Sulopenem versus Amoxicillin/Clavulanate for the Treatment of Uncomplicated Urinary Tract Infection.

Background: Existing antibiotics for uncomplicated urinary tract infections are becoming less reliably effective owing to increasing antimicrobial resistance. Our objective was to evaluate the safety and efficacy of sulopenem/probenecid for uncomplicated urinary tract infections.

Methods: We conducted a double-blind, randomized, controlled, noninferiority trial of 5 days of sulopenem versus amoxicillin/clavulanate for women with uncomplicated urinary tract infection. The primary end point was overall success, defined as combined clinical cure and microbiologic eradication by day 12, evaluated in the microbiologic-modified intent-to-treat population, which comprised all randomly assigned patients who received any trial medication and had a positive urine culture with 10⁵ colony-forming units (CFU)/ml or more of an Enterobacterales uropathogen (e.g., Escherichia coli, Klebsiella species).

Results: A total of 2222 patients were enrolled, and the median age was 51 years (interquartile range, 35-62 years). Ninety-one (9.2%) patients in the primary population (microbiologic-modified intent-to-treat population), the combined population of patients with a positive baseline urine culture and without regard to amoxicillin/clavulanate susceptibility, had a baseline pathogen resistant to three or more classes of antibiotics. Overall success in the microbiologic-modified intent-to-treat population occurred in 318 of 522 (60.9%) participants treated with sulopenem versus 260 of 468 (55.6%) participants treated with amoxicillin/clavulanate (difference, 5.4 percentage points; 95% confidence interval [CI], -0.8 to 11.5), meeting criteria for noninferiority. In the primary population with a baseline uropathogen susceptible to amoxicillin/clavulanate, success occurred in 296 of 480 (61.7%) participants treated with sulopenem versus 243 of 442 (55.0%) participants treated with amoxicillin/clavulanate (difference, 6.7 percentage points; 95% CI, 0.3 to 13.0). In the primary population with a baseline uropathogen not susceptible to amoxicillin/clavulanate, success occurred in 22 of 42 (52.4%) patients treated with sulopenem versus 17 of 25 (68.0%) patients treated with amoxicillin/clavulanate (difference, -15.6 percentage points; 95% CI, -37.5 to 9.1]. Treatment-emergent adverse events occurred more frequently with sulopenem compared with amoxicillin/clavulanate, including diarrhea (8.1% vs. 4.1%), nausea (4.3% vs. 2.9%), and headache (2.2% vs. 1.5%).

Conclusions: Sulopenem was noninferior to amoxicillin/clavulanate for the treatment of adult women with uncomplicated urinary tract infection, but was associated with more frequent mild adverse events. (Funded by Iterum Therapeutics; REASSURE ClinicalTrials.gov number, NCT05584657.).