基于PK/PD 模型的恩诺沙星对嗜水气单胞菌防耐药突变研究

The problem of bacterial resistance is getting worse, however, most of the veterinary antimicrobial drug resistance study was focused on the emergence and transmission mechanism of drug resistance, there is no in-depth exploration on the dosing strategy to prevent drug resistance. This project is to study the influence of different dosing strategy of enrofloxacin on the drug susceptibility change of Aeromonas hydrophila by establishing the in vivo pharmacokinetic/pharmacodynamics (PK/PD) model in crucian carp based on mutant prevention concentration and mutant selection window theories, the relationship between PK/PD parameters and the pathogen-resistant mutations will be analyzed and explored. In addition, considering the pharmacokinetic differences among different individual animals and the wide distribution of antibiotic sensitivity of bacterial pathogens, Monte Carlo simulation will be used to screen the mutant prevention dosage regimen, which will attain the ideal goal of clinical cure and inhibition of bacterial drug resistance. This project firstly study the anti-mutant dosing strategy of antimicrobial agents in the aquaculture field based on PK/PD model and Monte Carlo simulation, which provides a new way of thinking and reference for effective inhibition of the bacterial resistance and the design of antimicrobial application strategy.

细菌耐药问题日趋严重，然而国内在兽用药物耐药性研究方面多集中于耐药性产生及传播机制研究，并未就防止耐药性产生的给药策略进行深入探索。本项目拟在防突变浓度、突变选择窗理论指导下，通过建立鲫鱼体内药动/药效学同步模型，研究恩诺沙星不同给药策略对嗜水气单胞菌敏感性变化的影响, 分析、探索PK/PD参数与病原菌耐药突变的相关性。此外，考虑到动物个体之间药物处置过程存在差异以及病原菌药物敏感性的广泛分布，拟采用蒙特卡洛模拟筛选防耐药突变给药方案，达到临床中治愈疾病的同时又能抑制细菌耐药性产生的理想目标。本项目首次在水产领域基于PK/PD模型和蒙特卡洛模拟开展抗菌药物防耐药突变给药策略研究，为有效抑制细菌耐药和制定抗菌药物应用策略提供了新的思路和参考依据。

细菌耐药问题日趋严重，本项目通过建立鲫鱼体内PK/PD同步模型，结合蒙特卡洛模拟筛选防耐药突变给药方案。首先开展了恩诺沙星对120株嗜水气单胞菌的体外药效学研究，测得MIC在0.015-0.96 μg/mL之间，MPC在0.096-9.6 μg/mL之间；恩诺沙星对嗜水气单胞菌的抗菌效应成浓度依赖性变化，8×MIC恩诺沙星发挥最大抗菌效应；嗜水气单胞菌经中等药物浓度暴露后药物敏感性变化最大。接着开展了不同剂量、给药途径恩诺沙星在健康和感染鲫鱼体内的药动学研究，恩诺沙星三种给药方式在鲫鱼体内均可以达到有效治疗浓度；药浴给药, 体内药物浓度明显低于口灌和肌内注射；口灌给药后，恩诺沙星在鲫鱼体内呈典型的线性药动学特征，药时曲线下面积和药物峰浓度随着给药剂量的增大而增大；与健康鲫鱼相比，恩诺沙星在感染鲫鱼体内，吸收和消除均比较慢，生物利用度较低。最后在上述研究的基础上开展恩诺沙星对嗜水气单胞菌半体内和体内药效学研究，通过建立PK/PD模型，得到PK/PD参数AUC24h/MIC和Cmax/MIC与耐药发生相关性最强，Cmax/MIC>13.7时无耐药发生，以此为目标值经蒙特卡洛模拟得到当给药剂量为16.59 mg/kg时达标概率>90%，可以有效治疗鲫鱼嗜水气单胞菌感染，并且最大可能的降低细菌耐药性的产生。