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

Rising bacterial resistance leads to diminishing clinical efficacy of tilmicosin against <i>Pasteurella multocida</i> in porcine respiratory disease. This study aimed to optimize the dosing regimen of tilmicosin against <i>P. multocida</i> 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.