Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Department of Medical Microbiology and Infectious Diseases, Research and Development Unit, Erasmus Medical Centre, Rotterdam, The Netherlands.
J Antimicrob Chemother. 2018 Mar 1;73(3):709-719. doi: 10.1093/jac/dkx441.
Urinary tract infections (UTIs) are among the most common bacterial infections and a frequent indication for antibiotic use. Fosfomycin, an important oral antibiotic for outpatient UTIs, remains a viable option for MDR uropathogens. We aimed to perform pharmacodynamic profiling simulating urinary concentrations to assess the adequacy of the current dosing regimen.
A dynamic in vitro bladder infection model was developed, replicating urinary fosfomycin concentrations after gastrointestinal absorption, systemic distribution and urinary elimination. Concentrations were measured by LC-MS/MS. Twenty-four Enterobacteriaceae strains (Escherichia coli, Klebsiella pneumoniae and Enterobacter cloacae; MIC range 0.25-64 mg/L) were examined. Pathogen kill and emergence of resistance was assessed over 72 h.
Observed in vitro fosfomycin concentrations accurately simulated urinary fosfomycin exposures (Tmax 3.8 ± 0.5 h; Cmax 2630.1 ± 245.7 mg/L; AUC0-24 33 932.5 ± 1964.2 mg·h/L). Fifteen of 24 isolates regrew, with significant rises in fosfomycin MIC (total population MIC50 4 to 64 mg/L, MIC90 64 to > 1024 mg/L, P = 0.0039; resistant subpopulation MIC50 128 to > 1024 mg/L, MIC90 >1024 mg/L, P = 0.0020). E. coli and E. cloacae isolates were killed with pharmacokinetic/pharmacodynamic EI50 of fAUC0-24/MIC = 1922, fCmax/MIC = 149 and fTime>4×MIC = 44 h. In contrast, K. pneumoniae isolates were not reliably killed.
Using dynamic in vitro simulations of urinary fosfomycin exposures, E. coli and E. cloacae isolates with MIC >16 mg/L, and all K. pneumoniae isolates, were not reliably killed. Emergence of resistance was significant. This challenges fosfomycin dosing and clinical breakpoints, and questions the utility of fosfomycin against K. pneumoniae. Further work on in vitro dose optimization is required.
尿路感染（UTIs）是最常见的细菌性感染之一，也是抗生素使用的常见指征。磷霉素作为治疗门诊 UTIs 的重要口服抗生素，对于多重耐药尿路病原体仍然是一种可行的选择。我们旨在通过模拟尿液浓度的药效动力学分析来评估当前给药方案的充分性。
建立了一个动态的膀胱感染体外模型，复制了胃肠道吸收、全身分布和尿液消除后的尿液磷霉素浓度。通过 LC-MS/MS 进行浓度测定。研究了 24 株肠杆菌科菌株（大肠杆菌、肺炎克雷伯菌和阴沟肠杆菌；MIC 范围为 0.25-64mg/L）。在 72 小时内评估了病原体的杀灭和耐药性的出现。
体外观察到的磷霉素浓度准确模拟了尿液中的磷霉素暴露情况（Tmax 为 3.8±0.5 小时；Cmax 为 2630.1±245.7mg/L；AUC0-24 为 33932.5±1964.2mg·h/L）。24 株分离株中有 15 株重新生长，磷霉素 MIC 显著升高（总体 MIC50 为 4 至 64mg/L，MIC90 为 64 至>1024mg/L，P=0.0039；耐药亚群 MIC50 为 128 至>1024mg/L，MIC90 为>1024mg/L，P=0.0020）。E. coli 和 E. cloacae 分离株的药代动力学/药效学 EI50 为 fAUC0-24/MIC=1922，fCmax/MIC=149，fTime>4×MIC=44 小时，被有效杀灭。相比之下，肺炎克雷伯菌分离株则不能被可靠地杀灭。
使用尿液中磷霉素暴露的动态体外模拟，MIC>16mg/L 的大肠杆菌和阴沟肠杆菌分离株，以及所有肺炎克雷伯菌分离株，均不能被可靠杀灭。耐药性的出现是显著的。这对磷霉素的给药剂量和临床折点提出了挑战，并对磷霉素治疗肺炎克雷伯菌的有效性提出了质疑。需要进一步进行体外剂量优化的研究。
