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Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia.

Das, Shampa, Fitzgerald, Richard, Ullah, Asad, Bula, Marcin, Collins, Andrea ORCID:, Mitsi, Elena, Reiné, Jesús, Hill, Helen, Rylance, Jamie ORCID:, Ferreira, Daniela ORCID:, Tripp, Karen, Bertasini, Andrea, Franzoni, Samantha, Massimiliano, Mameli, Lahlou, Omar, Motta, Paola, Barth, Philip, Velicitat, Patrick, Knechtle, Philipp and Hope, William (2020) 'Intrapulmonary Pharmacokinetics of Cefepime and Enmetazobactam in Healthy Volunteers: Towards New Treatments for Nosocomial Pneumonia.'. Antimicrobial Agents and Chemotherapy, Vol 65, e01468-20.

AAC01468-20R1-Merged_PDF Hope paper - DFerreira.pdf - Accepted Version

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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 .

Item Type: Article
Subjects: QV Pharmacology > Anti-Bacterial Agents. Tissue Extracts > QV 350.5.C3 Cephalosporins
WC Communicable Diseases > Infection. Bacterial Infections > Bacterial Infections > WC 202 Pneumonia (General or not elsewhere classified)
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI):
Depositing User: Julie Franco
Date Deposited: 27 Jan 2021 18:05
Last Modified: 16 Jun 2021 01:02


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