Pharmacokinetic/Pharmacodynamic Determination and Preclinical Pharmacokinetics of the β-Lactamase Inhibitor ETX1317 and Its Orally Available Prodrug ETX0282.

Abstract

Increasingly resistant Enterobacteriaceae have emerged as a health threat in both hospital and community settings. Infections of the urinary tract, once often treated with oral agents in the community, are requiring increased hospitalization and use of intravenously administered agents for effective treatment. These isolates often carry extended spectrum β-lactamases (ESBLs) and carbapenemases that necessitate the need for an inhibitor to cover a broad range of β-lactamases. ETX1317 is a novel diazabicyclooctane class serine β-lactamase inhibitor that restores the antibacterial activity of several classes of β-lactams, including third-generation cephalosporins such as cefpodoxime. ETX1317 is currently being developed as an orally available prodrug, ETX0282, to be administered with cefpodoxime proxetil (CPDP). The combination has demonstrated oral efficacy in murine models of infection. Pharmacokinetics established in preclinical species and pharmacokinetic/pharmacodynamic attributes suggest the orally administered combination ETX0282 + CPDP could serve as an effective treatment option against contemporary ESBL and carbapenemase-producing Enterobacteriaceae.