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A First-in-Human Study To Assess the Safety and Pharmacokinetics of LYS228, a Novel Intravenous Monobactam Antibiotic in Healthy Volunteers.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2019 Jun 24; Vol. 63 (7). Date of Electronic Publication: 2019 Jun 24 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- Infections caused by antibiotic-resistant Gram-negative bacteria expressing extended-spectrum β-lactamases and carbapenemases are a growing global problem resulting in increased morbidity and mortality with limited treatment options. LYS228 is a novel intravenous monobactam antibiotic targeting penicillin binding protein 3 with potent activity against Enterobacteriaceae , including multidrug-resistant clinical isolates expressing serine and metallo-β-lactamases. In this study, we evaluated the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of LYS228 in healthy volunteers. LYS228 was safe: no serious adverse events were reported. Adverse events, with the exception of catheter-related events, occurred sporadically, with similar incidences between LYS228 and placebo groups. No apparent adverse event-dose relationship was identified. LYS228 was not associated with any clinically significant dose-related hematologic, hepatic, or renal laboratory abnormalities. The most frequently observed adverse events were local injection site reactions, noted in 91.7% and 75.0% of subjects administered multiple doses of LYS228 and placebo, respectively. LYS228 demonstrated pharmacokinetic properties consistent with those of other β-lactam antibiotics, with systemic exposures slightly greater than dose proportional, short terminal half-lives (between 1.0 and 1.6 h) with no significant accumulation, and rapid clearance predominantly through urinary excretion.<br /> (Copyright © 2019 Osborn et al.)
- Subjects :
- Adult
Anti-Bacterial Agents administration & dosage
Bacterial Proteins metabolism
Enterobacteriaceae drug effects
Enterobacteriaceae metabolism
Female
Healthy Volunteers
Humans
Male
Microbial Sensitivity Tests methods
Middle Aged
Monobactams administration & dosage
beta-Lactamases metabolism
Anti-Bacterial Agents adverse effects
Anti-Bacterial Agents pharmacokinetics
Monobactams adverse effects
Monobactams pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 63
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 31061156
- Full Text :
- https://doi.org/10.1128/AAC.02592-18