Pharmacokinetics and Tolerability of Intravenous Sulbactam-Durlobactam With Imipenem/Cilastatin in Hospitalized Adults with Complicated Urinary Tract Infections, Including Acute Pyelonephritis.

Durlobactam (ETX2514) is a novel β-lactamase inhibitor with broad spectrum activity against Ambler class A, C, and D β-lactamases. Durlobactam restores in vitro activity of sulbactam (SUL) against Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam (SUL-DUR) is under development for treating ABC infections. Eighty patients with complicated urinary tract infection (cUTI), including acute pyelonephritis (AP) were randomized 2:1 to SUL-DUR 1 g/1 g IV or placebo every 6 hours (q6h) for 7 days and background therapy with imipenem/cilastatin (IMI) 500 mg IV q6h to evaluate the tolerability of SUL-DUR in hospitalized patients. Patients with bacteremia could receive up to 14 days of therapy. SUL-DUR tolerability and pharmacokinetic (PK) parameters were determined. Efficacy at the Test-of-Cure (TOC) visit was recorded. SUL-DUR was well tolerated with no serious adverse events (AEs) reported. Headache (5.7%), nausea (3.8%), diarrhea (3.8%), and vascular pain (3.8%) were the most common drug-related AEs with SUL-DUR of mostly of mild or moderate severity. The PK profile of DUR and SUL in hospitalized patients was consistent with observations in healthy volunteers. Overall success in the microbiological-modified intent-to-treat (ITT) population was similar between the groups as would be expected with IMI background therapy in all patients (at TOC 76.6% (n=36) with SUL-DUR and 81.0% (n=17) with placebo). SUL-DUR in combination with IMI was well tolerated in patients with cUTI. Pharmacokinetics of SUL-DUR in hospitalized patients was similar to that observed in healthy volunteers.