Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.
Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.
J Antimicrob Chemother. 2017 Dec 1;72(12):3366-3373. doi: 10.1093/jac/dkx313.
Urinary tract infections are among the most common human infections. Due to the progressive increase in ESBL-producing bacteria and the unavailability of new antibiotics, re-evaluation of 'old' antibiotics is needed. However, the pharmacodynamics of nitrofurantoin under variable pH conditions are poorly understood. We determined the pharmacodynamic properties of nitrofurantoin at different pH levels using time-kill assays.
Time-kill assays were performed at four pH levels (5.5, 6.5, 7.5 and 8.5), exposing the bacteria to 2-fold increasing concentrations from 0.125 to 32 times the MIC. Seven ESBL-positive and two ESBL-negative strains (MICs 8-32 mg/L) were used. The Δlog10 cfu/mL values at 6 and 24 h were plotted against each log10-transformed concentration and analysed with non-linear regression analysis using the sigmoid maximum effect model with variable slope. Geometric means normalized by the MIC of the EC50, stasis and 1 and 3 log10 cfu/mL kill were calculated.
Minimum bactericidal effects differed significantly by species and pH level. At pH 5.5-6.5 bactericidal effects were observed at ≥ 0.5 × MIC for Escherichia coli and Enterobacter cloacae. At pH 8.5 only the two highest concentrations were considered bactericidal. Strong pH-dependent pharmacodynamic output parameters were observed in 6 h and especially 24 h modelling. At 24 h, pH 5.5-6.5 for E. coli and Klebsiella pneumoniae required significantly lower nitrofurantoin concentrations compared with pH 7.5 or 8.5. Although for E. cloacae similar strong decreasing trends were visible with decreasing pH, none of the tested pharmacodynamic parameters was significant.
Nitrofurantoin bactericidal activity against Enterobacteriaceae significantly increases at lower pH levels. Bactericidal activity of nitrofurantoin may be overestimated or underestimated, which may have implications for therapy and the interpretation of clinical breakpoints.
尿路感染是最常见的人类感染之一。由于产 ESBL 细菌的不断增加和新抗生素的缺乏，需要重新评估“旧”抗生素。然而，在不同 pH 值条件下，硝呋太尔的药效动力学特性还了解甚少。我们使用时间杀伤试验来确定不同 pH 值下硝呋太尔的药效动力学特性。
在四个 pH 值（5.5、6.5、7.5 和 8.5）下进行时间杀伤试验，将细菌暴露于从 MIC 的 2 倍递增浓度 0.125 至 32 倍。使用了 7 株 ESBL 阳性和 2 株 ESBL 阴性菌株（MICs 8-32mg/L）。在 6 和 24 小时时的Δlog10cfu/mL 值与每个 log10 转换浓度进行了绘图，并使用非线性回归分析，采用可变斜率的 sigmoid 最大效应模型进行了分析。计算了以 MIC 为归一化的 EC50、静止和 1 和 3 log10cfu/mL 杀灭的几何平均值。
最小杀菌效果因物种和 pH 值水平而异。在 pH 值 5.5-6.5 下，大肠埃希菌和阴沟肠杆菌的杀菌效果在≥0.5×MIC 时观察到。在 pH 值 8.5 下，只有两个最高浓度被认为具有杀菌作用。在 6 小时和特别是 24 小时建模中观察到了强烈的 pH 依赖性药效学输出参数。在 24 小时时，与 pH 值 7.5 或 8.5 相比，大肠埃希菌和肺炎克雷伯菌在 pH 值 5.5-6.5 时需要明显更低的硝呋太尔浓度。虽然对于阴沟肠杆菌，随着 pH 值的降低也出现了类似的强烈下降趋势，但测试的药效学参数均无统计学意义。
在较低的 pH 值下，硝呋太尔对肠杆菌科的杀菌活性显著增加。硝呋太尔的杀菌活性可能被高估或低估，这可能对治疗和临床折点的解释产生影响。
