Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
Microbiology and Infection Control, Statens Serum Institut, Copenhagen S, Denmark.
APMIS. 2024 Jul;132(7):492-498. doi: 10.1111/apm.13409. Epub 2024 Apr 1.
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 (r = 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.
抗菌药物呋喃妥因由于广泛存在的多药耐药大肠杆菌，对于治疗尿路感染（UTI）变得越来越重要。尽管已经使用了多年，但关于呋喃妥因药代动力学（PK）或药效动力学（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；（ii）利用这些数据在大肠杆菌引起的 UTI 实验模型中设计体内剂量分割研究，以确定最具预测性的 PK/PD 指数。口服 5、10 和 20mg/kg 呋喃妥因后，尿液中的呋喃妥因浓度约为血浆中的 100 倍。最低抑菌浓度（MIC）下的曲线下面积（AUC/MIC）与尿液中细菌减少量呈弱相关（r=0.24），而在 MIC 以上的时间（T>MIC）与细菌减少量之间没有发现这种相关性。单次大剂量治疗的大小与尿液中细菌的清除明显相关，而当相同剂量分为 2 或 3 份，每 8 或 12 小时服用一次时，这种相关性并不明显。总之，这些结果表明，呋喃妥因在尿液中对大肠杆菌的活性取决于 AUC/MIC。
