Komp Lindgren P, Klockars O, Malmberg C, Cars O
Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden.
Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Uppsala, Sweden
J Antimicrob Chemother. 2015 Apr;70(4):1076-82. doi: 10.1093/jac/dku494. Epub 2014 Dec 15.
To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI).
Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time-kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time-concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0-24 h (Δcfu0-24) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T>MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC).
A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8 × MIC. The outcome parameters Δcfu0-24 and AUBC had a good correlation with T>MIC (R ≈ 0.83 and R ≈ 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R ≈ 0.39 and R ≈ 0.53, respectively).
Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T>MIC displayed the best correlation.
为确定与呋喃妥因抗菌效果最相关的药代动力学/药效学指标，我们研究了呋喃妥因对单纯性尿路感染（UTI）常见病原体的活性。
使用了五株分离菌[两株大肠杆菌（一株产ESBL CTX-M-15）、两株粪肠球菌（包括一株耐万古霉素的）和一株腐生葡萄球菌]。采用Etest法测定呋喃妥因的最低抑菌浓度（MIC）。跟踪不同浓度呋喃妥因（基于分离菌特异性MIC的倍数）在24小时内的杀菌曲线。使用体外动力学模型模拟不同的时间-浓度曲线，使大肠杆菌在给药间隔的不同比例时间内接触呋喃妥因。将0-24小时菌落形成单位减少量（Δcfu0-24）和杀菌曲线下面积（AUBC）等结果参数与高于MIC的时间（T>MIC）以及抗生素浓度曲线下面积除以MIC（AUC/MIC）进行相关性分析。
所有分离菌在不同静态药物浓度下均呈现杀菌效果。所有分离菌的杀菌曲线图谱相似。在动力学模型中，呋喃妥因对大肠杆菌的作用在8×MIC浓度下6小时内使cfu/mL降低了4个对数级。结果参数Δcfu0-24和AUBC与T>MIC具有良好的相关性（R分别约为0.83和0.67），而log(AUC/MIC)的相关性则明显较差（R分别约为0.39和0.53）。
呋喃妥因对大肠杆菌和腐生葡萄球菌分离株高度有效；对粪肠球菌的杀灭作用虽不那么迅速，但仍很显著。对于大肠杆菌，呋喃妥因主要表现为浓度依赖性作用；这在动力学模型中得到了证实，其中T>MIC的相关性最佳。
