A 5-day course of nitrofurantoin was found superior to a single dose of fosfomycin for uncomplicated lower urinary tract infection (UTI) in women in a novel trial1 comparing efficacy of those regimens with 2 doses of fosfomycin and a 3-day course of pivmecillinam.
"Nitrofurantoin, pivmecillinam, and fosfomycin are considered first-line antibiotics for uncomplicated lower UTIs by most guidelines; however, there are no head-to-head trials comparing these 3 antibiotics," study lead author Carl Llor, PhD, of the Jordi Gol Primary Care Research Institute in Barcelona, Spain, and colleagues point out.
The investigators conducted the pragmatic, open-label randomized controlled trial with 768 women treated at primary care centers in Spain in the period between April 2022 and December 2024. The participants had presented with clinical features of uncomplicated lower UTI, including at least one of the specific symptoms of dysuria, urinary urgency, urinary frequency, or suprapubic tenderness, and had positive test results on urine dipstick for nitrites or leukocyte esterase.
Subject to exclusion criteria, including differential diagnoses of sexually transmitted infection or vulvovaginitis or suspicion of pyelonephritis, the participants were randomly assigned on a 1:1:1:1 basis to either a single fosfomycin 3-g dose, two 3-g doses of fosfomycin separated by 24 hours, nitrofurantoin 100 mg 3 times daily for 5 days, or pivmecillinam 400 mg 3 times daily for 3 days.
What You Need to Know
A 5-day course of nitrofurantoin was found superior to a single dose of fosfomycin for uncomplicated lower urinary tract infection (UTI) in women in a novel trial comparing efficacy of those regimens with 2 doses of fosfomycin.
The editorial acknowledged the methodological limitations of the open-label trial design, particularly the challenges associated with blinding 4 separate study groups. Despite these limitations, the authors argued that the study’s pragmatic design was appropriate given the complexity and real-world nature of the intervention.
The authors acknowledge that accurately diagnosing UTIs in primary care remains challenging.
In an accompanying editorial,2 Jesús Rodríguez-Baño, MD, PhD, and Pilar Retamar-Gentil, MD, PhD, both of the Unidad Clínica de Enfermedades Infecciosas y Microbiología at Hospital Universitario Virgen Macarena at Universidad de Sevilla in Seville, Spain, noted the limitations intrinsic to an open-label trial but agreed that the design was justified by the complexity of masking 4 groups and the pragmatic approach.
"Llor and colleagues should be commended for conducting a useful randomized trial in the typically busy environment of primary care clinics," they remarked.
The trial’s primary outcome was clinical cure, indicated by the patient reporting resolution of all infection symptoms by day 7. Secondary outcomes included days until symptom resolution, bacteriological eradication at day 14 or day 28, distribution of microorganisms causing UTI, and resistance rates of uropathogens to the study antibiotics.
The investigators reported that among the 720 women who remained in the trial, with sufficient data to be included in the primary analysis, single-dose fosfomycin had the lowest proportion of clinical resolution: 109 of 185 (59%). Nitrofurantoin resulted in the highest proportion of clinical resolution: 128 of 172 (74%), a statistically significantly higher cure rate.
Although pivmecillinam followed nitrofurantoin with resolution in 70% and the 2-dose fosfomycin with resolution in 67%, the trial was insufficiently powered to statistically rank the regimens. The groups were also not differentiated by adverse events, most of which were mild and self-limiting.
"Whatever the reason, the immediate conclusion is that a 5-day regimen of nitrofurantoin...should be recommended over a single 3-g dose of fosfomycin for uncomplicated lower UTIs in women," Rodríguez-Baño and Retamar-Gentil declared.
Llor and colleagues concluded the same, with acknowledgment that accurately diagnosing UTIs in primary care remains challenging. "Improved point-of-care diagnostics are urgently needed, as existing tools such as urine dipsticks have low sensitivity and specificity," they indicated.
References
1. Llor C, Monfà R, Garcia-Sangenís A, et al. 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
2. Rodríguez-Baño J, Retamar-Gentil P. Treatment of uncomplicated lower urinary tract infections in women. Lancet. 2026;407(10539):1574-1575. doi:10.1016/S0140-6736(25)02269-X
