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目的:研究健康受试者口服氟罗沙星的药动学(PK)和药效学(PD),从而优化氟罗沙星的临床给药方案。方法:采用三周期自身交叉对照的方式对15名健康受试者分别口服200,300,400 mg氟罗沙星片后,以高效液相色谱法(HPLC)测定血药浓度,进而求出药动学(PK)参数。体外药效学(PD)研究是测定氟罗沙星对临床分离的15种494株常见致病菌的最低抑菌浓度(MIC)。以AUC0-24/MIC作为氟罗沙星的PK/PD参数(靶值为100和125),采用蒙特卡洛(Monte Carlo)模拟评价氟罗沙星的3种治疗方案对不同分离菌株AUC0-24/MIC值的药效学累积反应分数(CFR)。结果:以CFR>90%作为抗感染经验治疗的合理选择,对于大肠杆菌和淋球菌引起的感染,或口服200 mg(qd)即可;对硝酸盐阴性杆菌、肠杆菌属和哈夫尼亚菌属引起的感染,或口服300 mg(qd)即可;对于表葡球菌、铜绿假单胞菌、志贺菌属、肺炎克雷伯杆菌、柠檬酸杆菌属、普通变形杆菌、肺炎链球菌、沙门菌属和金葡球菌(MSSA)引起的感染,或口服400 mg(qd)可获得预期满意的临床疗效并能有效预防细菌耐药性产生,而对于耐甲氧西林金葡菌(MRSA),PK/PD参数显示疗效不佳。结论:应用Monte Carlo模拟评价氟罗沙星的PK/PD参数,可以为氟罗沙星的临床最佳给药方案的制定提供参考依据。
Objective: To study the pharmacokinetics (PK) and pharmacodynamics (PD) of oral flurbarum in healthy subjects so as to optimize the clinical dosing regimen of fleroxacin. Methods: 15 healthy volunteers were treated with fleroxacin 200, 300 and 400 mg respectively by three-cycle self-cross-over control method. The plasma concentration of the drug was determined by high performance liquid chromatography (HPLC), and the pharmacokinetic parameters . In vitro pharmacodynamics (PD) study is the determination of fleroxacin clinical isolation of 15 kinds of 494 common pathogenic bacteria minimum inhibitory concentration (MIC). Using the AUC0-24 / MIC as the PK / PD parameter of fleroxacin (target values of 100 and 125), Monte Carlo simulation was used to evaluate the effect of three treatments of fleroxacin on different isolates of AUC0-24 / MIC Pharmacodynamic cumulative response score (CFR). Results: Treatment with CFR> 90% as a reasonable choice for anti-infective experience was recommended for infections caused by E. coli and Neisseria gonorrhoeae, or oral administration of 200 mg (qd); for nitrate-negative bacilli, Enterobacter and Hafnia Infections caused by bacteria, or oral administration of 300 mg (qd) can be; for Staphylococcus epidermidis, Pseudomonas aeruginosa, Shigella, Klebsiella pneumoniae, Citrobacter, Proteus vulgaris, Streptococcus pneumoniae , Salmonella and Staphylococcus aureus (MSSA), or oral administration of 400 mg (qd) results in the expected satisfactory clinical efficacy and effective prevention of bacterial resistance, whereas for MRSA ), PK / PD parameters show poor efficacy. Conclusion: The Monte Carlo simulation of the evaluation of fleroxacin PK / PD parameters may provide a reference for the formulation of fleroxacin ’s optimal clinical dosage regimen.