Nitrofurantoin performs better than single-dose fosfomycin in the treatment of uncomplicated urinary tract infections (UTIs) in women in the primary care setting, according to the SCOUT trial.
In a head-to-head comparison of four antibiotic regimens, nitrofurantoin emerged as the most effective in terms of the primary outcome of clinical resolution within 7 days, with pivmecillinam and two-dose fosfomycin coming after. Single-dose fosfomycin was the least effective.
Compared with 58.9 percent in the single-dose fosfomycin arm, 74.4 percent met the primary outcome in the nitrofurantoin arm (p=0.0168), 69.8 percent in the pivmecillinam arm (p=0.2352), and 67.4 percent in the two-dose fosfomycin arm (p=0.6935), reported lead investigator Dr Carl Llor from the Jordi Gol Primary Care Research Institute in Barcelona, Spain, during his presentation at the ESMID annual meeting. [Lancet 2026;407:1603-1613]
The results did not differ by menopause status, and they were even more significant in the subset of participants with a positive urine culture at baseline (86.7 percent of participants in the nitrofurantoin arm, 73.9 percent in the pivmecillinam arm, and 65.6 percent in the two-dose fosfomycin arm vs 51.9 percent in the single-dose fosfomycin arm), Llor noted.
As for clinical resolution at other time points, the proportion of participants who achieved clinical resolution was likewise largest with nitrofurantoin and smallest with single-arm fosfomycin both at day 14 (80.8 percent vs 68.1 percent) and day 28 (79.1 percent vs 66.5 percent).
Safety results
“When selecting an antibiotic regimen, efficacy is paramount, but other factors, such as adherence and tolerability, should also be considered,” Llor said.
“Shorter regimens, such as one or two doses of fosfomycin, might improve adherence due to their simplicity, as shown in our study. However, overall adherence across all four antibiotic regimens was high, and patient satisfaction did not differ substantially between treatments,” he pointed out.
In terms of adverse events (AEs), the frequency was similar across treatments (28.6 percent with nitrofurantoin, 21.2 percent with pivmecillinam, and 19.9 percent to 26.3 percent with fosfomycin), “although side-effect profiles varied: gastrointestinal symptoms were more common with fosfomycin; fatigue and somnolence with nitrofurantoin; and headache and nausea with pivmecillinam,” according to Llor.
Most AEs were mild or moderate in severity and led to discontinuation in few participants (2.6 percent with nitrofurantoin, 1.6 percent with pivmecillinam, 0.5 percent with two-dose fosfomycin, and none with single-dose fosfomycin). The incidence of serious AEs was low, between 0 percent and 1 percent. Pyelonephritis occurred in 1.1 percent of patients in the nitrofurantoin arm and in 0.5 percent in the pivmecillinam arm.
More participants who received fosfomycin required an additional antibiotic course: 30 percent in the single-dose arm, 19 percent in the two-dose arm, 16 percent in the nitrofurantoin arm, and 16 percent in the pivmecillinam arm.
Study details
“Current European and US guidelines on the treatment of UTIs recommend the use of either a single 3-g dose of fosfomycin or 100 mg of nitrofurantoin three times per day for 5 days. These recommendations are based on fosfomycin’s broad activity against β-lactamase–producing uropathogens and on the low resistance rates to both antibiotics reported in Europe and North America,” Llor said. [https://d56bochluxqnz.cloudfront.net/documents/full-guideline/EAUGuidelines-on-Urological-Infections-2026.pdf; Clin Infect Dis 2011;52:e103-e120]
“Our findings suggest that the role of fosfomycin as a first-line treatment for uncomplicated UTIs should be re-evaluated,” he added.
The study included 768 women (median age 48 years) with at least one UTI-specific symptom (dysuria, urinary urgency, urinary frequency, or suprapubic tenderness) and a positive urine dipstick test for either nitrites or leukocyte esterase. Llor acknowledged that the target sample size was not reached, as the study was terminated due to the exhaustion of available funding.
The participants were randomly allocated to one of the following treatment arms: a single 3-g dose of fosfomycin (n=191), two 3-g doses of fosfomycin (second dose taken 24 h after the first dose; n=194), nitrofurantoin 100 mg three times per day for 5 days (n=190), or pivmecillinam 400 mg three times per day for 3 days (n=193).
All participants completed symptom diaries. Clinical resolution was defined as the disappearance of all symptoms of infection.
Baseline urine culture results were available for 96 percent of participants, among whom 57 percent tested positive for at least one uropathogen. Urine contamination rate was under 13 percent.
UTI in primary care
“In primary care, uncomplicated UTIs are typically managed without microbiological analysis… Current methods—based on symptoms, signs, and dipstick tests—lack precision, leading to both overtreatment and undertreatment,” Llor said.
The investigator highlighted the urgent need for improved point-of-care diagnostics to guide antibiotic prescribing in primary care, given that existing tools such as urine dipsticks have low sensitivity and specificity and cannot provide information regarding the antibiotic susceptibility of pathogens. [Br J Gen Pract 2010;60:495-500]
In an editorial accompanying Llor and colleagues’ paper in The Lancet, Drs Jesús Rodríguez-Baño and Pilar Retamar-Gentil from The Institute of Biomedicine of Seville, Seville, Spain, commended Llor and colleagues for their work. [Lancet 2026;407:1687-1698]
“Despite its limitations, this important trial confirms that nitrofurantoin is superior to single-dose fosfomycin for uncomplicated lower UTIs in women and provides important information on limitations in the diagnosis of lower UTIs in real-world clinical settings,” Rodríguez-Baño and Retamar-Gentil wrote.