基于药动/药效同步模型研究加米霉素对猪链球菌的耐药折点及防耐药突变给药方案

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.

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。

畜禽养殖离不开抗菌药，如何科学合理地使用抗菌药是养殖业亟需解决的问题。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，明确其对包括猪链球菌在内的重要病原菌的耐药折点，有利于调整和优化临床给药方案和减缓细菌耐药性产生。本项目测定了加米霉素对猪链球菌的敏感性分布特征和抗生素后效应；解析了血清基质对加米霉素的增效作用与其提高猪链球菌的胞膜通透性相关；明确了核糖体RNA位点突变的猪链球菌耐药亚群具有更高的生长动力学优势；开展了加米霉素在猪和小鼠体内的药代动力学研究，建立了其对猪链球菌的PK/PD同步模型，解析了不同给药方案对猪链球菌的体内药效学特征和实现有效治疗的药效靶值，明确了加米霉素当前剂量对猪链球菌的治疗有效率为97.4%，其实现90%以上治疗有效率的最低剂量为2.53mg/kg。进一步结合突变选择窗理论，获得了加米霉素对猪链球菌防耐药突变相关的药效靶值，明确了其治愈猪链球菌感染的同时又能抑制其耐药亚群富集的给药方案为8.78mg/kg；运用非线性回归分析和蒙特卡罗模拟等方法，通过整合PK/PD参数靶值和猪链球菌的MIC群体分布，获得了加米霉素对猪链球菌的野生型和药效学折点分别为2mg/L和8mg/L。项目研究结果为开发猪链球菌感染的有效治疗策略以及确立加米霉素的最终临床折点提供了科学指导。