Nitrofurantoin outperforms single-dose fosfomycin for uncomplicated UTIs in Spanish primary care

This Phase 4 randomized clinical trial was conducted across Spanish primary care centers to compare the efficacy and safety of four antibiotic regimens for uncomplicated lower urinary tract infections. The study population consisted of 768 women aged 18 years or older who presented with at least one UTI-specific symptom, including dysuria, urinary urgency, urinary frequency, or suprapubic tenderness, and had a positive urine dipstick test for either nitrites or leukocyte esterase. Participants were randomly allocated to receive one of four treatment arms: a single 3 g dose of fosfomycin, two 3 g doses of fosfomycin, nitrofurantoin (100 mg three times per day for 5 days), or pivmecillinam (400 mg three times per day for 3 days). The study design was a completed randomized clinical trial, though doctors and patients were not masked to group assignment, and race and ethnicity data were not collected.

The primary outcome was the proportion of patients achieving clinical resolution, defined as the disappearance of all infection symptoms, assessed at day 7. Results indicated that nitrofurantoin was superior to single-dose fosfomycin, with a clinical resolution rate of 74% (128 of 172 patients) versus 59% (109 of 185 patients) for single-dose fosfomycin. This difference represented an effect size of 15.5 percentage points, with a 95% confidence interval of 5.9 to 25.1 and a p-value of 0.0168. When compared to pivmecillinam, single-dose fosfomycin showed a lower resolution rate of 59% versus 70% (127 of 182 patients), an effect size of 10.9 percentage points, though this difference was not statistically significant (95% CI 1.1 to 20.6; p=0.2352). Comparison with two-dose fosfomycin revealed a resolution rate of 67% (122 of 181 patients) versus 59% for single-dose fosfomycin, an effect size of 8.5 percentage points, which was also not statistically significant (95% CI -1.4 to 18.3; p=0.6935).

Safety and tolerability findings were reported for all groups. Adverse events occurred in 38 (19.9%) of 191 patients in the single-dose fosfomycin group, 51 (26.3%) of 194 patients in the two-dose fosfomycin group, 51 (26.8%) of 190 patients in the nitrofurantoin group, and 41 (21.2%) of 193 patients in the pivmecillinam group. Most adverse events were mild and self-limiting, primarily gastrointestinal in nature. Four serious adverse events occurred during the study period, of which one was related to the study treatment, specifically a case of pyelonephritis in the pivmecillinam group. Discontinuations due to adverse events were not reported. The study was funded by the Carlos III Institute of Health, the Spanish Ministry of Science and Innovation, and the European Regional Development Fund.

These results suggest that nitrofurantoin is the most effective treatment among the options evaluated, while single-dose fosfomycin is the least effective. This finding challenges the historical role of fosfomycin as a first-line antibiotic for uncomplicated UTIs, particularly when administered as a single dose. The lack of masking and the absence of race and ethnicity data represent key methodological limitations that may influence the generalizability of the findings. Additionally, the study did not report discontinuations, which limits the full assessment of tolerability.

Clinically, this evidence supports re-evaluating the use of single-dose fosfomycin for uncomplicated UTIs in favor of nitrofurantoin or other regimens with demonstrated higher efficacy. The non-significant differences between two-dose fosfomycin and single-dose fosfomycin suggest that increasing the fosfomycin dose regimen may improve outcomes, but nitrofurantoin remains the clear leader in this comparison. Further questions remain regarding long-term outcomes and the impact of patient demographics not captured in this trial. Practitioners must weigh the higher efficacy of nitrofurantoin against its dosing schedule and potential side effects when making treatment decisions.