Cefepime-nacubactam and aztreonam-nacubactam non-inferior for complicated UTI and pyelonephritis

BACKGROUND: Nacubactam (OP0595) is a newly developed diazabicyclooctane β-lactamase inhibitor used in combination with cefepime or aztreonam. We assessed the efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam versus imipenem-cilastatin in complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis. METHODS: The Integral-1 global, phase 3, multicentre, randomised, double-blind study recruited adults (aged ≥18 years) with cUTI or acute uncomplicated pyelonephritis at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Japan, Latvia, Lithuania, and Slovakia. Patients were randomly assigned (2:1:1) to receive intravenous cefepime (2 g) plus nacubactam (1 g), aztreonam (2 g) plus nacubactam (1 g), or imipenem (1 g) plus cilastatin (1 g) every 8 h for 5-14 days. Randomisation was stratified by diagnosis and geographical region. The primary endpoint was the proportion of patients achieving composite clinical and microbiological success at test of cure in the microbiological modified intention-to-treat population-all patients who were randomly assigned, received any amount of the study drug, and had a baseline qualifying pathogen that was susceptible to imipenem and meropenem. The prespecified non-inferiority margin was more than 15 percentage points difference; the superiority margin was more than zero percentage points difference, for the lower bound of the two-sided 95% CI for imipenem-cilastatin. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT05887908. FINDINGS: Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned and 431 were included in the primary efficacy analysis (cefepime-nacubactam [n=214], aztreonam-nacubactam [n=112], or imipenem-cilastatin [n=105]); 228 patients (53%) were male and 203 (47%) were female. The primary endpoint was achieved by 176 (82%) of 214, 81 (72%) of 112, and 64 (61%) of 105 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively. The percentage difference in the success rate versus imipenem-cilastatin was 21·3% (95% CI 10·9 to 32·0) for cefepime-nacubactam (non-inferior and superior), and 11·4% (-1·2 to 23·7) for aztreonam-nacubactam (non-inferior). Treatment-emergent adverse events were reported in 100 (33%) of 306, 45 (30%) of 152, and 65 (43%) of 150 patients in the cefepime-nacubactam, aztreonam-nacubactam, and imipenem-cilastatin groups, respectively. No treatment-related deaths occurred. INTERPRETATION: Cefepime-nacubactam and aztreonam-nacubactam are potential treatment options for Gram-negative cUTI and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains. FUNDING: Meiji Seika Pharma and Japan Agency for Medical Research and Development.