PDF(Pubmed)
Abstract：
Objective: FL058 is a novel beta-lactamase inhibitor with a broad spectrum of activity and a favorable safety profile. The objective of this study was to evaluate pharmacokinetic/pharmacodynamic (PK/PD) relationships for the combination of FL058 and meropenem in an in vitro infection model. Methods: By simulating human concentration-time profiles in the in vitro model, meropenem combined with FL058 when administered 1 g/0.5 g, 1 g/1 g, 2 g/1 g, and 2 g/2 g q8h by 3-h infusion achieved approximately 2- and 4-log10 kill to KPC/OXA-producing Klebsiella pneumoniae and Escherichia coli; the combination therapy could not inhibit NDM-producing K. pneumoniae but could maintain NDM-producing E. coli around a baseline. Results: The PK/PD indexes that best described the bacterial killing from baseline in log10 CFU/mL at 24 h were the percent time of free drug above the minimal inhibitory concentration (MIC) (%fT > MIC, MIC with FL058 at 4 mg/L) for meropenem and the percent time of free drug above 1 mg/L (%fT > 1 mg/L) for FL058. The targets for achieving a static effect and the 1- and 2-log10 kill were 74, 83, and 99 for %fT > MIC of meropenem and 40, 48, and 64 for %fT > 1 mg/L of FL058, respectively. The PK/PD index of %fT > 1 mg/L can provide a basis for evaluating clinical dosing regimens for FL058 combined with meropenem. Conclusion: FL058 combined with meropenem might be a potential treatment for KPC- and/or OXA-48-producing Enterobacterales infection.
摘要：
目的：FL058是一种新型的β-内酰胺酶抑制剂，具有广谱的活性和良好的安全性。这项研究的目的是评估FL058和美罗培南组合在体外感染模型中的药代动力学/药效学（PK/PD）关系。方法：通过在体外模型中模拟人体浓度-时间曲线，美罗培南联合FL058给药时1g/0.5g，1g/1g,2g/1g,通过3小时输注2g/2gq8h，对产KPC/OXA的肺炎克雷伯菌和大肠杆菌的杀死约2-和4-log10；联合疗法不能抑制产NDM的肺炎克雷伯菌，但可以维持产NDM的大肠杆菌在基线附近。结果：在24小时以log10CFU/mL为基准，最好地描述了细菌杀伤的PK/PD指标是游离药物超过最小抑制浓度（MIC）的时间百分比（％fT>MIC，对于美罗培南，使用FL058的MIC为4mg/L），对于FL058，游离药物超过1mg/L（％fT>1mg/L）的时间百分比。对于美罗培南的％fT>MIC，实现静态效果和1-和2-log10杀伤的目标分别为74、83和99，对于％fT>1mg/L的FL058，分别为40、48和64。％fT>1mg/L的PK/PD指数可为评估FL058联合美罗培南的临床给药方案提供依据。结论：FL058联合美罗培南可能是产生KPC和/或OXA-48的肠杆菌感染的潜在治疗方法。
