Cefepime-Nacubactam and Aztreonam-Nacubactam in Phase 3 cUTI Trial

Key Takeaways

• Both nacubactam-based regimens were associated with non-inferior test-of-cure success versus imipenem-cilastatin, and cefepime-nacubactam also met superiority criteria.
• This global, multicentre, randomized, double-blind phase 3 trial enrolled adults with complicated urinary tract infection or acute uncomplicated pyelonephritis, with 614 randomized and 431 in the primary efficacy analysis.
• Treatment-emergent adverse events were reported across all groups, and no treatment-related deaths occurred.

In the Integral-1 phase 3 trial, cefepime-nacubactam achieved 82% composite clinical and microbiological success at test of cure, compared with 61% for imipenem-cilastatin in adults with complicated urinary tract infection or acute uncomplicated pyelonephritis. Aztreonam-nacubactam also cleared the prespecified non-inferiority margin versus imipenem-cilastatin. Integral-1 was a global, multicentre, randomised, double-blind phase 3 study of intravenous therapy. The trial compared two nacubactam-based regimens with imipenem-cilastatin in urinary infection.

Researchers enrolled adults aged 18 years or older at 79 sites in Bulgaria, China, Czech Republic, Estonia, Georgia, Japan, Latvia, Lithuania, and Slovakia. Patients were assigned 2:1:1 to intravenous cefepime 2 g plus nacubactam 1 g, aztreonam 2 g plus nacubactam 1 g, or imipenem 1 g plus cilastatin 1 g. Each regimen was given every 8 hours for 5 to 14 days, and randomisation was stratified by diagnosis and geographical region. Between May 22, 2023, and Nov 26, 2024, 614 patients were randomly assigned, and 431 entered the primary efficacy analysis, including 228 men and 203 women. The primary endpoint was composite clinical and microbiological success at test of cure in the microbiological modified intention-to-treat population.

At test of cure, success occurred in 176 of 214 patients (82%) with cefepime-nacubactam, 81 of 112 (72%) with aztreonam-nacubactam, and 64 of 105 (61%) with imipenem-cilastatin. The prespecified primary efficacy population included randomly assigned patients who received study drug and had a baseline qualifying pathogen susceptible to imipenem and meropenem. The percentage difference versus imipenem-cilastatin was 21.3% (95% CI 10.9 to 32.0) for cefepime-nacubactam and 11.4% (-1.2 to 23.7) for aztreonam-nacubactam. Non-inferiority required a lower two-sided 95% CI bound above minus 15 percentage points, while superiority required a lower bound above zero. Cefepime-nacubactam met non-inferiority and superiority criteria, whereas aztreonam-nacubactam met non-inferiority alone.

Safety was assessed in all patients who received at least one dose of study drug. Treatment-emergent adverse events occurred in 100 of 306 patients (33%) with cefepime-nacubactam, 45 of 152 (30%) with aztreonam-nacubactam, and 65 of 150 (43%) with imipenem-cilastatin. No treatment-related deaths occurred in any group during the study period. The authors described both nacubactam-based regimens as potential options for Gram-negative complicated urinary tract infection and acute uncomplicated pyelonephritis, including infections caused by antimicrobial-resistant strains.