Comparative in vivo activity of human-simulated plasma and epithelial lining fluid exposures of WCK 5222 (cefepime/zidebactam) against KPC- and OXA-48-like-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model
Comparative in vivo activity of human-simulated plasma and epithelial lining fluid exposures of WCK 5222 (cefepime/zidebactam) against KPC- and OXA-48-like-producing Klebsiella pneumoniae in the neutropenic murine pneumonia model
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DOI：
10.1093/jac/dkab183
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发表时间：
2021-06-07
影响因子：
5.2
通讯作者：
Nicolau, David P.
中科院分区：
文献类型：
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作者：
Lasko, Maxwell J.;Abdelraouf, Kamilia;Nicolau, David P.
目的：这是使用人体模拟血浆和 ELF 暴露对 WCK 5222（头孢吡肟/齐德巴坦 2/1 g，每 8 小时输注 1 小时）对中性粒细胞减少性鼠肺炎模型中产生丝氨酸碳青霉烯酶的肺炎克雷伯菌的功效进行比较评估。方法：使用 10 种临床分离株：8 种是产生丝氨酸碳青霉烯酶的（KPC，n） = 4；OXA-48 样，n = 4) WCK 5222 MIC (1:1) 范围为 1 至 4 mg/L 的肠杆菌；两个是之前研究过的 MDR 分离株，用作质量控制。小鼠肺接种50μL 10(7)cfu/mL。治疗小鼠接受人体模拟的头孢吡肟、齐地巴坦或 WCK 5222 方案，这些方案源自健康受试者的血浆或上皮衬里液 (ELF) 特征。比较血浆和 ELF 中人源化暴露产生的肺部细菌密度。结果：初始肺部细菌密度范围为 6.06 至 6.87 Log(10) cfu/肺，24 小时后平均细菌负荷增加至 9.06 +/- 0.42。头孢吡肟和齐德巴坦单一疗法的人体模拟血浆和 ELF 暴露没有活性。人体模拟 WCK 5222 血浆暴露导致所有分离株的细菌负荷减少 >1 Log(10) cfu/肺。所有分离株的人源化 WCK 5222 ELF 暴露均实现 >1 Log(10) cfu/肺减少。虽然在 5/8 株分离株中观察到 WCK 5222 的血浆和 ELF 暴露在细菌负担减少方面存在统计学上的显着差异，但所有治疗均实现了 >1 Log(10) cfu 减少的转化杀灭目标。结论：临床上可实现的 WCK 5222 血浆和 ELF 暴露在中性粒细胞减少性鼠肺炎模型中产生了体内碳青霉烯类耐药肠杆菌的杀灭作用，这可以预测对人类的疗效。
Objectives: This was a comparative assessment of WCK 5222 (cefepime/zidebactam 2/1 g as a 1 h infusion every 8 h) efficacy using human-simulated plasma and ELF exposures against serine-carbapenemase-producing Klebsiella pneumonlae in the neutropenic murine pneumonia model.Methods: Ten clinical isolates were utilized: eight were serine-carbapenemase-producing (KPC, n = 4; OXA-48-like, n = 4) Enterobacterales with WCK 5222 MICs (1:1) ranging from 1 to 4 mg/L; and two were previously studied MDR isolates serving as quality controls. Lungs of mice were inoculated with 50 mu L of 10(7) cfu/mL. Treatment mice received human-simulated regimens of cefepime, zidebactam or WCK 5222 derived from plasma or epithelial Lining fluid (ELF) profiles obtained from healthy subjects. Lung bacterial densities resulting from the humanized exposures in plasma and ELF were compared.Results: Initial Lung bacterial densities ranged from 6.06 to 6.87 Log(10) cfu/Lungs, with a mean bacterial burden increase to 9.06 +/- 0.42 after 24 h. Human-simulated plasma and ELF exposures of cefepime and zidebactam monotherapy had no activity. Human-simulated WCK 5222 plasma exposures resulted in a >1 Log(10) cfu/Lungs reduction in bacterial burden for all isolates. Humanized WCK 5222 ELF exposures achieved a >1 Log(10) cfu/Lungs reduction for all isolates. While statistically significant differences in bacterial burden reduction were observed between the plasma and ELF exposures for WCK 5222 in 5/8 isolates, all treatments achieved the translational kill target of a >1 Log(10) cfu reduction.Conclusions: Clinically achievable WCK 5222 plasma and ELF exposures produced in vivo killing of carbapenem-resistant Enterobacterales in the neutropenic murine pneumonia model that is predictive of efficacy in humans.