Description

Background

Escherichia coli is the predominant uropathogen and the most common cause of bloodstream infections. In the hospital setting, patients with febrile UTI (fUTI) are normally treated with intravenous antibiotics for 2-4 days until clinical improvement followed by oral step-down treatment guided by microbiological antibiotic susceptibility testing results. However, oral treatment options are increasingly limited due to emerging resistance in uropathogens and the lack of new antibiotics.

This non-inferiority, open label, randomized clinical trial (RCT), conducted in Sweden and Norway, will evaluate the efficacy of an oral narrow-spectrum penicillin (pivmecillinam) as oral step-down for patients with fUTI caused by Escherichia coli. Pivmecillinam is a first line antibiotic for acute cystitis and is sometimes used also for fUTI in Denmark and Norway although no previous RCT has evaluated its efficacy for this indication. Pivmecillinam will be compared to standard of care, i.e. step-down treatment with other orally administered antibiotics, such as ciprofloxacin or trimethoprim-sulfamethoxazole, or continued intravenous antibiotic treatment. The target sample size is 560 participants, to be enrolled over a three-year period.

Patient population:

The following PICO (Population/Intervention/Control/Outcome) applies: Population - Patients with E. coli fUTI receiving initial intravenous antibiotic treatment; Intervention - Oral follow-up treatment with pivmecillinam; Control - Standard of care; Outcome - Clinical response (primary endpoint).

Objectives

The primary objective is to investigate if the clinical response with oral follow-up treatment with pivmecillinam 400 mg four times a day (QID) is non-inferior to standard of care in patients with E. coli fUTI 7 (+/-2) days after end of treatment (EOT).

Secondary objectives are to investigate treatment effects on:

1. Sustained clinical response 28 days after EOT
2. Microbiological response 7 days after EOT
3. Sustained microbiological response 28 days after EOT
4. Adverse events up to 7 days after EOT
5. Disturbances in the intestinal microbiome (60 patients) up to 3 months after EOT
6. Pharmacokinetics of mecillinam in plasma and urine (30 patients) during one dosing interval
7. Cost effectiveness of pivmecillinam compared to standard treatment

Primary endpoint:

The primary endpoint is defined as clinical response, defined as: 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 EOT. The evaluation of clinical response (primary endpoint) will be performed by blinded assessors.

Statistical analysis:

Non-inferiority will be defined as \< 10% lower clinical response at TOC. The primary analysis will be based on all randomized patients (intention-to-treat, ITT). Per-protocol (PP) analysis will be performed as supplementary analysis, and the consistency of ITT and PP results will be evaluated. Assuming 80% clinical response rate in both arms, a non-inferiority limit of 10%-points, 1:1 randomization, and 10% loss to follow-up, 280 patients in each arm (total 560 randomized patients) would give 80% power to detect non-inferiority at a one-sided alpha=0.025.

Intervention and control group:

Patients with fUTI caused by E. coli treated with adequate intravenous antibiotics for 2-4 days will be randomized to i) oral step-down treatment with pivmecillinam (high dose, 400 mg QID), or ii) standard of care. Patients randomized to pivmecillinam will be provided with tablets for a total treatment duration of 7 (female patients with no complicating factors) or 10 days (all other patients).

The control group will receive standard treatment, as determined by the responsible physician in accordance with current treatment guidelines and guided by the antibiotic susceptibility testing results of the isolated pathogen. The total treatment duration will be 7 to 14 days. In Norway, where pivmecillinam is already recommended for some patients with fUTI, participants randomized to the control group can be prescribed any antibiotic considered standard of care except for pivmecillinam. The following antibiotics will be considered adequate if the isolated bacteria are reported susceptible to the prescribed drug by the clinical microbiological laboratory. 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).

Diagnostic and monitoring procedures:

TOC will be performed 7 (+/- 2) days after EOT by phone interview. A second follow-up will be performed 28 (+/- 2) days after EOT to assess sustainable clinical response. Urine samples will be collected 7 and 28 days after EOT to evaluate microbiological response.

Fecal samples for microbiome analysis will be collected from 30 patients treated with pivmecillinam and 30 patients treated with ciprofloxacin at the time of randomization (prior to oral treatment), at EOT, and 7 days, 28 days, and 3 months after EOT (±2 days).

The pharmacokinetics of mecillinam in plasma and urine will be assessed in 30 patients treated with pivmecillinam. Blood samples will be drawn in conjunction with the third dose or later, at 0 h (before dose), and 1 h, 2 h, 4 h and 6 h (after dose). Urine sampling will be performed within one dosing interval after ≥3 doses during 0-3 h and 3-6 h.

Risk/benefit assessment:

Pivmecillinam is commonly used and proven safe for uncomplicated cystitis, and the risks of study participants is considered very low. If pivmecillinam shows non-inferiority to standard of care, the results of the study will benefit patients with fUTI as well as health care and society at large. A shift to oral treatment means shorter hospitalization and no need for repeated visits or intravenous catheters, thereby reducing suffering, the risk of healthcare-associated infections, and costs. Using a narrow-spectrum antibiotic instead of broad-spectrum antibiotics reduces the risks of side effects and emergence and spread of resistant bacteria. The study will also provide a better understanding of the relative collateral damage of the study drugs on the microbiome and pivmecillinam pharmacokinetics, which will inform future treatment decisions and dosing.