Fosfomycin as Oral Transition Therapy Versus Continued Intravenous β-Lactams for Complicated Urinary Tract Infections Caused by Extended-Spectrum β-Lactamase-Producing Enterobacterales: A Multicenter, Open-Label, Randomized Controlled Trial.

Abstract

Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales are an increasing cause of complicated urinary tract infections (UTIs). Reliance on carbapenems to treat these infections accelerates resistance, underscoring the urgent need for effective oral transition options to preserve last-line agents and lessen healthcare burden. We conducted a multicenter, open-label, randomized, noninferiority trial at four tertiary hospitals in South Korea (November 2022-June 2025). Adults hospitalized with complicated UTIs due to ESBL-producing Enterobacterales who improved after 3-7 days of intravenous antibiotics were randomized (1:1) to either continue intravenous carbapenem or β-lactam/β-lactamase inhibitor therapy or switch to oral fosfomycin trometamol (3 g once daily). The primary outcome was clinical cure, defined as resolution of urinary tract infection-related symptoms and signs within 4 days after completion of treatment. Secondary outcomes included microbiological cure, readmission, adverse events, and 30-day recurrence. Of the 344 screened patients, 299 were randomized (152 oral fosfomycin; 147 intravenous therapy). Clinical cure occurred in 92.8% of the oral fosfomycin group and 95.2% of the intravenous group (risk difference, -2.47%; 95% CI -7.84 to 2.89), confirming noninferiority. Microbiological cure was similarly high in both groups: urine (98.0% vs 96.6%) and blood (97.3% vs 97.5%). Safety profiles and 30-day outcomes were also comparable. Oral fosfomycin was noninferior to continued intravenous therapy when used as oral transition therapy for complicated UTIs caused by ESBL-producing Enterobacterales. These findings provide evidence to support oral fosfomycin transition as a carbapenem-sparing antibiotic stewardship strategy for patients with complicated UTIs caused by ESBL-producing Enterobacterales. KCT0007669.