In this study, the rational dose regimens of tilmicosin against Lawsonia intracellularis (L. intracellularis) were studied using pharmacokinetic-pharmacodynamic (PK-PD) model approach to provide a maximal efficacy. The healthy and infected pigs were orally administrated the tilmicosin premix at a single dose of 10 mg/kg, and then the plasma and ileum content were collected at different time points. The time to peak (T_max), the peak concentration (C_max), the area under concentration time curve (AUC_0–24h), the apparent volume of distribution by bioavailability (V/F), the body clearance rate by bioavailability (CL/F) and the mean residence time (MRT) of tilmicosin premix for plasma were 2.00 h, 1.08 ± 0.04 μg/mL, 9.61 ± 1.47 μg h/mL, 34.43 ± 1.02 L/kg, 0.71 ± 0.03 L/h/kg and 15.03 ± 0.04 h in healthy pigs, and 2.00 h, 0.99 ± 0.03 μg/mL, 9.30 ± 1.43 μg h/mL, 58.59 ± 1.81 L/kg, 0.44 ± 0.02 L/h/kg and 15.75 ± 0.03 h in infected pigs, respectively. The T_max, C_max, AUC_0–24h, V/F, CL/F and MRT of tilmicosin premix for ileum content were 2.00 h, 3.78 ± 0.03 μg/mL, 20.41 ± 1.64 μg h/mL, 11.29 ± 0.97 L/kg, 0.44 ± 0.02 L/h/kg and 11.29 ± 0.09 h in healthy pigs, and 2.00 h, 3.41 ± 0.06 μg/mL, 22.65 ± 1.32 μg h/mL, 8.16 ± 1.51 L/kg, 0.41 ± 0.01 L/h/kg and 11.44 ± 0.05 h in infected pigs, respectively. Based on the intracellular minimum inhibitory concentration (MIC) of L. intracellularis isolate was 2 μg/mL, the results of the mutant prevention concentration (MPC), the post-antibiotic effect (PAE) and time-killing curves all showed strong concentration-dependenttendencies. Integrating the in vivo pharmacokinetic data of infected pigs and ex vivo pharmacodynamic data using the sigmoid E_max (Hill) equation to obtain the ileum content AUC_0–24h/MIC values of 6.87, 26.80, and 36.02 h to achieve the bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria, respectively. Based on these results, a dosage regimen of daily 14.39 mg/kg for 3 d could be sufficient in the treatment of L. intracellularis. This study will provide a guidance of dosage regimen formulation for drug against animal intracellular bacterial infections.

在这项研究中，使用药代动力学-药效学（PK-PD）模型方法研究了替米克星对胞内劳森菌（L. intracellularis）的合理剂量方案，以提供最大的疗效。健康和感染的猪以10 mg / kg的单剂量口服替米考星预混物，然后在不同时间点收集血浆和回肠含量。达到峰值的时间（T _max），峰值浓度（C _max），浓度时间曲线下的面积（AUC _0-24h），替米考星预混物在血浆中的生物利用度（V / F）分布的表观分布量，生物利用度（CL / F）的清除率和平均停留时间（MRT）为2.00 h，1.08±0.04μg/ mL，健康猪为9.61±1.47μgh / mL，34.43±1.02 L / kg，0.71±0.03 L / h / kg和15.03±0.04 h，2.00 h，0.99±0.03μg/ mL，9.30±1.43μgh / mL在感染猪中分别为58.59±1.81 L / kg，0.44±0.02 L / h / kg和15.75±0.03 h。T _max，C _max，AUC _0-24h，回肠含量的替米考星预混物的V / F，CL / F和MRT为2.00 h，3.78±0.03μg/ mL，20.41±1.64μgh / mL，11.29±0.97 L / kg，0.44±0.02 L / h / kg和健康猪为11.29±0.09 h，感染猪为2.00 h，3.41±0.06μg/ mL，22.65±1.32μgh / mL，8.16±1.51 L / kg，0.41±0.01 L / h / kg和11.44±0.05 h ， 分别。根据细胞内劳森氏菌分离物的细胞内最低抑菌浓度（MIC）为2μg/ mL，突变预防浓度（MPC），抗生素后效果（PAE）和时间杀灭曲线的结果均显示强浓度-相依倾向。整合体内感染猪和药代动力学数据体外使用乙状结肠Ë药效学数据_最大值（Hill）方程获得回肠含量AUC _0-24h / MIC值分别为6.87、26.80和36.02 h，以实现抑菌活性，杀菌活性和虚拟消灭细菌。根据这些结果，每日剂量14.39 mg / kg连续3 d足以治疗胞内劳森氏菌。这项研究将提供针对动物细胞内细菌感染的药物剂量方案的指导。