Nitrofurantoin outperformed fosfomycin for uncomplicated UTIs in randomized trial

A large randomized clinical trial published in The Lancet found that nitrofurantoin was more effective than fosfomycin and pivmecillinam in treating uncomplicated urinary tract infections (UTIs) in women, leading the authors to suggest that “the role of fosfomycin as a first-line antibiotic for uncomplicated UTI should be reevaluated.”

UTIs remain one of the most common bacterial infections among women, with clinical guidelines often recommending antibiotics such as nitrofurantoin, fosfomycin, and pivmecillinam. However, direct comparisons between these therapies have been limited, prompting researchers to evaluate their relative effectiveness and safety in a real-world primary care setting.

Head-to-head antibiotic comparison

This phase 4, pragmatic, multicenter, randomized clinical trial was conducted across primary care centers in Spain between 2022 and 2024. A total of 768 women aged 18 years or older with at least 1 UTI symptom—such as dysuria, urinary urgency, frequency, or suprapubic tenderness—and a positive urine dipstick test were randomly assigned into 4 treatment groups.

Participants received either a single 3 g dose of fosfomycin, two 3 g doses of fosfomycin, nitrofurantoin (100 mg 3 times daily for 5 days), or pivmecillinam (400 mg 3 times daily for 3 days). The primary end point was clinical resolution at day 7, defined as complete symptom disappearance.

Among the 720 women included in the primary analysis, nitrofurantoin demonstrated the highest clinical resolution rate at 74% (128 of 172 patients). In comparison, pivmecillinam achieved a 70% resolution rate (127 of 182), followed by 2-dose fosfomycin at 67% (122 of 181). Single-dose fosfomycin had the lowest effectiveness, with only 59% of patients (109 of 185) achieving symptom resolution.

The difference between nitrofurantoin and single-dose fosfomycin was statistically significant, with a 15.5 percentage point advantage favoring nitrofurantoin (95% CI; 5.9%-25.1% [P = .0168]). These findings highlight meaningful differences in treatment efficacy among commonly prescribed antibiotics.

Safety profile and clinical implications

Adverse events were relatively common across all treatment groups but were generally mild and self-limiting. Rates ranged from 19.9% in the single-dose fosfomycin group to 26.8% in the nitrofurantoin group. Most adverse effects were gastrointestinal, such as nausea or diarrhea.

Four serious adverse events were reported during the study period, though only 1—a case of pyelonephritis in the pivmecillinam group—was considered related to the study treatment. Overall, the safety profiles of all 4 regimens were comparable and consistent with prior evidence.

The findings carry important implications for clinical practice, particularly regarding the use of fosfomycin. While single-dose fosfomycin has been widely favored for its convenience and adherence benefits, its lower effectiveness in this study suggests it may not be the optimal first-line therapy for uncomplicated UTIs.

Researchers noted that even increasing fosfomycin to a 2-dose regimen did not match the effectiveness of nitrofurantoin, further supporting reconsideration of its role in treatment guidelines.

Reference

Llor C, Monfà R, Garcia-Sangenís A. Clinical and bacteriological effectiveness of three different short-course antibiotic regimens and single-dose fosfomycin for uncomplicated lower urinary tract infections in women (SCOUT): a pragmatic, multicentre, open-label, randomised clinical trial. Lancet. 2026;407(10539):1603-1613. doi:10.1016/S0140-6736(25)02171-3