加米霉素是治疗家畜呼吸系统疾病的新型大环内酯类抗菌药。我们的前期研究发现，加米霉素的体外选择压力可以诱导猪链球菌23SrRNA位点突变亚群的富集，导致菌株敏感性下降。同时，加米霉素对猪链球菌的突变选择指数在血清基质中显著小于人工培养基。然而，加米霉素在动物体内治疗过程中是否也会导致猪链球菌耐药突变亚群的出现？相关耐药折点是多少？目前尚不清楚。因此，我们提出，在明确体内猪链球菌耐药亚群消长规律的基础上，可以通过合理优化加米霉素的用药方案以防止其耐药亚群的出现和富集。本项目基于突变选择窗理论，拟结合药动/药效（PK/PD）同步模型、蒙特卡罗模拟及非线性回归等方法，阐明加米霉素不同给药方案对猪链球菌耐药突变选择的影响，获得加米霉素对猪链球菌的耐药折点及临床中治愈感染的同时又能抑制猪链球菌耐药亚群选择性富集的给药方案，为减缓猪链球菌耐药性的发展以及加米霉素最终临床折点的确定提供更充分的科学依据。

Gamithromycin is a novel macrolide antimicrobial agent that has been developed recently for the treatment of livestock respiratory diseases. Our previous studies indicated that the enrichment of drug-resistant Streptococcus suis subpopulations carrying 23S rRNA mutants can be induced by the in vitro gamithromycin pressure, resulting in decreased susceptibility of S. suis to gamithromycin. In addition, the mutant selection index of gamithromycin against S. suis in serum-containing medium was significantly lower than that in artificial medium. However, it still remains unclear whether the emergence of drug-resistant S. suis subpopulations can be induced during in vivo gamithromycin treatment and the susceptibility breakpoint of gamithromycin against S. suis. Therefore, we propose that the emergence of drug-resistant S. suis subpopulations could be prevented by reasonably optimizing the dosing regimen of gamithromycin, if the growth and decline rule of drug-resistant S. suis subpopulations was well understood. Based on the mutant selection window theory, this project aims to clarify the effects of different gamithromycin dosing regimens on the selection of drug-resistant S. suis subpopulations, obtaining the effective treatment regimens with the ability to prevent the selective enrichment of drug-resistant S. suis subpopulations and the susceptibility breakpoint of gamithromycin against S. suis by integrating the pharmacokinetic/pharmacodynamic (PK/PD) model, Monte Carlo simulation and nonlinear regression analysis. This project will provide more adequate scientific basis for the determination of gamithromycin final clinical breakpoints and retarding the development of drug-resistant S. suis.