Fosfomycin versus ciprofloxacin as oral stepdown treatment for Escherichia coli febrile urinary tract infection in women: a randomised, placebo-controlled, double blind, multicenter trial.

BACKGROUND: We aimed to determine the non-inferiority of fosfomycin, compared to ciprofloxacin, as oral stepdown treatment for E. coli febrile urinary tract infections (fUTIs) in women. METHODS: This was a double-blind, randomised controlled trial in 15 Dutch hospitals. Adult women receiving 2-5 days of empirical intravenous antimicrobials for E.coli fUTI, were assigned to stepdown treatment with once-daily 3 gr fosfomycin or twice-daily 0.5 gr ciprofloxacin, for 10 days of total antibiotic treatment. For the primary endpoint clinical cure at day 6-10 post-end-of-treatment a non-inferiority margin of 10% was chosen. The trial was registered on Trialregister.nl (NTR6449). RESULTS: After enrolment of 97 patients between 2017-2020, the trial ended prematurely because of the Covid-19 pandemic. The primary endpoint was met in 36/48 patients (75.0%) assigned to fosfomycin and 30/46 patients (65.2%) assigned to ciprofloxacin (Risk Difference: 9.6%, 95%-Confidence-Interval: -8.8% to 28.0%). In patients assigned to fosfomycin and ciprofloxacin, microbiological cure at day 6-10 post-end-of-treatment occurred in 29/37 (78.4%) and 33/35 (94.3%; RD: -16.2%, 95%CI: -32.7 to -0.0%), and clinical cure at day 30-35 post-end-of-treatment occurred in 35/47 (75.6%) and 33/44 (75.0%; RD: 0.4%, 95%CI: -18·4% to 17·6%) respectively. Any adverse event was reported in 35/48 (72.9%) and 32/46 (69.6%) patients (RD: 3.3%, 95%CI: -15.0% to 21.6%%), and any gastro-intestinal adverse event in 25/48 (52.1%) and 14/46 (30.4%) patients (RD: 20.8%, 95%CI: 1.6% to 40.0%), respectively. CONCLUSIONS: Fosfomycin is non-inferior to ciprofloxacin as oral stepdown treatment for fUTI caused by E.coli in women. Fosfomycin use is associated with more gastro-intestinal events.