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 randomized controlled non-inferiority multicenter trial evaluates pivmecillinam as oral step-down therapy for Escherichia coli febrile urinary tract infection. The primary objective is to determine whether clinical response with oral pivmecillinam 400 mg four times daily is non-inferior to standard of care antibiotic regimens in patients with E. coli febrile urinary tract infection, assessed 7 (±2) days after end of treatment. This comparison is clinically relevant as it addresses the need for effective oral step-down antibiotic options in the management of complicated urinary tract infections, potentially reducing the duration of intravenous therapy and associated healthcare costs while maintaining therapeutic efficacy.

The secondary objectives include evaluation of sustained clinical response, microbiological response, sustained microbiological response, and adverse events. Additional secondary endpoints assess disturbances in the intestinal microbiome, pharmacokinetics of mecillinam in plasma and urine, and cost effectiveness of pivmecillinam therapy. These secondary measures provide comprehensive assessment of treatment efficacy, safety profile, ecological impact on commensal flora, pharmacological characteristics, and economic implications of pivmecillinam use in this clinical indication.

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population includes **adults** aged **18 years and older** of **both genders** (male and female). Participants were selected based on a diagnosis of **febrile urinary tract infection (fUTI)** caused by **Escherichia coli**. Key selection criteria included documented **fever** of at least 38°C measured in a healthcare institution, presence of at least one urinary symptom such as **flank pain**, **pelvic pain**, **dysuria**, **urinary frequency**, **urgency**, **nausea**, or **vomiting**, and **costovertebral angle tenderness** on physical examination. Eligible participants had confirmed E. coli growth in urine with **antimicrobial susceptibility** to mecillinam and had received adequate **intravenous antibiotic treatment** for a minimum of 2 days to which the isolated pathogen was susceptible. Participants were required to demonstrate **defervescence** and **hemodynamic stability** for at least 24 hours prior to enrollment. No vulnerable populations were included in this trial. Information regarding lifestyle considerations such as diet, physical activity, or habits was not provided by the sponsor.

This clinical trial investigates **pivmecillinam** as an oral step-down treatment for patients with **Escherichia coli febrile urinary tract infection** compared to standard of care. The study is designed as a **randomized controlled non-inferiority multicenter trial** in **Phase IV**. The primary objective is to evaluate whether oral follow-up treatment with **pivmecillinam** 400 mg four times daily is non-inferior to standard of care in patients with E. coli febrile urinary tract infection, assessed 7 days (±2 days) after end of treatment. Febrile urinary tract infection is defined as fever ≥ 38°C measured in a healthcare institution accompanied by at least one of the following symptoms: flank pain or pelvic pain, nausea or vomiting, **dysuria**, urinary frequency or urgency, and **costovertebral angle tenderness** on physical examination.

The trial employs multiple comparator treatments administered via **infusion** or **oral use**, including **ertapenem sodium**, **amikacin sulfate**, **cefotaxime**, **imipenem and cilastatin**, **gentamicin sulfate**, **ciprofloxacin**, **meropenem**, **ceftriaxone**, **amoxicillin**, **amoxicillin and beta-lactamase inhibitor**, **piperacillin and beta-lactamase inhibitor**, **cefuroxime**, **sulfamethoxazole and trimethoprim**, **tobramycin**, **fosfomycin**, **ampicillin**, and **aztreonam**. All investigational products are of chemical origin. The maximum treatment period for the test product pivmecillinam is 8 days, while comparator treatments may extend up to 12 days depending on the specific **antibiotic** regimen used.

Eligible participants must be ≥18 years of age with a diagnosis of febrile urinary tract infection, confirmed growth of E. coli in urine with **antimicrobial susceptibility** to mecillinam, and adequate **intravenous antibiotic treatment** for at least 2 days to which the isolated E. coli is susceptible. Participants must demonstrate **defervescence** and **hemodynamic stability** for at least 24 hours prior to enrollment, as determined by the responsible physician. Signed informed consent is required for participation.

The primary endpoint is clinical response at test of cure, defined as: i) no new healthcare contacts or antibiotic treatments for suspected or proven urinary tract infection, ii) sustained defervescence (< 38°C), and iii) patient-documented resolution of febrile urinary tract infection symptoms that were present at trial entry with no new symptoms at test of cure, performed 7 (±2) days after end of treatment. Secondary endpoints include sustained clinical response assessed 28 (±2) days after end of treatment, **microbiological response** at test of cure, sustained microbiological response at the second follow-up, occurrence and severity of **adverse events** from start of study treatment until test of cure, disturbances in the **intestinal microbiome** analyzed through repeated fecal samples from 30 patients treated with pivmecillinam or ciprofloxacin, **pharmacokinetics** of mecillinam in plasma and urine with **PK/PD target attainment** assessed through blood and urine sampling from 30 patients, and cost-effectiveness of pivmecillinam compared with standard of care.

The estimated recruitment start date is September 1, 2025, with an estimated end date of March 31, 2029. Participant involvement includes the screening visit for eligibility assessment, enrollment following adequate intravenous antibiotic treatment and clinical stabilization, the treatment period with oral pivmecillinam or standard of care, the test of cure visit 7 (±2) days after end of treatment, and a second follow-up visit 28 (±2) days after end of treatment. Selected participants will provide additional fecal samples for **microbiome** analysis and blood and urine samples for pharmacokinetic assessment. The total duration of participant involvement extends approximately 28 to 30 days from end of treatment. Conditions that may lead to early termination from the study include new healthcare contacts or antibiotic treatments for suspected or proven urinary tract infection, recurrent fever, development of new urinary tract infection symptoms, occurrence of severe adverse events, withdrawal of consent, or clinical deterioration requiring alternative treatment as determined by the responsible physician.

This clinical trial evaluates pivmecillinam as an oral step-down treatment for Escherichia coli febrile urinary tract infection compared to standard of care antibiotic regimens. The primary objective is to investigate whether oral follow-up treatment with pivmecillinam is non-inferior to standard of care in patients with E. coli febrile urinary tract infection at 7 days after end of treatment.

The experimental medication is pivmecillinam hydrochloride, administered via the oral route. The maximum daily dose is 1.6 grams, with a maximum total dose of 12.8 grams over a treatment period of up to 8 days. Pivmecillinam hydrochloride is of chemical origin and belongs to the penicillin class of antibiotics.

Ertapenem sodium is used as a comparator treatment administered via infusion. The maximum daily dose is 1 gram, with a maximum total dose of 12 grams over a treatment period of up to 12 days. This carbapenem antibiotic is of chemical origin.

Amikacin sulfate serves as a comparator treatment administered via infusion. The maximum daily dose is 30 milligrams per kilogram body weight, with a maximum total dose of 30 milligrams per kilogram over a treatment period of up to 12 days. This aminoglycoside antibiotic is of chemical origin.

Cefotaxime combined with lidocaine is used as a comparator treatment administered via infusion. The maximum daily dose is 12 grams, with a maximum total dose of 144 grams over a treatment period of up to 12 days. This cephalosporin antibiotic combination is of chemical origin.

Imipenem and cilastatin sodium combination is used as a comparator treatment administered via infusion. The maximum daily dose is 4 grams, with a maximum total dose of 48 grams over a treatment period of up to 12 days. This carbapenem antibiotic combination is of chemical origin.

Gentamicin sulfate combined with betamethasone valerate is used as a comparator treatment administered via infusion. The maximum daily dose is 7 milligrams per kilogram body weight, with a maximum total dose of 7 milligrams per kilogram over a treatment period of up to 12 days. This combination contains an aminoglycoside antibiotic and a corticosteroid.

Ciprofloxacin, available as ciprofloxacin hydrochloride and ciprofloxacin, is used as a comparator treatment administered via oral route. The maximum daily dose is 1.5 grams, with a maximum total dose of 18 grams over a treatment period of up to 12 days. This fluoroquinolone antibiotic is of chemical origin.

Linezolid is used as a comparator treatment administered via infusion. The maximum daily dose is 3 grams, with a maximum total dose of 36 grams over a treatment period of up to 12 days. This oxazolidinone antibiotic is of chemical origin.

Ceftriaxone sodium combined with lidocaine hydrochloride is used as a comparator treatment administered via infusion. The maximum daily dose is 2 grams, with a maximum total dose of 24 grams over a treatment period of up to 12 days. This cephalosporin antibiotic combination is of chemical origin.

Amoxicillin sodium is used as a comparator treatment administered via oral route. The maximum daily dose is 3 grams, with a maximum total dose of 36 grams over a treatment period of up to 12 days. This penicillin antibiotic is of chemical origin.

Amoxicillin sodium and clavulanic acid combination is used as a comparator treatment administered via oral route. The maximum daily dose is 3.38 grams, with a maximum total dose of 40.56 grams over a treatment period of up to 12 days. This beta-lactam and beta-lactamase inhibitor combination is of chemical origin.

Piperacillin sodium and tazobactam sodium combination is used as a comparator treatment administered via infusion. The maximum daily dose is 18 grams, with a maximum total dose of 216 grams over a treatment period of up to 12 days. This penicillin and beta-lactamase inhibitor combination is of chemical origin.

Cefuroxime axetil is used as a comparator treatment administered via infusion. The maximum daily dose is 4.5 grams, with a maximum total dose of 54 grams over a treatment period of up to 12 days. This cephalosporin antibiotic is of chemical origin.

Sulfamethoxazole and trimethoprim combined with bromhexine hydrochloride is used as a comparator treatment administered via oral route. The maximum daily dose is 2.88 grams, with a maximum total dose of 34.56 grams over a treatment period of up to 12 days. This combination contains sulfonamide and diaminopyrimidine antibiotics with a mucolytic agent.

Tobramycin is used as a comparator treatment administered via infusion. The maximum daily dose is 7 milligrams per kilogram body weight, with a maximum total dose of 7 milligrams per kilogram over a treatment period of up to 12 days. This aminoglycoside antibiotic is of chemical origin.

Fosfomycin calcium is used as a comparator treatment administered via infusion. The maximum daily dose is 24 grams, with a maximum total dose of 288 grams over a treatment period of up to 12 days. This phosphonic acid antibiotic is of chemical origin.

Ampicillin sodium is used as a comparator treatment administered via infusion. The maximum daily dose is 12 grams, with a maximum total dose of 144 grams over a treatment period of up to 12 days. This penicillin antibiotic is of chemical origin.

Aztreonam is used as a comparator treatment administered via infusion. The maximum daily dose is 8 grams, with a maximum total dose of 96 grams over a treatment period of up to 12 days. This monobactam antibiotic is of chemical origin.

Efficacy will be assessed through the evaluation of clinical response as the primary endpoint, measured at test of cure (TOC) 7 (+/-2) days after end of treatment. The primary endpoint comprises three components: no new healthcare contacts or antibiotic treatments for suspected or proven urinary tract infection, sustained defervescence (temperature < 38°C), and patient-documented resolution of febrile urinary tract infection symptoms that were present and recorded at trial entry with no new symptoms developing.

Secondary efficacy endpoints include sustained clinical response evaluated at 28 (+/- 2) days after end of treatment, defined as no new healthcare contacts or antibiotic treatments for suspected or proven urinary tract infection, no recurrent fever (≥ 38°C), and no recurrent urinary tract infection symptoms after completion of initial therapy. Microbiological response will be assessed through urine samples collected at test of cure 7 (+/-2) days after end of treatment to detect growth of Escherichia coli. Sustained microbiological response will be evaluated through urine sampling at the second follow-up 28 (+/- 2) days after end of treatment. Additional secondary endpoints include the occurrence and severity of adverse events from start of study treatment until test of cure, which will be recorded by patients in a diary, documented in medical records, or reported at the test of cure follow-up. Disturbances in the intestinal microbiome will be analyzed through repeated collection of fecal samples from 30 patients treated with pivmecillinam or ciprofloxacin. Pharmacokinetics of mecillinam in plasma and urine and pharmacokinetic/pharmacodynamic target attainment will be assessed by blood and urine sampling from 30 patients treated with pivmecillinam. Cost-effectiveness of pivmecillinam compared with standard of care will also be evaluated.