Dose Optimization of Tilmicosin against Pasteurella multocida in Swine by Physiologically Based Pharmacokinetic-Pharmacodynamic Model

Rising bacterial resistance leads to diminishing clinical efficacy of tilmicosin against Pasteurella multocida in porcine respiratory disease. This study aimed to optimize the dosing regimen of tilmicosin against P. multocida using the physiologically based pharmacokinetic-pharmacodynamic model (PBPK-PD). A swine PBPK model for tilmicosin was developed using microdialysis and the literature data. It accurately predicted pharmacokinetics in lung and edible tissues, though it overestimated plasma levels. The PBPK-PD model was integrated with dynamic time-killing studies in a hollow fiber infection model. The withdrawal interval was projected using Monte Carlo analysis. The PK-PD parameters, AUC/MIC, for bacteriostatic, bactericidal, and elimination effect were 12.13, 28.48, and 51.08 h and 7.17, 46.54, and 78.66 h in pulmonary interstitial fluid and plasma, respectively. The dosage of 40 mg/kg once daily for 3 consecutive days could achieve bactericidal efficacy with the estimated withdrawal interval of 8 days. The optimized dosing regimen will enhance the efficacy and avoid resistance selection.