The antimicrobial agent nitrofurantoin is becoming increasingly important for treatment of urinary tract infections (UTIs) due to widespread occurrence of multidrug‐resistant Escherichia coli. Despite many years of use, little data on nitrofurantoin pharmacokinetics (PK) or ‐dynamics (PD) exist. The objective of this study was to (i) evaluate the pharmacokinetics of nitrofurantoin in a mouse model and (ii) use that data to design an in vivo dose fractionation study in an experimental model of UTI with E. coli for determination of the most predictive PK/PD index. Nitrofurantoin concentrations in urine were approximately 100‐fold larger than concentrations in plasma after oral administration of 5, 10, and 20 mg/kg nitrofurantoin. The area under the curve over the minimum inhibitory concentration (AUC/MIC) was weakly correlated to bacterial reduction in urine (r2 = 0.24), while no such correlation was found for the time that nitrofurantoin stayed above the MIC (T > MIC). Increasing size of single‐dose treatment was significantly correlated to eradication of bacteria in the urine, while this was not apparent when the same doses were divided in 2 or 3 doses 8 or 12 h apart. In conclusion, the results indicate that nitrofurantoin activity against E. coli in urine is driven by AUC/MIC.

中文翻译：

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呋喃妥因在小鼠尿路感染模型中抗大肠杆菌的药代动力学和药效学评价

由于多重耐药性的广泛发生，抗菌剂呋喃妥因对于治疗尿路感染 (UTI) 变得越来越重要大肠杆菌。尽管使用多年，但有关呋喃妥因药代动力学 (PK) 或动力学 (PD) 的数据很少。本研究的目的是 (i) 评估呋喃妥因在小鼠模型中的药代动力学，以及 (ii) 使用该数据在尿路感染实验模型中设计体内剂量分割研究大肠杆菌用于确定最具预测性的 PK/PD 指数。口服 5、10 和 20 mg/kg 呋喃妥因后，尿中呋喃妥因浓度比血浆浓度高约 100 倍。最低抑菌浓度曲线下面积 (AUC/MIC) 与尿液中细菌减少量 (r2= 0.24)，而当呋喃妥因保持在 MIC (T > MIC) 之上时，没有发现这种相关性。增加单剂量治疗量与尿液中细菌的根除显着相关，而当将相同剂量分成 2 或 3 个剂量（间隔 8 或 12 小时）时，这一点并不明显。总之，结果表明呋喃妥因的活性大肠杆菌尿液中的浓度由 AUC/MIC 驱动。