Evaluation of Pivmecillinam and Amoxicillin/Clavulanic Acid for Oral Step-Down Therapy in Febrile UTIs Due to ESBL-Producing Enterobacterales

The primary objective of this study is to evaluate the **non-inferiority** of a per oral step-down treatment regimen using Pivmecillinam with Amoxicillin/Clavulanic acid compared to Ciprofloxacin and Trimethoprim-sulfamethoxazole in patients with febrile urinary tract infections (UTIs) caused by extended spectrum beta-lactamases-producing Enterobacterales (ESBL-producing Enterobacterales). This is clinically relevant as it seeks to identify effective alternative oral therapies for multidrug-resistant UTIs, potentially reducing reliance on current standard treatments and addressing antibiotic resistance issues.

Secondary objectives include: - Assessing the growth of ESBL-producing Enterobacterales in follow-up urine cultures at the test of cure (TOC) as a microbiological endpoint. - Determining the presence of ESBL-producing Enterobacterales in fecal cultures at follow-up at TOC. - Evaluating mortality from all causes within 28 days.

The clinical trial involves **adult men and women** over the age of 18, who are experiencing **urinary tract infection** and/or bacteremia caused by extended spectrum beta-lactamases-producing Enterobacterales. The sponsor has not provided the total number of participants. The study population was selected based on specific criteria, including a positive urine and/or blood culture for EPE, and having received 1-5 days of intravenous treatment with empirical antibiotics. Participants must have experienced a fever of at least 38.0°C at least once, either at home or in the hospital, and have a clinical suspicion of a urinary tract infection at the emergency room, indicated by symptoms such as flank pain, dysuria, positive dipstick analysis, or percussion tenderness over the kidneys. The trial does not include a vulnerable population, and both male and female subjects are eligible. Participants must have signed informed consent, and the treating physician must have deemed it safe to discontinue parenteral treatment and start per oral antibiotics. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of alternative oral antibiotics for the treatment of febrile **urinary tract infections** (UTIs) caused by extended spectrum beta-lactamases (ESBL)-producing Enterobacterales. The trial aims to establish a non-inferior oral step-down treatment regimen compared to standard therapies such as ciprofloxacin and trimethoprim-sulfamethoxazole. The study will involve adult participants who have been diagnosed with UTIs or bacteremia due to ESBL-producing Enterobacterales and have received initial intravenous antibiotic treatment. The trial is expected to run from April 2023 to December 2026, with participant involvement lasting up to 9 days of treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, culture results, and clinical symptoms. Following the screening, participants will be randomized to receive either the test or comparator oral antibiotic regimen. The primary endpoint will be assessed 7 to 10 days after the discontinuation of antibiotic treatment, focusing on the clinical response, defined as the resolution of symptoms and the absence of the need for further antibiotic therapy. Secondary endpoints include microbiological outcomes and overall survival within 28 days.

Study visits will include follow-up assessments to monitor clinical and microbiological responses, with a final end-of-study visit to evaluate the overall treatment outcome. Participants may be withdrawn from the study if they experience adverse events, require additional antibiotic treatment, or if the treating physician deems it unsafe to continue. The trial will ensure that all procedures adhere to ethical standards, with informed consent obtained from all participants prior to enrollment.

The clinical trial involves the use of several **experimental medications** and comparator treatments. The primary experimental medication is **Amoxicillin/Clavulanic acid Aurobindo**, which is administered in the form of film-coated tablets. Each tablet contains 500 mg of amoxicillin and 125 mg of clavulanic acid. The medication is taken orally, with a maximum daily dose of 1500 mg and a total maximum dose of 13500 mg over a treatment period of up to 9 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Ciprofloxacin Orion** serves as a comparator treatment in the study. It is also provided as film-coated tablets, each containing 500 mg of ciprofloxacin. The administration route is oral, with a maximum daily dose of 1000 mg and a total maximum dose of 9000 mg over a 9-day period. Compliance is similarly monitored to ensure accurate dosing.

Another comparator treatment is **Eusaprim forte**, which consists of tablets containing 160 mg of trimethoprim and 800 mg of sulfamethoxazole. This medication is administered orally, with a maximum daily dose of 1600 mg and a total maximum dose of 14400 mg over the course of 9 days. Participant adherence to the dosing regimen is closely observed.

**Ertapenem Fresenius Kabi** is included as a comparator and is provided as a solution for infusion. Each dose contains 1 g of ertapenem, administered intravenously. The maximum daily dose is 1 g, with a total maximum dose of 9 g over a 9-day treatment period. Compliance is ensured through controlled administration in a clinical setting.

Lastly, **Selexid** is used as a comparator treatment, available in film-coated tablets containing 400 mg of pivmecillinam hydrochloride. The medication is taken orally, with a maximum daily dose of 1200 mg and a total maximum dose of 10800 mg over 9 days. Participant compliance is monitored to maintain the integrity of the dosing schedule.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **clinical response** 7 to 10 days after the discontinuation of antibiotic treatment, known as the test of cure (TOC). This endpoint is achieved if the patient exhibits no symptoms, such as the resolution of fever and dysuria for more than 24 hours, and no further antibiotic treatment is deemed necessary by the treating physician.

Secondary endpoints include the microbiological endpoint, which involves the growth of ESBL-producing Enterobacterales (EPE) in follow-up urine culture at TOC, the presence of EPE in fecal culture at follow-up at TOC, and death from all causes within 28 days. These endpoints will be measured and collected at specified timepoints to ensure comprehensive evaluation of the treatment's efficacy.