Non-Inferiority Trial Comparing 7-Day Versus 14-Day Linezolid and Drug Combination Regimens for Uncomplicated Enterococcal Bacteremia

The primary objective of this clinical trial is to demonstrate the **non-inferiority** of a 7-day antibiotic treatment regimen compared to a 14-day regimen in the treatment of uncomplicated enterococcal bacteremia, specifically caused by **E. faecalis** or **E. faecium**. This is clinically relevant as it may lead to shorter treatment durations, potentially reducing healthcare costs and minimizing the risk of antibiotic resistance.

Secondary objectives include:

• Evaluating the clinical response, length of hospital stay, relapse rate, and presence of infective endocarditis during the first 90 days.
• Describing the efficacy of early oral sequential treatment.
• Evaluating the frequency of diarrhea due to **C. difficile**.
• Determining which microbiological factors influence the clinical course and the risk of relapse.
• Evaluating the safety related to both arms through the communication and evaluation of adverse events from the signing of the informed consent until 90 days after the administration of the study drugs.
• Establishing and testing the definition of "uncomplicated enterococcal bacteremia".

The clinical trial focuses on adult patients aged 18 years and older, both **male** and **female**, who are hospitalized with uncomplicated bacteremia caused by **E. faecalis** or **E. faecium**. The sponsor has not provided information regarding the total number of participants. The study population includes individuals who have shown negative control blood cultures between days 2-3 of treatment and have experienced the disappearance of fever within the first 72 hours of active treatment. Participants are required to have signed informed consent. The trial does not specify particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, although specific details about this group are not provided.

The clinical trial is designed to evaluate the **safety** and efficacy of a 7-day antibiotic treatment regimen compared to a 14-day regimen for uncomplicated bacteremia caused by **E. faecalis** or **E. faecium**. This is a randomized, double-blind, controlled trial with a non-inferiority design. The trial aims to demonstrate that the shorter treatment duration is not inferior in terms of efficacy. The estimated duration of the trial is from July 15, 2022, to September 30, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), hospitalization with the specified bacteremia, negative control blood cultures between days 2-3 of treatment, and disappearance of fever within the first 72 hours. Informed consent is required. The trial includes follow-up visits to monitor clinical success, adverse events, and secondary infections. The end-of-study visit will assess the primary endpoint of clinical success at the test of cure (TOC) in the intention-to-treat population (ITTP).

The expected length of participant involvement is up to 14 days, corresponding to the maximum treatment period. Conditions that may lead to early termination from the study include the development of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. Secondary endpoints include rates of relapse or infective endocarditis, survival, length of hospital stay, duration of intravenous and total therapy, infection with **C. difficile**, and changes in the Sequential Organ Failure Assessment (SOFA) score.

The clinical trial involves the administration of several **antibiotics** to evaluate the safety and efficacy of short-duration therapy for uncomplicated enterococcal bacteremia. The experimental medication, **Linezolid**, is provided in two forms: Linezolid Normon 600 mg film-coated tablets and Linezolid 600 mg film-coated tablets. Both formulations are administered orally at a dosage of 600 mg twice daily, with a maximum daily dose of 1200 mg. The treatment period is limited to 14 days. Participant compliance is monitored through regular assessments and pill counts.

Another experimental treatment includes **Piperacillin Sodium** combined with **Tazobactam Sodium**, administered intravenously. The pharmaceutical form is denoted as PHF00230MIG, with a maximum daily dose of 12 grams. The treatment duration is also capped at 14 days. This combination acts as a **beta-lactamase inhibitor**, enhancing the efficacy of piperacillin against resistant bacterial strains.

**Amoxicillin Sodium** is utilized in two forms: as a powder and solvent for solution for injection/infusion, and as a standalone oral formulation. The intravenous form is administered with a maximum daily dose of 3 grams, while the oral form is also dosed at 3 grams daily. Both forms are used for a maximum of 14 days. The oral formulation is identified as PHF00231MIG.

**Daptomycin** is administered intravenously, with a dosage based on body weight, specifically 10 mg/kg per day. The pharmaceutical form is PHF675, and the treatment period is restricted to 14 days. Daptomycin is known for its efficacy against gram-positive bacterial infections.

**Vancomycin** is another intravenous treatment option, dosed at 30 mg/kg per day. The pharmaceutical form is PHF00230MIG, and the treatment duration is limited to 14 days. Vancomycin is particularly effective against methicillin-resistant Staphylococcus aureus (MRSA) and other resistant gram-positive bacteria.

**Ampicillin Sodium** is administered intravenously, with a maximum daily dose of 8 grams. The pharmaceutical form is PHF00243MIG, and the treatment period is 14 days. Ampicillin is a broad-spectrum penicillin antibiotic effective against a variety of bacterial infections.

Lastly, **Amoxicillin Sodium** combined with **Clavulanic Acid** is administered orally, with a maximum daily dose of 2625 mg. The pharmaceutical form is PHF00231MIG, and the treatment duration is 14 days. This combination is effective against beta-lactamase-producing bacteria, enhancing the spectrum of amoxicillin.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is defined as clinical success at the Test of Cure (TOC) in the Intention-To-Treat Population (ITTP). Secondary endpoints include the rates of diagnosis of relapse or infective endocarditis during the On-Treatment Clinical Decision (OCD) and follow-up visits in the Clinically Evaluable Population (CEP), survival rates during OCD and follow-up visits, length of hospital stay, duration of intravenous and total therapy in the CEP, incidence of infection with Clostridioides difficile, adverse events and their severity, secondary infections, and changes in the Sequential Organ Failure Assessment (SOFA) score during OCD and follow-up visits.