恩诺沙星控制嗜水气单胞菌性鲫败血症的防耐药用药方案

摘要

The widespread use of antibiotics in aquaculture has led to increasing problems caused by bacterial re-sistance. Given this, there is an urgent need to develop a medication regimen that prevents the formation of drug resistant bacteria. We estimated a number of pharmacodynamic (including mutant prevent concentration and mu-tant selection window) and pharmacokinetic parameters for the antibiotic drug enrofloxacin. Our objective was to develop a medication regimen against hemorrhagic septicemia in crucian carp(Carassius auratus), a disease caused by Aeromonas hydrophila. The minimal inhibitory concentration (MIC) was 0.125 μg/mL, the post-antibiotic effect (PAE) of enrofloxacin on the pathogenic bacterial strains was observed up to (1.67±0.42) h, (2.03±0.17) h, and (2.38±0.06) h at 2MIC, 4MIC, and 8MIC, respectively, the mutant prevention concentration (MPC) was 1.125 μg/mL, and the mutant selection window was between 0.125 and 1.125 μg/mL. We developed integrated enrofloxacin concentration-time curves for the serum of crucian carp following administration of a range of doses. Enrofloxacin persisted in the serum at concentrations above the MPC for 5 h at a dose of 5 mg/kg;9.5 h at a dose of 10 mg/kg, and 23 h at a dose of 20 mg/kg. The serum PK/PD parameters AUC24/MIC and Cmax/MIC were 137.22 and 15.05, respectively, at a dose of 5 mg/kg, 285.25 and 41.43, respectively, at a dose of 10 mg/kg, and 426.25 and 52.32, respectively, at a dose of 20 mg/kg.The drug remained in the plasma with a concentration>MPC for (24-PAE) h and AUC24/MIC≥100 or Cmax/MIC>8. Our results suggest that hemorrhagic septicemia can be controlled using a dosing regimen of 20 mg/kg enrofloxacin, at intervals of 24 h.The proposed withdrawal time in crucian carp should not be less than 25 d. The methods described in this study also can be used for developing dose guidelines for other anti-bacterial drugs to prevent selection for drug-resistance.%　　为了合理地使用抗生素,制定防止耐药菌产生的用药方案,本研究利用近年来提出的防耐药突变浓度(MPC)和耐药选择窗(MSW)这两个药效学(PD)参数,并结合药代动力学(PK)参数,制定恩诺沙星防耐药突变用药方案,控制由嗜水气单胞菌引起的鲫细菌性败血症。研究结果显示,恩诺沙星对该致病性嗜水气单胞菌的体外药效学参数为：最小抑菌浓度(MIC)为0.125μg/mL；2MIC、4MIC、8MIC的抗菌后效应(PAE)分别为(1.67±0.42) h、(2.03±0.17) h、(2.38±0.06) h； MPC为1.125μg/mL； MSW为0.125~1.125μg/mL。根据鲫(Carassius auratus)口灌恩诺沙星后的药代动力学曲线,得出血浆药物浓度>MPC的时间分别为5 h、9.5 h、23 h。PK/PD综合参数：24 h内血药浓度-时间曲线下面积与MIC的比值(AUC24/MIC)分别为137.22、285.15、426.25；峰浓度与MIC的比值(Cmax/MIC)分别为15.05、41.43、52.32。综合血浆药物浓度>MPC的时间超过(24-PAE)h、AUC24/MIC≥100或Cmax/MIC>8的指标,建议恩诺沙星在控制由嗜水气单胞菌引起的鲫细菌性败血症时的给药方案为：给药剂量20 mg/kg体质量,1次/d。根据肌肉内恩诺沙星的药动学方程,药残达到国家限量标准所需时间约为25 d,所以建议休药期不低于25 d。本研究方案也可广泛用于其他水产养殖抗菌药物的防耐药突变用药方案的制定。