Pivmecillinam as Oral Step-Down Treatment for Escherichia Coli Febrile Urinary Tract Infection Versus Standard of Care

Condition(s) studied

Investigational drug(s) / intervention(s)

Pivmecillinam: Patients randomized to pivmecillinam will be provided with 400 mg tablets for 3 to 8 days of treatment, to be taken four times daily, resulting in a total treatment duration of 7 or 10 days (including the initial 2-4 days of intravenous treatment). The shorter treatment duration of 7 days will be used for female patients with no complicating factors (structural or functional urologic abnormalities, urinary tract catheterization, and diabetes mellitus). The longer treatment duration of 10 days will be used for all other patients.

Standard of Care (Investigator Choice): The control group will receive standard of care antibiotic treatment at the discretion of the responsible physician and according to existing treatment guidelines, with a total treatment duration of 7 to 14 days. The following antibiotics will be considered adequate. Intravenous antibiotics: 1) Penicillins; ampicillin, piperacillin/tazobactam, 2) cephalosporins; cefotaxime, cefuroxime, ceftriaxone, 3) carbapenems; ertapenem, imipenem, meropenem, 4) monobactams; aztreonam, 5) aminoglycosides; amikacin, gentamicin, tobramycin, 6) other; fosfomycin. Oral antibiotics: 1) ciprofloxacin, 2) trimethoprim-sulfamethoxazole, 3) amoxicillin or amoxicillin/clavulanic acid provided that the isolated E. coli is determined susceptible according to the EUCAST-breakpoint for systemic infections, i.e., MIC ≤ 8 mg/l, and high dosing is used (≥750 mg amoxicillin x 3 and ≥750 mg amoxicillin/125 mg clavulanic acid x 3, respectively) and 4) tebipenem (if approved by the EMA).

Study summary

The goal of this clinical trial is to learn if oral treatment with pivmecillinam is effective to treat febrile urinary tract infections in adult patients. Hospitalized patients who have received 2-4 days of intravenous antibiotic therapy for febrile urinary tract infections, and have responded to treatment, will be randomized to either pivmecillinam or standard treatment (other oral or intravenous antibiotics).

The main question the study aims to answer is if oral follow-up with pivmecillinam is as effective as standard treatment. Patients will be evaluated for clinical response (resolution of fever and urinary tract symptoms) and microbiological response (no growth of bacteria in urine) 7 and 28 days after the end of treatment. Patients will also be asked about side effects. Some of the participants will also be examined for changes in the gut microbiome and drug exposures in blood and urine.

Participants will:

1. Keep a patient diary to record antibiotic intake, body temperature, urinary tract symptoms, and suspected side effects until 7 days after end of treatment.
2. Participate in phone interviews 7 and 28 days after end of treatment to assess clinical response.
3. Provide urine samples 7 and 28 days after end of treatment to evaluate microbiological response.
4. A subgroup (60 patients) will provide fecal samples at five time-points over three months to assess antibiotic-induced changes in the gut microbiome.
5. A subgroup (30 patients) treated with to pivmecillinam will provide blood and urine samples to determine the pharmacokinetics of mecillinam during one dosing interval.

Eligibility

Primary outcome measure(s)

• Clinical response (primary endpoint). — 7 (+/-2) days after EOT
  Clinical response: i) no new healthcare contacts or antibiotic treatments for suspected or proven UTI, ii) sustained defervescence (\< 38°C), and iii) patient-documented resolution of fUTI symptoms that were present and recorded in the eCRF at trial entry (and no new fUTI symptoms) at test of cure (TOC), which will be performed 7 (+/-2) days after end of treatment (EOT). The evaluation of clinical response (primary endpoint) will be performed by blinded assessors.

Trial sites (13)

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