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Abstract：
BACKGROUND: Antibiotic resistance has become a serious global problem and is steadily increasing worldwide in almost every bacterial species treated with antibiotics. In aquaculture, the therapeutic options for the treatment of A. hydrophila infection were only limited to several antibiotics, which contributed for the fast-speed emergence of drug tolerance. Accordingly, the aim of this study was to establish a medication regimen to prevent drug resistant bacteria. To determine a rational therapeutic guideline, integrated pharmacodynamics and pharmacokinetics parameters were based to predict dose and dosage interval of enrofloxacin in grass carp Ctenopharyngodon idella infected by a field-isolated A. hydrophila strain.
RESULTS: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.
CONCLUSIONS: Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.
RESULTS: The pathogenic A. hydrophila strain (AH10) in grass carp was identified and found to be sensitive to enrofloxacin. The mutant selection window (MSW) of enrofloxacin on isolate AH10 was determined to be 0.5-3 μg/mL based on the mutant prevention concentration (MPC) and minimum inhibitory concentration (MIC) value. By using high-performance liquid chromatography (HPLC) system, the Pharmacokinetic (PK) parameters of enrofloxacin and its metabolite ciprofloxacin in grass carp were monitored after a single oral gavage of 10, 20, 30 μg enrofloxacin per g body weight. Dosing of 30 μg/g resulted in serum maximum concentration (Cmax) of 7.151 μg/mL, and concentration in serum was above MPC till 24 h post the single dose. Once-daily dosing of 30 μg/g was determined to be the rational choice for controlling AH10 infection and preventing mutant selection in grass carp. Data of mean residue time (MRT) and body clearance (CLz) indicated that both enrofloxacin and its metabolite ciprofloxacin present similar eliminating rate and pattern in serum, muscle and liver. A withdraw time of more than 32 d was suggested based on the drug eliminating rate and pharmacokinetic model described by a polyexponential equation.
CONCLUSIONS: Based on integrated PK/PD parameters (AUC/MIC, Cmax/MIC, and T>MPC), the results of this study established a principle, for the first time, on drawing accurate dosing guideline for pharmacotherapy against A. hydrophila strain (AH10) for prevention of drug-resistant mutants. Our approach in combining PK data with PD parameters (including MPC and MSW) was the new effort in aquaculture to face the challenge of drug resistance by drawing a specific dosage guideline of antibiotics.
摘要：
背景：抗生素耐药性已成为一个严重的全球性问题，并且在全球范围内几乎所有用抗生素治疗的细菌物种中都在稳步增长。在水产养殖中,治疗嗜水气单胞菌感染的治疗选择仅限于几种抗生素，这有助于药物耐受性的快速出现。因此，这项研究的目的是建立预防耐药菌的用药方案。为了确定合理的治疗指南，基于整合的药效学和药代动力学参数来预测恩诺沙星在被田间分离的嗜水气单胞菌感染的草鱼Ctenophyngodonidella中的剂量和剂量间隔。
结果：鉴定了草鱼中的致病性嗜水气单胞菌菌株（AH10），并发现对恩诺沙星敏感。根据突变预防浓度（MPC）和最小抑制浓度（MIC）值，确定恩诺沙星对分离株AH10的突变选择窗口（MSW）为0.5-3μg/mL。通过使用高效液相色谱(HPLC)系统,在每次口服每克体重10、20、30μg恩诺沙星后，监测恩诺沙星及其代谢物环丙沙星在草鱼中的药代动力学（PK）参数。30μg/g的剂量导致血清最大浓度（Cmax）为7.151μg/mL，单剂量后24小时，血清浓度高于MPC。确定每日一次给药30μg/g是控制AH10感染和防止草鱼突变选择的合理选择。平均停留时间（MRT）和机体清除率（CLz）的数据表明，恩诺沙星及其代谢物环丙沙星在血清中的消除率和模式相似，肌肉和肝脏。根据多指数方程描述的药物消除率和药代动力学模型，建议撤回时间超过32d。
结论：基于综合PK/PD参数（AUC/MIC，Cmax/MIC,和T>MPC)，这项研究的结果确立了一个原则，第一次,关于为预防耐药突变体而针对嗜水气单胞菌菌株（AH10）的药物治疗制定准确的给药指南。我们将PK数据与PD参数（包括MPC和MSW）相结合的方法是水产养殖通过绘制特定的抗生素剂量指南来应对耐药性挑战的新努力。
结果：鉴定了草鱼中的致病性嗜水气单胞菌菌株（AH10），并发现对恩诺沙星敏感。根据突变预防浓度（MPC）和最小抑制浓度（MIC）值，确定恩诺沙星对分离株AH10的突变选择窗口（MSW）为0.5-3μg/mL。通过使用高效液相色谱(HPLC)系统,在每次口服每克体重10、20、30μg恩诺沙星后，监测恩诺沙星及其代谢物环丙沙星在草鱼中的药代动力学（PK）参数。30μg/g的剂量导致血清最大浓度（Cmax）为7.151μg/mL，单剂量后24小时，血清浓度高于MPC。确定每日一次给药30μg/g是控制AH10感染和防止草鱼突变选择的合理选择。平均停留时间（MRT）和机体清除率（CLz）的数据表明，恩诺沙星及其代谢物环丙沙星在血清中的消除率和模式相似，肌肉和肝脏。根据多指数方程描述的药物消除率和药代动力学模型，建议撤回时间超过32d。
结论：基于综合PK/PD参数（AUC/MIC，Cmax/MIC,和T>MPC)，这项研究的结果确立了一个原则，第一次,关于为预防耐药突变体而针对嗜水气单胞菌菌株（AH10）的药物治疗制定准确的给药指南。我们将PK数据与PD参数（包括MPC和MSW）相结合的方法是水产养殖通过绘制特定的抗生素剂量指南来应对耐药性挑战的新努力。
