A nacubactam combination beat a carbapenem in a complicated-UTI trial

Cefepime combined with nacubactam, a newly developed β-lactamase inhibitor, cured more complicated urinary tract infections than the carbapenem imipenem in the phase 3 Integral-1 trial, meeting the bar for both non-inferiority and superiority [s1]. The result matters because it points to a way of treating resistant Gram-negative infections without reaching for a carbapenem — the broad-spectrum class whose overuse drives the next, harder-to-treat tier of resistance [s1][s2].

Complicated urinary tract infections and kidney infections caused by Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae increasingly involve strains that produce β-lactamases, enzymes that inactivate many standard antibiotics. When that happens, clinicians often fall back on carbapenems, and that reliance has a cost: carbapenem-resistant Enterobacterales sit in the "critical" tier of the World Health Organization's 2024 bacterial priority pathogens list, the group for which new treatments are most urgently needed [s2]. Nacubactam — a diazabicyclooctane inhibitor, formerly known as OP0595 — is designed to disable those enzymes and restore the activity of a partner β-lactam, in this case the cephalosporin cefepime or the monobactam aztreonam [s1].

What the trial did

Integral-1 was a global, multicentre, randomised, double-blind phase 3 trial run at 79 sites across nine countries and funded by Meiji Seika Pharma, the drug's developer, together with a Japanese government research agency [s1]. Adults with a complicated urinary tract infection or acute uncomplicated pyelonephritis were randomly 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 given every eight hours for 5–14 days [s1].

The primary endpoint was a demanding composite: both clinical cure and microbiological eradication of the qualifying pathogen at the test-of-cure visit, assessed in patients whose baseline organism was susceptible to the carbapenem comparators [s1]. The trial prespecified a non-inferiority margin of 15 percentage points and, if that was met, a test for outright superiority [s1]. Between May 2023 and November 2024, 614 patients were randomised and 431 formed the primary efficacy population — 214 on cefepime–nacubactam, 112 on aztreonam–nacubactam and 105 on imipenem–cilastatin [s1].

What it found

Composite success was achieved by 176 of 214 patients (82%) on cefepime–nacubactam, 81 of 112 (72%) on aztreonam–nacubactam and 64 of 105 (61%) on imipenem–cilastatin [s1]. Against the carbapenem, the difference was 21.3 percentage points for cefepime–nacubactam (95% confidence interval 10.9 to 32.0), clearing both the non-inferiority and the superiority bars, and 11.4 points for aztreonam–nacubactam (95% CI −1.2 to 23.7), which met non-inferiority [s1]. Because the lower bound of the cefepime–nacubactam interval stayed above zero, the trial supports treating that combination as more effective than imipenem in this population, not merely no worse [s1].

Treatment-emergent adverse events were reported in 33% of the cefepime–nacubactam group, 30% of the aztreonam–nacubactam group and 43% of the imipenem–cilastatin group, and no treatment-related deaths occurred [s1].

How to read it

A superiority result in an antibiotic trial is less common than non-inferiority, and it deserves a close look at why. The comparator's cure rate — 61% — is on the low side for a carbapenem, and part of the gap may reflect the specific pathogens and resistance patterns enrolled rather than a uniform advantage of nacubactam in every setting [s1]. The primary population was also restricted to patients whose organisms were susceptible to imipenem and meropenem, so the trial speaks to a defined group rather than to the hardest carbapenem-resistant cases [s1]. And as an intravenous, hospital regimen dosed every eight hours, this is a treatment for serious infection, not a convenience over oral options [s1].

The strategic point is the one the resistance data make. Using a combination that pairs an older β-lactam with a new enzyme inhibitor, and reserving carbapenems, is the core logic of antimicrobial stewardship — the mechanism by which the critical-priority resistance the WHO tracks is meant to be slowed [s2]. Related coverage has examined a trial of the narrow-spectrum antibiotic temocillin as another carbapenem-sparing option and why antibiotics do nothing for colds and how that misuse feeds resistance.

What to watch

Nacubactam is not yet a marketed drug, and a single trial in a susceptible population is the start of the evidence, not the end. What will decide its place is performance against genuinely resistant organisms, regulatory review, and whether stewardship programmes fold it into pathways in a way that actually reduces carbapenem use rather than adding another broad agent alongside them [s1][s2].

This article describes research and is not medical advice. Antibiotic choice for a urinary or kidney infection is a decision for treating clinicians based on culture and susceptibility results.

Sources

• Efficacy and safety of cefepime-nacubactam and aztreonam-nacubactam compared with imipenem-cilastatin for complicated urinary tract infection or acute uncomplicated pyelonephritis (Integral-1) — The Lancet, 15 May 2026
• WHO bacterial priority pathogens list, 2024 — World Health Organization, 17 May 2024