Oral pivmecillinam versus usual antibiotic step-down for E. coli febrile urinary tract infection

Pivmecillinam as Oral Step-Down Treatment for Escherichia Coli Febrile Urinary Tract Infection Versus Standard of Care: A Randomized Controlled Non-Inferiority Multicenter Trial

This trial will try oral pivmecillinam as follow-up treatment for adults with E. coli febrile urinary tract infection who have improved after 2–4 days of IV antibiotics.

Quick facts

• Phase: PHASE4
• Study type: Interventional
• Enrollment: 560 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Uppsala University (other)
• Locations: 13 sites (Haukeland and 12 other locations)
• Trial ID: NCT07236944 on ClinicalTrials.gov

What this trial studies

This open-label, randomized non-inferiority trial enrolls adults hospitalized with febrile urinary tract infection caused by E. coli who have received 2–4 days of intravenous antibiotics and become clinically stable. Participants are randomized to oral pivmecillinam or investigator-chosen standard-of-care step-down (other oral antibiotics or continued IV therapy) and are followed for clinical and microbiological response 7 and 28 days after end of treatment. Safety and side effects are recorded for all participants, and subsets undergo gut microbiome analyses and drug exposure measurements in blood and urine. The target enrollment is about 560 participants across centers in Sweden and Norway over roughly three years.

Who should consider this trial

Good fit: Adults (≥18) hospitalized with febrile UTI due to E. coli who have received 2–4 days of IV antibiotics, are defervesced and hemodynamically stable, and whose urine isolate is susceptible to mecillinam.

Not a fit: Patients with non–E. coli pathogens, mecillinam-resistant isolates, ongoing hemodynamic instability or severe sepsis, or penicillin allergy are unlikely to benefit from pivmecillinam step-down therapy.

Why it matters

Potential benefit: If successful, pivmecillinam could provide a narrow-spectrum oral step-down option that reduces use of broader antibiotics and may shorten hospital stays.

How similar studies have performed: Pivmecillinam is established for acute cystitis and used in practice for some fUTI cases, but no previous randomized controlled trial has tested it specifically as step-down therapy for febrile UTI.

Eligibility criteria

Inclusion Criteria:

1. ≥18 years of age.
2. Diagnosis of fUTI, defined as i) fever ≥ 38°C and ii) at least one of the following: flank pain or pelvic pain, nausea or vomiting, dysuria, urinary frequency or urgency, and costovertebral angle tenderness on physical examination.
3. Growth of E. coli in urine with antimicrobial susceptibility to mecillinam.
4. Adequate intravenous antibiotic treatment for fUTI (defined below) for 2 days to which the isolated E. coli is determined susceptible.
5. Defervescence and hemodynamic stability for at least 24 hours, according to the responsible physician.
6. Planned treatment with one of the following antibiotics, should the patient be randomized to the standard-of-care arm. 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).
7. Signed informed consent.

Exclusion Criteria:

1. Adequate intravenous antibiotic treatment for \> 4 days prior to randomization or other adequate (microbiologically active) oral antibiotic treatment for the same fUTI episode prior to recruitment.
2. Growth of other bacterial species than E. coli, or fungi, in urine.
3. Contraindication for pivmecillinam (e.g. allergy).
4. Clinical suspicion of bacterial prostatitis.
5. Renal abscess.
6. Kidney transplant.
7. Myelosuppressive disorder with neutrophil count \< 0.5 x 10(9)/L at randomization.
8. Planned antibiotic treatment for fUTI \> 14 days.
9. Likely to be prescribed antibiotic prophylaxis after treatment.
10. Other intravenous or oral antibiotic treatment; ongoing or planned during the follow-up period (i.e. until 28 days after EOT for fUTI).
11. Severe renal impairment (eGFR \< 20 mL/min) at randomization.
12. Morbid obesity (BMI \> 40 kg/m2).
13. Pregnancy or breastfeeding.
14. Unlikely to follow instructions or the study protocol.
15. Previous participation in the study.
16. If consenting to microbiome analysis: i) contraindication for ciprofloxacin (e.g. allergy), ii) unlikely to be able to provide fecal samples per protocol, iii) treatment with antibiotics in the past 3 months before the current fUTI episode, iv) chronic intestinal disease or previous surgery in the gastrointestinal tract.
17. If consenting to pharmacokinetic analysis: expected difficulties in providing blood and urine samples per protocol.

Where this trial is running

Haukeland and 12 other locations

• Haukeland University Hospital — Haukeland, Norway (NOT_YET_RECRUITING)
• Oslo University Hospital — Oslo, Norway (NOT_YET_RECRUITING)
• Södra Älvsborg Hospital — Borås, Sweden (NOT_YET_RECRUITING)
• Eskilstuna Hospital — Eskilstuna, Sweden (NOT_YET_RECRUITING)
• Sahlgrenska University Hospital — Gothenburg, Sweden (RECRUITING)
• Blekinge Hospital — Karlskrona, Sweden (NOT_YET_RECRUITING)
• Skåne University Hospital — Lund, Sweden (NOT_YET_RECRUITING)
• Örebro University Hospital — Örebro, Sweden (RECRUITING)
• Karolinska University Hospital — Stockholm, Sweden (NOT_YET_RECRUITING)
• Sundsvall Hospital — Sundsvall, Sweden (NOT_YET_RECRUITING)
• Umeå University Hospital — Umeå, Sweden (NOT_YET_RECRUITING)
• Uppsala University Hospital — Uppsala, Sweden (RECRUITING)
• Central Hospital Växjö — Vaxjo, Sweden (NOT_YET_RECRUITING)

Study contacts

• Principal investigator: Thomas Tängdén, MD, Professor — Department of Medical Sciences, Uppsala University
• Study coordinator: Thomas Tängdén, MD, Professor

Conditions: Febrile Urinary Tract Infection, Urinary Tract Infection, Pivmecillinam, Escherichia coli