Comparative Effectiveness of Empiric Antibiotics for Uncomplicated Urinary Tract Infection in Postmenopausal Women

To compare the effectiveness of antibiotic regimens for acute uncomplicated urinary tract infection (UTI) in postmenopausal women using real-world clinical data.

We conducted a retrospective cohort study in the TriNetX database of women aged 40 years or older with menopausal or postmenopausal status who developed acute uncomplicated cystitis or UTI between March 2006 and March 2026. Patients were stratified by initial antibiotic therapy of nitrofurantoin, trimethoprim-sulfamethoxazole (TMP-SMX), or fosfomycin. The primary outcome was a composite measure of treatment failure within 7 days of treatment initiation, including antibiotic escalation, pyelonephritis, bacteremia, sepsis, hospitalization, critical care services, and mortality. Propensity score matching was used to balance demographics, laboratory values, comorbidities, and prior gynecological procedures. Outcomes were compared between matched groups with a two-sided z test for proportions.

A total of 236,927 postmenopausal women initiating antibiotics to treat uncomplicated UTI were identified (nitrofurantoin n=152,793; TMP-SMX n=80,815; and fosfomycin n=3,319). After matching, TMP-SMX was associated with a higher risk of composite treatment failure compared with nitrofurantoin (10.2% vs 8.0%, relative risk ratio [RR] 1.28, 95% CI, 1.23-1.32). In addition, TMP-SMX was associated with higher rates of antibiotic escalation, pyelonephritis, bacteremia, sepsis, hospitalization, critical care services, and mortality. Compared with fosfomycin, TMP-SMX was associated with a higher risk of composite treatment failure (13.3% vs 9.6%, RR 1.39, 95% CI, 1.21-1.59), as well as higher rates of sepsis, hospitalization, and critical care services. Nitrofurantoin and fosfomycin had similar rates of composite treatment failure (9.0% vs 9.6%, RR 0.93, 95% CI, 0.80-1.09), although hospitalization was less frequent with nitrofurantoin (1.8% vs 3.0%, RR 0.60, 95% CI, 0.44-0.82).

Among postmenopausal women with acute uncomplicated UTI, treatment with TMP-SMX was associated with higher rates of adverse outcomes and serious infectious complications compared with nitrofurantoin and fosfomycin. Nitrofurantoin and fosfomycin demonstrated similar short-term outcomes. These findings support the need for postmenopausal-specific evidence to inform empiric UTI treatment selection.