Portillo-Calderón I, Ortiz-Padilla M, de Gregorio-Iaria B, Merino-Bohorquez V, Blázquez J, Rodríguez-Baño J, Rodríguez-Martínez J M, Pascual A, Docobo-Pérez F
Unidad Clínica de Enfermedades Infecciosas, Microbiología y Medicina Preventiva, Hospital Universitario Virgen Macarena, Seville, Spain.
Instituto de Biomedicina de Sevilla IBIS, Hospital Universitario Virgen Macarena/CSIC/Universidad de Sevilla, Seville, Spain.
Antimicrob Agents Chemother. 2023 May 1;65(5). doi: 10.1128/AAC.02213-20. Epub 2021 Mar 8.
To evaluate human-like intravenous doses of fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy in monotherapy and in combination against six fosfomycin-heteroresistant isolates using a hollow-fiber infection model (HFIM).Six fosfomycin-heteroresistant isolates (4 with strong mutator phenotype) and the control strain ATCC 25922 were used. Mutant frequencies for rifampin (100mg/L), fosfomycin (50 and 200mg/L) and amikacin (32mg/L) were determined. Fosfomycin and amikacin MICs were assessed by agar dilution (AD), gradient strip (GSA) and broth microdilution (BMD) assays. Fosfomycin and amikacin synergies were studied by checkerboard and time-kill assays at different concentrations. Fosfomycin (8g/Q8h) and amikacin (15mg/kg/Q24h) efficacy alone and in combination were assessed using a HFIM.Five isolates were resistant to fosfomycin by AD and BMD, but all susceptible by GSA. All isolates were considered susceptible to amikacin. Antibiotic combinations were synergistic in two isolates and no antagonism was detected. In time-kill assays, all isolates survived under fosfomycin at 64mg/L, although, at 307mg/L, only the normomutators and two hypermutators survived. Four isolates survived under 16mg/L amikacin and none at 45mg/L. No growth was detected under combination conditions. In HFIM, fosfomycin and amikacin monotherapies failed to sterilise bacterial cultures, however, fosfomycin and amikacin combination showed a rapid eradication.There may be a risk of treatment failure of fosfomycin-heteroresistant isolates using either amikacin or fosfomycin in monotherapy. These results support that the combination amikacin-fosfomycin can rapidly decrease bacterial burden and prevent the emergence of resistant subpopulations against fosfomycin-heteroresistant strains.
使用中空纤维感染模型（HFIM）评估人用剂量的磷霉素（8g/每8小时）和阿米卡星（15mg/kg/每24小时）单药治疗及联合治疗对6株磷霉素异质性耐药菌株的疗效。使用了6株磷霉素异质性耐药菌株（4株具有强突变表型）和对照菌株ATCC 25922。测定了利福平（100mg/L）、磷霉素（50和200mg/L）和阿米卡星（32mg/L）的突变频率。通过琼脂稀释法（AD）、梯度纸条法（GSA）和肉汤微量稀释法（BMD）测定磷霉素和阿米卡星的最低抑菌浓度（MIC）。通过棋盘法和不同浓度下的时间杀菌试验研究磷霉素和阿米卡星的协同作用。使用HFIM评估磷霉素（8g/每8小时）和阿米卡星（15mg/kg/每24小时）单独及联合使用时的疗效。5株菌株通过AD和BMD对磷霉素耐药，但通过GSA均敏感。所有菌株对阿米卡星均敏感。抗生素联合在2株菌株中具有协同作用，未检测到拮抗作用。在时间杀菌试验中，所有菌株在64mg/L的磷霉素作用下存活，尽管在307mg/L时，只有正常突变体和2株高突变体存活。4株菌株在16mg/L的阿米卡星作用下存活，在45mg/L时均未存活。联合用药条件下未检测到生长。在HFIM中，磷霉素和阿米卡星单药治疗未能清除细菌培养物，然而，磷霉素和阿米卡星联合使用显示出快速清除效果。单药使用阿米卡星或磷霉素治疗磷霉素异质性耐药菌株可能存在治疗失败的风险。这些结果支持阿米卡星-磷霉素联合使用可迅速降低细菌负荷并防止针对磷霉素异质性耐药菌株的耐药亚群出现。
