Abstract

Objectives

Cefepime/taniborbactam is a cephalosporin/cyclic boronate β-lactamase inhibitor combination under development for the treatment of infections due to MDR Enterobacterales and Pseudomonas aeruginosa. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic index, relative to taniborbactam exposure, that correlated most closely with the efficacy of the cefepime/taniborbactam combination and the magnitude of index required for efficacy against serine-β-lactamase-producing strains.

Methods

Twenty-six clinical Enterobacterales (expressing ESBLs, plasmid-mediated AmpC and/or carbapenemases of classes A or D; cefepime/taniborbactam combination MICs 0.06–16 mg/L) and 11 clinical P. aeruginosa (AmpC overproducing or KPC expressing; cefepime/taniborbactam combination MICs 1–16 mg/L) were evaluated. A cefepime human-simulated regimen (HSR) equivalent to a clinical dose of 2 g q8h as a 2 h infusion was given in combination with taniborbactam for 24 h. For a subset of P. aeruginosa isolates, a sub-therapeutic cefepime exposure was utilized.

Results

Dose-fractionation studies revealed that dosing frequency had no impact on taniborbactam potentiation of cefepime activity. Relative to the initial bacterial burden, the median taniborbactam fAUC_0–24/MIC associated with 1 log kill in combination with the cefepime HSR for Enterobacterales and P. aeruginosa isolates was 2.62 and 0.46, respectively. In combination with sub-therapeutic cefepime, the median taniborbactam fAUC_0–24/MIC associated with 1 and 2 log kill against AmpC-overproducing P. aeruginosa was 2.00 and 3.30, respectively, relative to the bacterial burden in the cefepime-treated groups. The taniborbactam HSR (equivalent to 0.5 g q8h as a 2 h infusion) was adequate to attain ≥1 log reduction against all test isolates.

Conclusions

Our data show that the cefepime/taniborbactam combination (2 g/0.5 g q8h as a 2 h infusion) exerts potent in vivo activity against cefepime-resistant isolates, including serine-carbapenemase producers.

中文翻译：

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新一代 β-内酰胺酶抑制剂 taniborbactam（以前的 VNRX-5133）与头孢吡肟联合用于对抗产丝氨酸-β-内酰胺酶革兰氏阴性菌的体内药效学。

摘要

目标

头孢吡肟/taniborbactam 是一种头孢菌素/环硼酸酯 β-内酰胺酶抑制剂组合，正在开发中，用于治疗 MDR 肠杆菌属和铜绿假单胞菌引起的感染。使用中性粒细胞减少的鼠大腿感染模型，我们旨在确定相对于 taniborbactam 暴露量的药代动力学/药效学指数，该指数与头孢吡肟 / taniborbactam 组合的功效和对抗丝氨酸-β-内酰胺酶的功效所需的指数大小最密切相关- 产生菌株。

方法

26 种临床肠杆菌（表达 ESBL、质粒介导的 AmpC 和/或 A 类或 D 类碳青霉烯酶；头孢吡肟/坦尼硼巴坦组合 MIC 0.06–16 mg/L）和 11 种临床铜绿假单胞菌（AmpC 过量生产或 KPC 表达；头孢吡肟/ taniborbactam 组合 MIC 1–16 mg/L) 进行了评估。头孢吡肟人体模拟方案 (HSR) 相当于临床剂量 2 g q8h 作为 2 小时输注，与 taniborbactam 联合给药 24 小时。对于铜绿假单胞菌分离株的子集，使用了亚治疗性头孢吡肟暴露。

结果

剂量分级研究表明，给药频率对头孢吡肟活性的 taniborbactam 增强没有影响。相对于初始细菌负荷，对于肠杆菌属和铜绿假单胞菌分离株，与头孢吡肟 HSR 联合使用 1 log 杀灭相关的中值 taniborbactam f AUC _0–24 /MIC分别为 2.62 和 0.46。与亚治疗头孢吡肟联合使用时，中位 taniborbactam f AUC _0–24 /MIC 与对 AmpC 过量产生的铜绿假单胞菌的1 和 2 log 杀灭率相关相对于头孢吡肟治疗组的细菌负荷，分别为 2.00 和 3.30。taniborbactam HSR（相当于 0.5 g q8h，每 2 小时输注一次）足以使所有测试分离株的对数减少≥1。

结论

我们的数据显示头孢吡肟/丹尼波巴坦组合（2 g/0.5 g q8h，每 2 小时输注一次）对头孢吡肟耐药菌株（包括丝氨酸-碳青霉烯酶生产者）发挥有效的体内活性。