TMP-SMX linked to higher UTI treatment failure in postmenopausal women vs. nitrofurantoin and fosfomycin

Trimethoprim-sulfamethoxazole (TMP-SMX) was associated with significantly higher rates of treatment failure, antibiotic escalation, and serious infectious complications compared with nitrofurantoin and fosfomycin in postmenopausal women treated for acute uncomplicated urinary tract infections (UTIs), according to a large retrospective cohort study published in O&G Open.

UTIs are among the most common conditions managed by obstetrician-gynecologists, accounting for millions of outpatient visits annually in the United States.

“Postmenopausal women may be at increased risk of adverse UTI outcomes,” noted the study authors in O & G. “Compared with premenopausal women, they experience higher rates of recurrence and UTI-associated hospitalization. Estrogen deficiency is associated with changes in the urogenital epithelium and microbiome that may promote colonization by opportunistic and resistant organisms such as Klebsiella and extended-spectrum β-lactamase (ESBL)–producing Escherichia coli.”

Structural and functional conditions common in this population, including genitourinary syndrome of menopause, pelvic organ prolapse, and urinary incontinence, may further increase susceptibility through impaired bladder emptying and urinary retention.

Despite this elevated risk profile, current empiric treatment recommendations from the American College of Physicians and the Infectious Diseases Society of America—which identify nitrofurantoin, TMP-SMX, and fosfomycin as first-line agents—are derived largely from studies of predominantly premenopausal women.

Recommendations catered for postmenopausal women are lacking, according to the study authors.

“However, postmenopausal women have not been specifically represented in past studies, and the Infectious Diseases Society of America explicitly limits their scope to premenopausal women,” they said. “The American College of Obstetricians and Gynecologists also does not have specific guidelines for the management of uncomplicated UTIs in postmenopausal women.”

How did the study compare empiric antibiotic effectiveness in postmenopausal women?

The researchers conducted a retrospective cohort study using the TriNetX database, identifying women aged 40 years or older with menopausal or postmenopausal status who developed acute uncomplicated cystitis or UTI between March 2006 and March 2026. A total of 236,927 postmenopausal women initiating antibiotics were identified: nitrofurantoin (n = 152,793), TMP-SMX (n = 80,815), and fosfomycin (n = 3,319). Propensity score matching was used to balance demographics, laboratory values, comorbidities, and prior gynecological procedures across groups.

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.

How did TMP-SMX compare with nitrofurantoin and fosfomycin?

After matching, TMP-SMX was associated with a higher risk of composite treatment failure compared with nitrofurantoin (10.2% vs. 8.0%; relative risk [RR] 1.28; 95% CI, 1.23–1.32). TMP-SMX was also associated with higher rates across every individual component of the composite endpoint, including antibiotic escalation, pyelonephritis, bacteremia, sepsis, hospitalization, critical care services, and mortality.

Compared with fosfomycin, TMP-SMX was again associated with higher 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 demonstrated similar rates of composite treatment failure (9.0% vs. 9.6%; RR 0.93; 95% CI, 0.80–1.09), though hospitalization was significantly less frequent with nitrofurantoin (1.8% vs. 3.0%; RR 0.60; 95% CI, 0.44–0.82).

The findings underscored the absence of postmenopausal-specific evidence in current empiric UTI treatment guidelines, supporting “the need for postmenopausal-specific evidence to inform empiric UTI treatment selection,” according to the study’s authors.

Reference:

Lacsamana JM, Han B, Lepe K, Canumay S, Johnson R, Oshiro BT. Comparative effectiveness of empiric antibiotics for uncomplicated urinary tract infection in postmenopausal women. O&G Open. 2026;3(4). doi:10.1097/og9.0000000000000191