Safety, Pharmacokinetics, and Drug-Drug Interaction Potential of Intravenous Durlobactam, a β-Lactamase Inhibitor, in Healthy Subjects
Open Access
- 1 July 2020
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 64 (7)
- https://doi.org/10.1128/AAC.00071-20
Abstract
Durlobactam (DUR; also known as ETX2514) is a novel beta-lactamase inhibitor with broad activity against Ambler class A, C, and D beta-lactamases. Addition of DUR to sulbactam (SUL) in vitro restores SUL activity against clinical isolates of Acinetobacter baumannii . The safety and pharmacokinetics (PK) of DUR alone and with SUL and/or imipenem-cilastatin (IMI-CIL) were evaluated in healthy subjects. This was a randomized, placebo-controlled study. In part A, subjects, including a co-hort of elderly subjects (which received DUR at 1 g), received single ascending doses of DUR ranging from 0.25 to 8 g. In part B, multiple ascending doses of DUR rang-ing from 0.25 to 2 g were administered every 6 h (q6h) for 29 doses. In parts C and D, the drug-drug interaction (DDI) potential, including the safety, of DUR (1 g) with SUL (1 g) and/or IMI-CIL (0.5/0.5 g) was investigated after single and multiple doses. Plasma and urine concentrations of DUR, SUL, and IMI-CIL were determined. Among 124 subjects, DUR was generally safe and well tolerated when it was administered either alone or in combination with SUL and/or IMI-CIL. After single and multiple doses, DUR demonstrated linear dose-proportional exposure across the studied dose ranges. Renal excretion was a predominant clearance mechanism. No drug-drug in-teraction potential between DUR and SUL and/or IMI-CIL was identified. SUL-DUR at 1 g (of each component) administered q6h with a 3-h intravenous (i.v.) infusion is under development for the treatment of serious infections due to A. baumannii .Funding Information
- Entasis Therapeutics, Inc.
This publication has 26 references indexed in Scilit:
- Antimicrobial Susceptibility of Acinetobacter calcoaceticus–Acinetobacter baumannii Complex and Stenotrophomonas maltophilia Clinical Isolates: Results From the SENTRY Antimicrobial Surveillance Program (1997–2016)Open Forum Infectious Diseases, 2019
- Carbapenem-Nonsusceptible Acinetobacter baumannii, 8 US Metropolitan Areas, 2012–2015Emerging Infectious Diseases, 2018
- Prevalence of Carbapenem-Resistant Gram-Negative Infections in the United States Predominated by Acinetobacter baumannii and Pseudomonas aeruginosaOpen Forum Infectious Diseases, 2017
- Infections Due to Acinetobacter baumannii in the ICU: Treatment OptionsSeminars in Respiratory and Critical Care Medicine, 2017
- Clinical and Pathophysiological Overview of Acinetobacter Infections: a Century of ChallengesClinical Microbiology Reviews, 2017
- Emergence of antimicrobial resistance among Acinetobacter species: a global threatCurrent Opinion in Critical Care, 2016
- Secular trends in Acinetobacter baumannii resistance in respiratory and blood stream specimens in the United States, 2003 to 2012: A survey studyJournal of Hospital Medicine, 2015
- Excess Mortality Associated With Colistin-Tigecycline Compared With Colistin-Carbapenem Combination Therapy for Extensively Drug-Resistant Acinetobacter baumannii BacteremiaCritical Care Medicine, 2015
- Carbapenem resistance and mortality in patients with Acinetobacter baumannii infection: systematic review and meta-analysisClinical Microbiology & Infection, 2014
- Antimicrobial-Resistant Pathogens Associated with Healthcare-Associated Infections Summary of Data Reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009–2010Infection Control & Hospital Epidemiology, 2013