Non-inferiority of oral pivmecillinam and intravenous gentamicin versus standard empirical antibiotic therapy for complicated urinary tract infections in hospitalised adults

The primary objective is to evaluate the non-inferiority of oral pivmecillinam at 800 mg three times daily, combined with a single intravenous dose of gentamicin, compared to standard empirical treatments consisting of intravenous ampicillin plus gentamicin or intravenous piperacillin/tazobactam for achieving clinical cure on day 3 in hospitalized adults with complicated urinary tract infections. Secondary objectives include:

• Assessment of all-cause mortality at 30, 90, and 365 days.
• Evaluation of microbiological efficacy through the proportion of patients achieving microbiological cure on day 3.
• Determination of the time to transition to oral-only antibiotic therapy.
• Measurement of the total duration of antibiotic treatment and length of hospital stay.
• Monitoring the incidence of treatment failure and relapse within 90 days.
• Assessment of safety, specifically the incidence of treatment-related adverse events such as acute kidney injury, nephrotoxicity, Clostridioides difficile, or candidiasis.
• Evaluation of post-discharge antibiotic prescription redemption within 90 days.

The sponsor did not provide information regarding the total number of participants. The study population consists of adult patients, including both males and females, diagnosed with complicated urinary tract infections requiring hospitalization. Eligible individuals are those aged 18 years or older presenting with symptoms or signs of acute pyelonephritis or lower urinary tract infection. Participants must be hospitalized and undergoing planned empirical intravenous antibiotic treatment as determined by the treating physician.

This phase IV, open-label, randomised, multicenter, non-inferiority trial evaluates empirical antibiotic treatments for complicated urinary tract infections requiring hospitalisation. Participants are assigned to one of three parallel treatment arms. The investigational regimen consists of a single intravenous administration of gentamicin (5 mg/kg) combined with oral pivmecillinam (800 mg three times daily). The comparator arms involve either intravenous ampicillin or intravenous piperacillin and beta-lactamase inhibitor. The primary endpoint is clinical cure on day 3, defined by the resolution of symptoms, fever, and clinical improvement without the need for escalated antimicrobial therapy. Secondary endpoints include microbiological cure, mortality at 30, 90, and 365 days, nephrotoxicity, and hospital readmission. The study includes a screening process for adults aged 18 years or older presenting with symptoms of acute pyelonephritis or lower complicated urinary tract infections. Following treatment, participants undergo up to 12 months of follow-up to monitor safety and clinical outcomes.

The experimental treatment consists of pivmecillinam hydrochloride administered as an oral dose of 2400 mg and gentamicin sulfate combined with betamethasone valerate via intravenous administration at a dosage of 5 mg/kg.

The comparator treatments include ampicillin sodium administered via intravenous administration at a dose of 8 g, or a combination of piperacillin sodium and tazobactam sodium via intravenous administration at a dose of 16 g.

The primary efficacy endpoint is the achievement of clinical cure on day 3, defined as the resolution of complicated urinary tract infection-related symptoms and fever, alongside clinical improvement and the absence of a requirement for escalating systemic antimicrobial therapy.

Secondary efficacy parameters include:

• Microbiological cure on day 3.
• Mortality rates at 30, 90, and 365 days.
• Time to oral-only antibiotic therapy.
• Length of hospital stay.
• Total antibiotic treatment duration, encompassing combined intravenous and oral administration.
• Incidence of nephrotoxicity within 30 days.
• Proportion of treatment-related serious adverse reactions and suspected unexpected serious adverse reactions.
• Occurrence of secondary infections, specifically Clostridioides difficile or genital/oral Candida, within 30 days of enrollment.
• Hospital readmission within 90 days due to urinary tract infection.
• Post-discharge antibiotic prescription redemption within 90 days for antibiotics associated with urinary tract infection.