Oral Fosfomycin versus Ciprofloxacin for Febrile Urinary Tract Infection in Men: a pilot study

Rationale: Due to rising resistance of Enterobacteriaceae against the orally available antibiotics ciprofloxacin and trimethoprim-sulfamethoxazole, difficulties arise in the treatment of febrile urinary tract infection (FUTI) in men. Fosfomycin possesses a high bactericidal activity to Escherichia coli with resistance rates of 1%. Fosfomycin 3000mg, dosed every 24 hours, reaches sufficient antibiotic levels in urine, prostate and bladder, has good tolerability and is considered safe. Therefore, fosfomycin is a potential alternative antibiotic option for treatment of FUTI in men.

Objective: To determine the efficacy of oral fosfomycin in comparison to the standard of care oral ciprofloxacin, in the treatment of FUTI after initial empirical treatment with intravenous antibiotics.

Study design: An open label multicenter pilot study with historical controls.

Study population: Consenting men (≥18 years), on appropriate intravenous therapy for FUTI caused by E. coli and fulfilling criteria for an iv-to-oral switch.

Intervention: After an empirical intravenous antibiotic treatment an iv-oral switch to oral fosfomycin 3000mg, every 24 hours, up to 14 days. Patients will be compared to historical controls who were included in a randomized trial with similar inclusion criteria and who were treated with oral ciprofloxacin.

Eligible patients who refuse to be treated with fosfomycin, will be treated with ciprofloxacin. Those patients will be asked to participate in the trial for observational purposes only as they can serve as control patients as well.

Main study parameters/endpoints: The primary endpoint is the clinical cure rate (resolution of symptoms) 10 to 18 days post-treatment (= test of cure, TOC). Secondary endpoints are clinical cure rate during late follow-up (LFU, 70 to 84 days post-treatment), microbiological cure rate, time to resolution of symptoms, rate of UTI relapse and rate of adverse events.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The burden for participants is considered low as patients are treated and evaluated following Good Clinical Practice. This study is considered to be of low-risk for the following reasons; the pathogen causing FUTI has documented susceptibility to fosfomycin; patients are not acutely ill at the moment of randomization as they fulfil the criteria for iv-oral switch and fosfomycin has a good safety profile. Fosfomycin has been used extensively as single-dose oral therapy; previous studies have demonstrated a pharmacokinetic profile suitable for treating FUTI in men with a high bio-availability, reaching sufficient levels in urine, prostate and bladder wall. Clinical cure for FUTI has been described in case series. Overall the future benefit of this trial, obtaining a new antibiotic option for FUTI in men, outweighs the low risks involved for participants.

Oral fosfomycin might be an effective antibiotic to treat men with febrile urinary tract infection caused by E. coli

2 time points: 10-18 and 70-84 days post-treatment.

Men with febrile urinary tract infection who are admitted for empirical intravenous antibiotic treatment will be switched to oral fosfomycin for a total treatment duration of 14 days