensitive strain 0901J(1), 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(10) reduction in bacteria in the liver and lung when the AUC(0-24 h)/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 P. multocida 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 P. multocida 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 mu g/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.

Automated summary

PK/PD modeling and Monte Carlo simulations were used to predict the efficacy of florfenicol against Pasteurella multocida strains in ducks. The optimal PK/PD parameter was determined, and a rational dosage regimen was suggested for different strains of P. multocida. Additionally, the PK/PD cutoff values for florfenicol against P. multocida were provided for the current marketed dose and the predicted daily dose in mainland China.