Non‑inferiority of oral fosfomycin versus fluoroquinolone or TMP‑SMX combination therapy as step‑down treatment for febrile urinary tract infection in men caused by Escherichia coli

The primary objective is to demonstrate that the oral fosfomycin‑trometamol regimen is not inferior to standard oral fluoroquinolones or trimethoprim‑sulfamethoxazole as step‑down therapy for febrile urinary tract infection in men caused by Escherichia coli, thereby establishing comparable clinical efficacy. Secondary objectives include:

• Comparison of the cumulative incidence of infectious and urological complications between the fosfomycin‑trometamol and standard therapy groups.
• Evaluation of tolerance and safety profiles of the antibiotic regimens.
• Assessment of rectal carriage of phenotypically antibiotic‑resistant Enterobacterales (resistant to fluoroquinolones, trimethoprim‑sulfamethoxazole, fosfomycin, and third‑generation cephalosporins) on Day 26 (14 days post‑treatment).
• Determination of the recurrence rate of urinary tract infections (relapse or reinfection) on Day 40 (28 days post‑treatment).
• Identification of risk factors associated with treatment failure in both study arms.

The trial enrolled adult male participants aged 18 years and older who presented with febrile male urinary tract infections caused by Escherichia coli. The sponsor did not provide the total number of participants. Eligibility required a documented body temperature of ≥38 °C within 72 hours of diagnosis, at least one characteristic urinary symptom, and a positive urine culture showing monomicrobial E. coli bacteriuria ≥10³ CFU/mL with susceptibility to fosfomycin and to either fluoroquinolones or trimethoprim‑sulfamethoxazole according to EUCAST criteria. Participants also had to have received effective empiric antibiotic therapy and demonstrate favorable clinical evolution (temperature <38 °C and symptom improvement) after 72 ± 24 hours, and they must have been able to take oral medication. Selection was based on these inclusion parameters, with no specific lifestyle restrictions reported, and required general health sufficient to tolerate oral treatment and absence of contraindicating conditions.

The study is a randomized, multicenter, phase III non‑inferiority trial evaluating oral fosfomycin versus fluoroquinolones or cotrimoxazole as step‑down therapy for febrile urinary tract infection caused by susceptible Escherichia coli in men. Eligible participants (male, ≥18 years, temperature ≥38 °C, positive urine culture, clinical improvement after 72 ± 24 h of empiric therapy) are screened, then randomized to receive either fosfomycin‑trometamol (3 g daily) or an oral comparator (ciprofloxacin 1000 mg, ofloxacin 400 mg, levofloxacin 500 mg, or sulfamethoxazole‑trimethoprim) for 12 days. Study visits include: screening visit (eligibility assessment, baseline cultures); randomization/baseline visit (drug allocation, start of oral treatment); end‑of‑treatment visit (Day 12, assessment of adherence and adverse events); primary evaluation (Day 26, 14 days post‑treatment, clinical cure assessment without additional antibiotics); and final follow‑up (Day 40, evaluation of recurrence and resistance carriage). Participant involvement spans approximately 40 days from screening to final follow‑up. Early termination may occur for lack of clinical response, emergence of severe adverse events, protocol violations, or need for alternative antibiotic therapy.

The investigational arm utilizes fosfomycin administered orally at a dose of 3 g per intake. The pharmaceutical form is a powder for oral solution (fosfomycin‑trometamol). Participants receive the medication according to the study‑defined dosing schedule, and adherence is monitored by pill count and patient diary entries.

Comparator treatments include ciprofloxacin hydrochloride, supplied as the oral tablet formulation PHF00134MIG, at a dose of 1000 mg per administration. Ofloxacin is provided as the oral tablet PHF00230MIG, dosed at 400 mg per intake. Levofloxacin is also supplied as the oral tablet PHF00230MIG, with a dose of 500 mg per intake. The sulfamethoxazole‑trimethoprim combination is delivered as the oral tablet PHF00170MIG; although a specific milligram dose is not listed, the product contains bromhexine hydrochloride, sulfamethoxazole, trimethoprim, and tolu balsam. All comparator agents are administered orally in accordance with the protocol‑specified regimen, and compliance is assessed through standard monitoring procedures such as pill counts and electronic case report forms.

The primary efficacy assessment will be a binary outcome defined as clinical cure, characterized by a body temperature < 38 °C and the absence of urinary tract infection symptoms, without the need for additional antibiotic therapy. Evaluation will occur on Day 26, which is 14 days after completion of the 12‑day oral treatment assigned by randomization.

Secondary efficacy assessments will include:

• Cumulative incidence of infectious and urological complications
• Adherence to the assigned oral regimen and the occurrence, nature, and severity of antibiotic‑related adverse events
• Rectal carriage of phenotypically antibiotic‑resistant Enterobacterales on Day 26
• Recurrence of febrile or non‑febrile urinary tract infections (relapse or reinfection) assessed on Day 40, 28 days after treatment completion
• Analysis of clinical and biological characteristics of patients who experience treatment failure compared with those who are cured during the initial episode