口服磷霉素对体外膀胱感染模型中肠杆菌科、铜绿假单胞菌和肠球菌属的药代动力学/药效学分析：对临床折点的影响。

Pharmacokinetic/pharmacodynamic analysis of oral fosfomycin against Enterobacterales, Pseudomonas aeruginosa and Enterococcus spp. in an in vitro bladder infection model: impact on clinical breakpoints.

机构信息

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.

出版信息

J Antimicrob Chemother. 2021 Nov 12;76(12):3201-3211. doi: 10.1093/jac/dkab313.

DOI:10.1093/jac/dkab313

PMID:34473271

Abstract

OBJECTIVES

Fosfomycin is an established treatment for uncomplicated urinary tract infections (UTIs), yet evidence supporting susceptibility breakpoints is limited. We examine the UTI susceptibility criteria.

METHODS

Fosfomycin susceptibility, heteroresistance and in vitro growth in a bladder infection model, after a single 3 g dose of oral fosfomycin, were bridged to human pharmacokinetics with pharmacokinetic/pharmacodynamic and Monte Carlo analyses. Data from common uropathogens (24 Escherichia coli, 20 Klebsiella pneumoniae, 4 Enterobacter cloacae, 14 Pseudomonas aeruginosa, 8 Enterococcus faecalis and 8 Enterococcus faecium) were compared and analysed to ascertain species-specific PTA.

RESULTS

Glucose-6-phosphate (G6P) increased MICs of E. coli, K. pneumoniae and E. cloacae (median 2-fold dilutions 3-5), but not of P. aeruginosa and Enterococcus. Atypical E. coli lacking G6P potentiation were killed in the bladder infection model despite high MICs (32-128 mg/L). Fosfomycin heteroresistance was uncommon in E. coli (MIC > 2 mg/L) but was detected in the majority of K. pneumoniae (MIC > 1 mg/L) and P. aeruginosa (MIC >8 mg/L). For these species, baseline heteroresistance was a strong predictor for treatment failure in the model. No heteroresistance was found in Enterococcus. The fAUC/MIC targets for stasis were 1935, 3393, 9968, 2738 and 283 for typical E. coli, K. pneumoniae, E. cloacae, P. aeruginosa and E. faecalis, respectively (synthetic human urine medium alone promoted a 1 log10 kill in E. faecium). A >95% PTA for stasis was only found at MIC ≤ epidemiological cut-off (ECOFF) for E. coli (4 mg/L). For other species, PTAs were low for WT populations.

CONCLUSIONS

With the exception of E. coli, fosfomycin is a poor target for other uropathogen species. A reduction in oral fosfomycin UTI breakpoints is supported.

摘要

目的

磷霉素是治疗单纯性尿路感染（UTI）的既定疗法，但支持药敏折点的证据有限。我们检查了 UTI 药敏标准。

方法

用口服磷霉素 3g 单剂量后，在膀胱感染模型中检测磷霉素的药敏、异质性耐药和体外生长，并用药代动力学/药效学和蒙特卡罗分析将其与人体药代动力学联系起来。将来自常见尿路病原体（24 株大肠埃希菌、20 株肺炎克雷伯菌、4 株阴沟肠杆菌、14 株铜绿假单胞菌、8 株粪肠球菌和 8 株屎肠球菌）的数据进行比较和分析，以确定种特异性 PTA。

结果

葡萄糖-6-磷酸（G6P）增加了大肠埃希菌、肺炎克雷伯菌和阴沟肠杆菌的 MIC（中位数为 2 倍稀释度 3-5），但对铜绿假单胞菌和肠球菌没有影响。缺乏 G6P 增强作用的非典型大肠埃希菌尽管 MIC 很高（32-128mg/L），但在膀胱感染模型中仍被杀死。大肠埃希菌的磷霉素异质性耐药性并不常见（MIC>2mg/L），但在大多数肺炎克雷伯菌（MIC>1mg/L）和铜绿假单胞菌（MIC>8mg/L）中都有发现。对于这些物种，基线异质性耐药性是模型中治疗失败的一个强有力的预测因素。肠球菌中没有发现异质性耐药性。在停滞状态下，fAUC/MIC 目标值分别为典型大肠埃希菌、肺炎克雷伯菌、阴沟肠杆菌、铜绿假单胞菌和粪肠球菌的 1935、3393、9968、2738 和 283（单独使用合成人尿培养基可使粪肠球菌 1 对数减少）。仅在大肠埃希菌的 MIC≤流行病学切点（ECOFF）（4mg/L）时，才能达到>95%的停滞 PTA。对于其他物种，WT 人群的 PTA 较低。