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

Is this trial a fit for you?

A plain-English reading of the study's rules. Only the study team can confirm whether you qualify.

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.

Why it matters

Who can join: the full rules

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 it's running

• Sahlgrenska University Hospital
  Gothenburg, Sweden Recruiting
• Örebro University Hospital
  Örebro, Sweden Recruiting
• Uppsala University Hospital
  Uppsala, Sweden Recruiting
• Haukeland University Hospital
  Haukeland, Norway Not yet recruiting
• Oslo University Hospital
  Oslo, Norway Not yet recruiting
• Södra Älvsborg Hospital
  Borås, Sweden Not yet recruiting

Study contacts

• Principal investigator: Thomas Tängdén, MD, Professor — Department of Medical Sciences, Uppsala University
• Study coordinator: Thomas Tängdén, MD, Professor
• Email: thomas.tangden@medsci.uu.se
• Phone: +46 708 370323

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How to take part

1. Review the eligibility criteria above with your treating physician.
2. Check the official listing on ClinicalTrials.gov for the latest contact details and recruitment status.
3. Contact the study coordinator or principal investigator to ask for pre-screening. Pre-screening is free and never obligates you to enroll.