基于体内PK/PD同歩模型的达氟沙星对鸡毒支原体、大肠杆菌混合感染防耐药突变研究

临床疾病常由多个病原混合感染引发，以疾病为导向，研究抗菌药对多个病原的体内PK/PD同步关系及突变选择窗（MSW），可更好地优化药效并减少耐药性的产生。达氟沙星是治疗鸡毒支原体（MG）、大肠杆菌（E. coli）混合感染的常用药物。前期研究发现，MG- E. coli混合感染雏鸡会改变达氟沙星的药动学特征，但是对其PK/PD同步模型及MSW的影响尚不清楚。本研究内容包括：1）在MG- E. coli混合感染雏鸡中，建立达氟沙星对MG、E. coli的体内PK/PD同步模型；2）以PK/PD结果为基础，通过药板筛选法及探针荧光定量PCR法确定达氟沙星对两种病原的体内MSW；3）利用蒙特卡罗分析整合药动学及病原敏感性差异，模拟PK/PD参数分布，以最佳PK/PD参数值为靶标，避开MSW，推导达氟沙星给药方案。本研究从多角度优化达氟沙星作用，为指导合理使用达氟沙星，减少耐药性产生与传播奠定基础。

Co-infection of bacteria and mycoplasma is very commonplace, therefore, it is crucial to explore the in vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Profiles and mutant selection window (MSW) of antibacterials against multiple pathogens based on co-infection model for promoting the eradication of bacteria and reducing drug resistance. Mycoplasma gallisepticum (MG) usually co-infected chickens with Escherichia coli (E. coli), which causes significant losses. Danofloxacin plays a key role in treating the infection. Our previous study has established the MG S6 - E. coli O78 co-infection model and demonstrated that the pathological status due to the infection influences the PK profile of danofloxacin. However, the impact on PK/PD profiles and MSW still need further study. Our study aims to: (1) establish the in vivo PK/PD model of danofloxacin against MG and E. coli respectively in the MG S6 - E. coli O78 co-infection chickens, (2) clarify the MSW of danofloxacin which would affect the susceptibility of MG and E. coli against danofloxacin, (3) derive a rational approach of danofloxacin with respect to bacteriological and resistance outcomes using the Monte Carlo Analysis. The investigation results provide a solid foundation for the usage of danofloxacin against MG-E. coli co-infection and controlling resistance.