Das, Shampa 
ORCID: 0000-0002-2540-4816, Fitzgerald, Richard, Ullah, Asad, Bula, Marcin, Collins, Andrea M, Mitsi, Elena, Reine, Jesus, Hill, Helen, Rylance, Jamie, Ferreira, Daniela M et al (show 10 more authors)
(2021)
Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 65 (1).
e01468-e01420.
Abstract
Cefepime-enmetazobactam is a novel β-lactam-β-lactamase inhibitor combination with broad-spectrum antimicrobial activity against a range of multidrug-resistant <i>Enterobacteriaceae</i> 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 <i>Enterobacteriaceae</i> 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 <i>Enterobacteriaceae</i>.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ESBL, Monte Carlo simulation, beta-lactams, cefepime, enmetazobactam, pneumonia, population pharmacokinetics |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 12 Jul 2021 09:45 |
| Last Modified: | 10 Feb 2024 03:15 |
| DOI: | 10.1128/AAC.01468-20 |
| Open Access URL: | https://archive.lstmed.ac.uk/16777/ |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3129727 |
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