Lei Zhixin, Liu Qianying, Khaliq Haseeb, Cao Jiyue, He Qigai
State Key Laboratory of Agriculture Microbiology, College of Veterinary Medicine, Huazhong Agriculture University, Wuhan, China.
Department of Veterinary Pharmacology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
J Vet Pharmacol Ther. 2019 May;42(3):324-335. doi: 10.1111/jvp.12754. Epub 2019 Feb 22.
Florfenicol, a structural analog of thiamphenicol, has broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria. This study was conducted to investigate the epidemiological, pharmacokinetic-pharmacodynamic cutoff, and the optimal scheme of florfenicol against Escherichia coli (E. coli) with PK-PD integrated model in the target infectious tissue. 220 E. coli strains were selected to detect the susceptibility to florfenicol, and a virulent strain P190, whose minimum inhibitory concentration (MIC) was similar to the MIC (8 μg/ml), was analyzed for PD study in LB and ileum fluid. The MIC of P190 in the ileum fluid was 0.25 times lower than LB. The ratios of MBC/MIC were four both in the ileum and LB. The characteristics of time-killing curves also coincided with the MBC determination. The recommended dosages (30 mg/kg·body weight) were orally administrated in healthy pigs, and both plasma and ileum fluid were collected for PK study. The main pharmacokinetics (PK) parameters including AUC , AUC , T , T , C , CL and K were 49.83, 52.33 μgh/ml, 1.32, 10.58 hr, 9.12 μg/ml, 0.50 L/hrkg, 0.24 hr and 134.45, 138.71 μghr/ml, 2.05, 13.01 hr, 16.57 μg/ml, 0.18 L/hrkg, 0.14 hr in the serum and ileum fluid, respectively. The optimum doses for bacteriostatic, bactericidal, and elimination activities were 29.81, 34.88, and 36.52 mg/kg for 50% target and 33.95, 39.79, and 42.55 mg/kg for 90% target, respectively. The final sensitive breakpoint was defined as 16 μg/ml. The current data presented provide the optimal regimens (39.79 mg/kg) and susceptible breakpoint (16 μg/ml) for clinical use, but these predicted data should be validated in the clinical practice.
氟苯尼考是甲砜霉素的结构类似物，对革兰氏阴性菌和革兰氏阳性菌均具有广谱抗菌活性。本研究旨在通过PK-PD整合模型，研究氟苯尼考在目标感染组织中对大肠杆菌的流行病学、药代动力学-药效学临界值及最佳用药方案。选取220株大肠杆菌检测其对氟苯尼考的敏感性，并选取一株毒力菌株P190（其最低抑菌浓度（MIC）与平均MIC（8μg/ml）相似），在LB培养基和回肠液中进行药效学研究。P190在回肠液中的MIC比在LB培养基中低0.25倍。回肠液和LB培养基中的MBC/MIC比值均为4。杀菌曲线特征也与MBC测定结果相符。对健康猪口服推荐剂量（30mg/kg体重），并采集血浆和回肠液进行药代动力学研究。血清和回肠液中的主要药代动力学（PK）参数，包括AUC、AUC、T、T、C、CL和K，分别为49.83、52.33μgh/ml、1.32、10.58小时、9.12μg/ml、0.50L/hrkg、0.24小时和134.45、138.71μghr/ml、2.05、13.01小时、16.57μg/ml、0.18L/hrkg、0.14小时。50%目标抑菌、杀菌和清除活性的最佳剂量分别为29.81、34.88和36.52mg/kg，90%目标的最佳剂量分别为33.95、39.79和42.55mg/kg。最终敏感临界值定义为16μg/ml。目前提供的数据给出了临床使用的最佳给药方案（39.79mg/kg）和敏感临界值（16μg/ml），但这些预测数据应在临床实践中进行验证。
