Antimicrobial Pharmacodynamics and Therapeutics, University of Liverpool, Liverpool Health Partners, Liverpool, United Kingdom.
Liverpool University Hospital Foundation Trust, Liverpool Health Partners, Liverpool, United Kingdom.
Antimicrob Agents Chemother. 2020 Dec 16;65(1). doi: 10.1128/AAC.01468-20.
Cefepime-enmetazobactam is a novel β-lactam-β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant This agent is being developed for a range of serious hospital infections. An understanding of the extent of partitioning of β-lactam-β-lactamase inhibitor combinations into the human lung is required to better understand the potential role of cefepime-enmetazobactam for the treatment of nosocomial pneumonia. A total of 20 healthy volunteers were used to study the intrapulmonary pharmacokinetics of a regimen of 2 g cefepime-1 g enmetazobactam every 8 h intravenously (2 g/1 g q8h i.v.). Each volunteer contributed multiple plasma samples and a single epithelial lining fluid (ELF) sample, obtained by bronchoalveolar lavage. Concentrations of cefepime and enmetazobactam were quantified using liquid chromatography-tandem mass spectrometry. The pharmacokinetic data were modeled using a population methodology, and Monte Carlo simulations were performed to assess the attainment of pharmacodynamic targets defined in preclinical models. The concentration-time profiles of both agents in plasma and ELF were similar. The mean ± standard deviation percentage of partitioning of total drug concentrations of cefepime and enmetazobactam between plasma and ELF was 60.59% ± 28.62% and 53.03% ± 21.05%, respectively. Using pharmacodynamic targets for cefepime of greater than the MIC and free enmetazobactam concentrations of >2 mg/liter in ELF of 20% of the dosing interval, a regimen of cefepime-enmetazobactam of 2 g/0.5 g q8h i.v. infused over 2 h resulted in a probability of target attainment of ≥90% for with cefepime-enmetazobactam MICs of ≤8 mg/liter. This result provides a rationale to further consider cefepime-enmetazobactam for the treatment of nosocomial pneumonia caused by multidrug-resistant .
头孢吡肟-乙二胺四乙酸是一种新型的β-内酰胺-β-内酰胺酶抑制剂组合，具有广谱抗菌活性，可对抗多种多药耐药菌。该药物正在开发用于治疗多种严重的医院感染。为了更好地了解头孢吡肟-乙二胺四乙酸在治疗医院获得性肺炎中的潜在作用，需要了解β-内酰胺-β-内酰胺酶抑制剂组合在人体肺部中的分布程度。
总共 20 名健康志愿者参与了一项研究，该研究旨在研究每 8 小时静脉注射 2 g 头孢吡肟-1 g 乙二胺四乙酸（2 g/1 g q8h i.v.）方案的肺部内药代动力学。每位志愿者提供了多个血浆样本和一个通过支气管肺泡灌洗获得的单一上皮衬液（ELF）样本。使用液相色谱-串联质谱法定量检测头孢吡肟和乙二胺四乙酸的浓度。使用群体方法学对药代动力学数据进行建模，并进行蒙特卡罗模拟评估临床前模型中定义的药效学目标的实现情况。
两种药物在血浆和 ELF 中的浓度-时间曲线相似。头孢吡肟和乙二胺四乙酸总药物浓度在血浆和 ELF 之间的分配百分比的平均值±标准偏差分别为 60.59%±28.62%和 53.03%±21.05%。
使用头孢吡肟的药效学目标为大于 MIC，ELF 中游离乙二胺四乙酸浓度为 20%给药间隔的 2 毫克/升以上，头孢吡肟-乙二胺四乙酸 2 g/0.5 g q8h i.v.输注 2 小时的方案，对于头孢吡肟-乙二胺四乙酸 MICs 为≤8 毫克/升的患者，目标实现的概率≥90%。
该结果为进一步考虑头孢吡肟-乙二胺四乙酸治疗多药耐药菌引起的医院获得性肺炎提供了依据。
