Evaluation of Continuous Versus Intermittent Infusion of Ampicillin Sodium and Ceftriaxone Sodium in Enterococcus faecalis Infective Endocarditis Treatment

The primary objective of this study is to demonstrate that **continuous infusion** of ampicillin-ceftriaxone is non-inferior in efficacy to intermittent infusion in patients with **Enterococcus faecalis infective endocarditis**, as defined by the frequency of disease recurrence. This is clinically relevant as it may offer an alternative treatment regimen that could potentially improve patient outcomes by reducing the recurrence of this serious infection.

Secondary objectives include: - Demonstrating that continuous infusion is non-inferior to intermittent infusion in terms of mortality frequency, treatment switching, and unplanned surgery. - Evaluating the rate of unplanned readmissions for any reason. - Analyzing and comparing adverse events related to study antibiotics in both regimens. - Comparing the efficiency of both regimens in terms of days of hospital stay avoided and healthcare-related infections. - Studying the strains responsible for recurrences to determine if they are recurrences or reinfections. - Confirming the ability of the continuous infusion regimen to maintain synergistic serum concentration for 24 hours. - Describing the pharmacokinetic profile of ampicillin and ceftriaxone in both dosage regimens. - Analyzing the synergistic activity between ampicillin and ceftriaxone in isolates responsible for relapses, compared with a control group.

The clinical trial involves participants diagnosed with **Enterococcus faecalis** infectious endocarditis. The study population includes adult patients aged 18 years and older, encompassing both male and female subjects. Participants were selected based on a possible or definitive diagnosis of infective endocarditis due to Enterococcus faecalis, as per the Duke-ISCVID criteria, and all have provided signed informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet, physical activity, or habits.

The clinical trial is designed to evaluate the **efficacy** and safety of continuous versus intermittent infusion of **ampicillin** and **ceftriaxone** in the treatment of **Enterococcus faecalis** infective endocarditis. This is a Phase IV, randomized, double-blind, controlled trial. The trial aims to demonstrate that continuous infusion administration is non-inferior to intermittent infusion in terms of efficacy, specifically focusing on the frequency of disease recurrence. The trial is expected to commence recruitment on September 2, 2024, and conclude by December 31, 2028.

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) and a diagnosis of infective endocarditis according to the Duke-ISCVID criteria. Following the screening, eligible participants will be randomized to receive either continuous or intermittent infusion of the study drugs. The treatment period will last for a maximum of 42 days, during which participants will have regular follow-up visits to monitor treatment response and safety. Key follow-up assessments will occur on day 14, where pharmacokinetic parameters and serum concentrations of the drugs will be measured. The end-of-study visit will occur one year after the completion of antibiotic treatment to assess the primary endpoint of treatment failure, defined as confirmed recurrence of infective endocarditis.

The expected length of participant involvement is approximately 14 months, including the treatment and follow-up periods. Conditions that may lead to early termination from the study include withdrawal of consent, occurrence of significant adverse events, or any condition that, in the investigator's opinion, warrants discontinuation for the safety of the participant. The trial will also evaluate secondary endpoints such as mortality, changes in antibiotic treatment, unplanned cardiac surgeries, and medication-related adverse events. The study will adhere to the terms of the marketing authorization for the investigational medicinal products, ensuring compliance with regulatory standards.

The clinical trial involves the administration of **ceftriaxone sodium** in combination with **lidocaine hydrochloride**. Ceftriaxone sodium is an antibiotic used in the treatment of bacterial infections, and it is administered in an **intravenous** form. The pharmaceutical form is designated as PHF00231MIG. The maximum daily dose of ceftriaxone sodium is 4 grams, with a total maximum dose of 168 grams over a treatment period of 42 days. Lidocaine hydrochloride, also known as lignocaine hydrochloride, is included as a local anesthetic to reduce pain at the injection site. The administration schedule involves continuous infusion, and participant compliance is monitored through regular assessments.

Another treatment used in the study is **ampicillin sodium**, an antibiotic administered intravenously. The pharmaceutical form is identified as PHF00243MIG. The maximum daily dose for ampicillin sodium is 12 grams, with a total maximum dose of 504 grams over the same 42-day treatment period. Similar to ceftriaxone sodium, ampicillin sodium is administered via continuous infusion, and compliance is monitored to ensure adherence to the dosing schedule. Both ceftriaxone sodium and ampicillin sodium are used in the study to evaluate their efficacy and safety in treating **Enterococcus faecalis infective endocarditis**.

Efficacy in this clinical trial will be assessed by evaluating the non-inferiority of continuous infusion of ampicillin-ceftriaxone compared to intermittent infusion in patients with **Enterococcus faecalis** infective endocarditis. The primary endpoint for efficacy is defined as the treatment failure, which is the confirmed recurrence of infective endocarditis due to **Enterococcus faecalis** (microbiological failure) one year after the completion of antibiotic treatment.

Secondary endpoints include several parameters: treatment failure assessed up to one year after treatment completion, mortality from any cause during hospitalization or from endocarditis-related causes, the number of patients requiring a change in antibiotic treatment during the 6-week treatment period, unplanned cardiac surgeries, unplanned readmissions, and medication-related adverse events from randomization until 30 days post-treatment. Additionally, the total number of antibiotic treatment days, the number of TADE treatment days for patients in the experimental arm, and the number of healthcare-associated infections will be monitored. Pharmacokinetic parameters such as the minimum free serum concentration and steady-state plasma concentration of ceftriaxone and ampicillin will be measured on day 14 after treatment initiation. Synergistic activity will be calculated through the reduction of the Minimum Inhibitory Concentration of ampicillin induced by ceftriaxone in the strains responsible for recurrences and control strains.