Evaluation of the Safety and Efficacy of Shortened Antibiotic Regimens in Left-Sided Infectious Endocarditis Using Vancomycin and Drug Combinations

The primary objective of this study is to evaluate the **safety** and **efficacy** of a shorter course of antibiotic treatment for **infectious endocarditis**. This is clinically relevant as it aims to determine whether an accelerated antibiotic regimen can effectively treat left-sided endocarditis caused by bacterial species such as **Staphylococcus aureus**, **Enterococcus faecalis**, or streptococci, potentially reducing treatment duration and associated healthcare burdens.

Secondary objectives include investigating the economic consequences of accelerated treatment, which could provide insights into cost-effectiveness and resource allocation in clinical settings.

The clinical trial focuses on evaluating the **safety and efficacy** of a shorter course of antibiotic treatment for **infectious endocarditis**, specifically targeting left-sided endocarditis caused by Staphylococcus aureus, Enterococcus faecalis, or streptococci. The study population includes both male and female participants, aged over 18 years, who are in-patients at a hospital ward. Participants must have left-sided endocarditis as per modified Duke's criteria and a verified infection with the specified bacterial species. Informed consent is a prerequisite for participation. The sponsor has not provided information regarding the total number of participants. The trial does not include a vulnerable population, and no specific lifestyle considerations such as diet or physical activity are highlighted in the selection criteria.

The clinical trial is designed to evaluate the **safety** and **efficacy** of a shorter course of antibiotic treatment for **infectious endocarditis**, specifically targeting left-sided endocarditis caused by **Staphylococcus aureus**, **Enterococcus faecalis**, or streptococci. The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The estimated duration of the trial is from January 2023 to June 2027, with participant involvement expected to last up to six months. The trial includes several key phases, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 18 years, in-patient status, and verified infection according to modified Duke's criteria.

Participants will be randomly assigned to receive one of the following intravenous antibiotics: **vancomycin**, **meropenem trihydrate**, **ceftriaxone sodium**, **benzylpenicillin sodium**, **ampicillin**, **cloxacillin sodium**, **cefotaxime**, or **daptomycin**. The maximum treatment period for each antibiotic is six weeks, with specific dosing regimens tailored to each drug. Follow-up visits will be scheduled to monitor the primary outcome, which includes events such as death, septic embolization, bacteraemia with the same microorganism, and unplanned heart surgery within six months post-randomization. Secondary outcomes will assess hospital care expenses, length of hospital stay, duration of antibiotic treatment, and complications related to intravenous access.

The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the treatment's impact. Participants may be withdrawn from the study early if they experience adverse effects, fail to adhere to the protocol, or withdraw consent. The trial aims to provide valuable insights into the potential benefits of accelerated antibiotic regimens for treating infectious endocarditis, contributing to improved patient outcomes and healthcare efficiency.

The clinical trial involves the administration of several **antibiotics** for the treatment of infectious endocarditis. The experimental medication **Vancomycin** is provided as "Vancomycin Viatris 1 000 mg pulver till infusionsvätska, lösning," a powder for solution for infusion. It is administered intravenously with a maximum daily dose of 3 grams and a total maximum dose of 126 grams over a treatment period of up to 6 weeks. The active substance is chemically derived vancomycin.

**Meropenem** is administered as "Meropenem Fresenius Kabi 1 g pulver till injektionsvätska eller infusionsvätska, lösning," a powder for solution for injection or infusion. The intravenous route is used, with a maximum daily dose of 6 grams and a total maximum dose of 252 grams over a 6-week period. The active substance is meropenem trihydrate, chemically derived.

**Ceftriaxone** is provided as "Ceftriaxon Fresenius Kabi 2 g pulver till infusionsvätska, lösning," a powder for solution for infusion. It is administered intravenously with a maximum daily dose of 4 grams and a total maximum dose of 168 grams over a 6-week period. The active substance is ceftriaxone sodium, chemically derived.

**Benzylpenicillin** is administered as "Bensylpenicillin Meda 3 g pulver till injektions/infusionsvätska, lösning," a powder for solution for injection or infusion. The intravenous route is used, with a maximum daily dose of 12 grams and a total maximum dose of 504 grams over a 6-week period. The active substance is benzylpenicillin sodium, chemically derived.

**Ampicillin** is provided as "Doktacillin 1g respektive 2 g pulver till injektions/infusionsvätska, lösning," a powder for solution for injection or infusion. It is administered intravenously with a maximum daily dose of 12 grams and a total maximum dose of 504 grams over a 6-week period. The active substance is ampicillin, chemically derived.

**Cloxacillin** is administered as "Cloxacillin Stragen 2 g pulver till injektions-/infusionsvätska, lösning," a powder for solution for injection or infusion. The intravenous route is used, with a maximum daily dose of 12 grams and a total maximum dose of 504 grams over a 6-week period. The active substance is cloxacillin sodium, chemically derived.

**Cefotaxime** is provided as "Cefotaxim Stragen 1 g pulver till injektions- och infusionsvätska, lösning," a powder for solution for injection or infusion. It is administered intravenously with a maximum daily dose of 9 grams and a total maximum dose of 378 grams over a 6-week period. The active substance is cefotaxime, chemically derived.

**Daptomycin** is administered as "Cubicin 350 mg powder for solution for injection or infusion," a powder for solution for injection or infusion. The intravenous route is used, with a maximum daily dose of 700 mg and a total maximum dose of 42.70 grams over a 6-week period. The active substance is daptomycin, chemically derived.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to evaluate the safety and efficacy of a shorter course of antibiotic treatment for left-sided endocarditis caused by specific bacterial species.

The efficacy of the clinical trial evaluating accelerated antibiotic treatment for **infectious endocarditis** will be assessed using a combination of primary and secondary endpoints. The primary endpoint is a composite measure that includes the occurrence of death, septic embolization, bacteraemia with the same microorganism, and heart surgery not planned at the time of randomization, all within six months post-randomization. These events will be systematically recorded and analyzed to determine the efficacy of the treatment regimen.

Secondary endpoints will focus on healthcare resource utilization and treatment-related complications. These include expenses related to hospital care and other treatments, the length of hospital stay, the duration of antibiotic treatment, and complications associated with intravenous access. Data collection for these endpoints will be conducted throughout the trial period, with specific timepoints aligned with the study's schedule to ensure comprehensive assessment.