RECRUITINGPhase 4INTERVENTIONAL

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

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

About This Trial

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.

Who May Be Eligible (Plain English)

Who May Qualify: 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 willing to sign a consent form. Who Should NOT Join This Trial: 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. ...See full criteria on ClinicalTrials.gov Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

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.

Treatments Being Tested

DRUG

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.

DRUG

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).

Locations (13)

Haukeland University Hospital

Haukeland, Norway

Oslo University Hospital

Oslo, Norway

Södra Älvsborg Hospital

Borås, Sweden

Eskilstuna Hospital

Eskilstuna, Sweden

Sahlgrenska University Hospital

Gothenburg, Sweden

Blekinge Hospital

Karlskrona, Sweden

Skåne University Hospital

Lund, Sweden

Örebro University Hospital

Örebro, Sweden

Karolinska University Hospital

Stockholm, Sweden

Sundsvall Hospital

Sundsvall, Sweden

Umeå University Hospital

Umeå, Sweden

Uppsala University Hospital

Uppsala, Sweden

Central Hospital Växjö

Vaxjo, Sweden