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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

Authors
  • Osborn, Megan
  • Stachulski, Noah
  • Sun, Haiying
  • Blais, Johanne
  • Venishetty, Vinay
  • Raccuglia, Marc
  • Kankam, Martin
  • Colvin, Richard
  • Segal, Florencia
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
Jun 24, 2019
Volume
63
Issue
7
Identifiers
DOI: 10.1128/AAC.02592-18
PMID: 31061156
PMCID: PMC6591616
Source
PubMed Central
Keywords
License
Green

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.

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