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):3374-3381. doi: 10.1093/jac/dkx328.
The increase in antibiotic resistance in Gram-negative bacteria and the limited therapeutic options due to the shortage of new antibiotics have increased the interest of the 'old' antibiotic fosfomycin in the treatment of infections. However, there are contradictory reports on the pharmacodynamics of and emergence of resistance to fosfomycin.
Time-kill assays were performed with 11 ESBL-positive and 3 ESBL-negative strains, exposing the bacteria to 2-fold static concentrations from 0.125× to 32× MIC. The sigmoid maximum effect (Emax) model was fitted to the time-kill curve data. Amplification of resistance over time was evaluated under various conditions of selective pressure by plating on 16× MIC plates.
Fosfomycin was bactericidal for all strains within 8 h. Using the Emax model, no significant differences between strains were observed for the pharmacodynamic parameters. However, the large variation in Hill slope factors for Escherichia coli of 0.87 up to 4.02 indicates that the killing behaviour appears to be more time dependent for some strains but concentration dependent for others. In the fosfomycin-exposed cultures under low and high selective pressure (≥2× MIC) the median resistance proportions between the resistant and total population increased from ≤2 × 10-6 (T = 0 h) to 0.652-0.899 (T = 24 h). Resistance appeared stable after repeated subculturing.
Killing behaviour of fosfomycin does not only differ between species but also within species and may have an impact on the design of optimal dosing regimens. Although fosfomycin was bactericidal against all strains (re)growth of resistant subpopulations occurred relatively fast. This may limit the use of fosfomycin as a single drug therapy.
革兰氏阴性菌的抗生素耐药性增加，以及由于新抗生素短缺而导致治疗选择有限，这增加了人们对旧抗生素磷霉素治疗感染的兴趣。然而，关于磷霉素的药效学和耐药性的出现存在相互矛盾的报道。
使用 11 株 ESBL 阳性和 3 株 ESBL 阴性菌株进行时间杀伤试验，将细菌暴露于 2 倍静态浓度，从 0.125×至 32×MIC。将最大效应（Emax）模型拟合到时间杀伤曲线数据中。在不同的选择压力条件下通过在 16×MIC 平板上进行平板接种来评估随时间的耐药性扩增。
磷霉素在 8 小时内对所有菌株均具有杀菌作用。使用 Emax 模型，在药效学参数方面，菌株之间没有观察到显著差异。然而，大肠杆菌的希尔斜率因子的变化范围从 0.87 到 4.02 很大，这表明某些菌株的杀菌行为似乎更依赖于时间，而另一些菌株则依赖于浓度。在低和高选择压力（≥2×MIC）下，暴露于磷霉素的培养物中，耐药和总群体之间的中位耐药比例从≤2 × 10-6（T=0 小时）增加到 0.652-0.899（T=24 小时）。经过反复传代后，耐药性似乎稳定。
磷霉素的杀菌行为不仅在不同物种之间有所不同，而且在同一物种内也有所不同，这可能会影响最佳给药方案的设计。尽管所有菌株（再）生长的耐药亚群都相对较快地出现，磷霉素对所有菌株均具有杀菌作用。这可能限制了磷霉素作为单一药物治疗的使用。
