Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Department of Research and Development, Evopoint Biosciences Co., Ltd, Beijing, China.
J Antimicrob Chemother. 2023 Sep 5;78(9):2343-2353. doi: 10.1093/jac/dkad242.
Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains.
Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh.
Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT > MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT > MIC = 0%. Across different threshold plasma funobactam concentrations (CTs), %fT > CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT > CT = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT > CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT > CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT > CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae.
Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT > CT)/MIC appeared to best describe in vivo activity.
亚胺培南/法硼巴坦（前称 XNW4107）是一种新型β-内酰胺/β-内酰胺酶抑制剂，对多药耐药鲍曼不动杆菌、铜绿假单胞菌和肠杆菌科菌株具有活性。我们使用中性粒细胞减少症小鼠大腿感染模型，旨在确定与亚胺培南/法硼巴坦组合的体内疗效最密切相关的药代动力学/药效学（PK/PD）指数，以及针对产生丝氨酸碳青霉烯酶的临床菌株所需的指数大小。
对三种菌株进行剂量分割。针对 7 株鲍曼不动杆菌、4 株铜绿假单胞菌和 4 株肺炎克雷伯菌（亚胺培南/法硼巴坦 MIC 为 0.25-16 mg/L），评估了人类模拟亚胺培南方案（HSR，500 mg q6h 1 h 输注）联合递增法硼巴坦暴露对 24 小时大腿内 log10cfu 的影响。
增加法硼巴坦的分割增强了疗效，表明时间依赖性杀伤。大腿内 log10cfu 变化与 %fT ＞ MIC 预测疗效不佳；观察到杀菌活性在 %fT ＞ MIC = 0%时。在不同的血浆中法硼巴坦 CT 阈值下，%fT ＞ CT（1 mg/L）与疗效相关性最高。将 %fT ＞ CT（1 mg/L）指数归一化为各自分离株的亚胺培南/法硼巴坦 MIC 值（%fT ＞ CT/MIC），允许整合分离株的敏感性，进一步增强了相关性。与 1 对数减少相关的中位数（%fT ＞ CT[1 mg/L]）/MIC 值分别为鲍曼不动杆菌和铜绿假单胞菌的 9.82 和 9.90。与静止相关的中位数（%fT ＞ CT[1 mg/L]）/MIC 值为肺炎克雷伯菌的 55.73。亚胺培南/法硼巴坦 500/250 mg q6h 1 h 输注 HSR 对 6/7 株鲍曼不动杆菌、4/4 株铜绿假单胞菌产生 1 对数杀伤，对 4/4 株肺炎克雷伯菌产生静止。
亚胺培南/法硼巴坦对产生丝氨酸碳青霉烯酶的菌株具有强大的体内疗效。新型 PK/PD 指数（%fT ＞ CT）/MIC 似乎能最好地描述体内活性。
