Evaluation of Cefazolin Sodium, Flucloxacillin Sodium Monohydrate, and Clindamycin in Reducing Antibiotic Duration for Complicated Staphylococcus aureus Bacteremia

The primary objective of the SAFE study is to evaluate whether a **4-week** course of total antibiotic treatment is non-inferior to a **6-week** course in patients with complicated **Staphylococcus aureus bacteremia** (SAB) who have shown a favorable response to initial treatment. This objective is clinically significant as it aims to determine if a shorter duration of antibiotic therapy can be equally effective, potentially reducing the risk of antibiotic resistance, side effects, and healthcare costs associated with prolonged treatment.

The clinical trial involves participants diagnosed with **Staphylococcus aureus bacteremia** (SAB), specifically focusing on adults with methicillin-sensitive complicated SAB. The study population includes both male and female subjects, with an age range encompassing adults and older adults. The trial does not include vulnerable populations. Participants were selected based on their satisfactory clinical response to initial treatment, which includes criteria such as negative blood cultures and a significant decline in C-reactive protein levels. The sponsor has not provided the total number of participants involved in the study. Lifestyle considerations such as diet, physical activity, or habits are not specified. The trial aims to evaluate the efficacy of a 4-week antibiotic treatment duration compared to a 6-week regimen in patients who have responded well to initial treatment. Key inclusion criteria include evidence of organ involvement or deep-seated infection, and predictors of complicated SAB, such as community acquisition or delayed treatment. The sponsor has not disclosed any additional information regarding the selection process or specific lifestyle factors of the participants.

The clinical trial is designed to evaluate the efficacy of a shortened antibiotic treatment duration for patients with **Staphylococcus aureus bacteremia**. This study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial aims to determine whether a 4-week antibiotic regimen is non-inferior to the standard 6-week treatment in patients who have shown a satisfactory clinical response to initial therapy. The trial is expected to conclude by December 31, 2025, with recruitment having commenced on September 1, 2020.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on specific criteria, such as having methicillin-sensitive complicated **Staphylococcus aureus bacteremia** and a satisfactory response to initial treatment. Follow-up visits will be scheduled to monitor the patient's progress and adherence to the treatment protocol. The end-of-study visit will assess the primary outcome, defined as the success of therapy at 180 days post-randomization, characterized by the patient's survival and absence of microbiologically confirmed disease relapse.

The expected duration of participant involvement is approximately 6 months, contingent upon the treatment arm to which they are assigned. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or any significant protocol deviations. The trial will utilize **cefazolin sodium**, **flucloxacillin sodium monohydrate**, and **clindamycin** as the active substances, administered via intravenous or oral routes, depending on the specific formulation. The study is not classified as a low-intervention trial, given its focus on modifying the duration of an established treatment regimen.

The clinical trial involves the administration of **Cefazolin Sodium**, marketed as CEFAZOLINE LDP-LABORATORIOS TORLAN 2 g. This medication is provided in the form of a powder for solution, intended for injection or infusion. The pharmaceutical form is a **solution for injection/infusion**, and it is administered via **intravenous administration**. The maximum daily dose is 6000 mg, with a total maximum dose of 6000 mg over a treatment period of up to 6 weeks. The medication is produced by LDP LABORATORIOS TORLAN, S.A., and is not a pediatric formulation.

Another experimental medication used in the trial is **Flucloxacillin Sodium Monohydrate**, available as Flucloxacillin 250 mg Powder for Solution for Injection or Infusion. This medication is also provided as a **solution for injection** and is administered intravenously. The maximum daily dose is 12000 mg, with a total maximum dose of 12000 mg over a treatment period of up to 6 weeks. The manufacturer of this medication is WOCKHARDT UK LTD, and it is not formulated for pediatric use.

The trial also includes the use of **Clindamycin**, marketed as Clindamycin 600 mg Capsules, hard. This medication is provided in the form of hard capsules and can be administered both orally and intravenously. The maximum daily dose is 1800 mg, with a total maximum dose of 1800 mg over a treatment period of up to 6 weeks. The medication is produced by MORNINGSIDE HEALTHCARE LTD and is not a pediatric formulation.

Throughout the trial, participant compliance with the dosing schedule will be monitored to ensure adherence to the prescribed treatment regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol.

Efficacy in the clinical trial titled "SAFE study" will be assessed primarily through the evaluation of the success of therapy at 180 days post-randomization. The primary endpoint is defined by the patient's survival and the absence of microbiologically confirmed disease relapse. Relapse is characterized by the reappearance of symptoms and/or signs of infection, with **Staphylococcus aureus** isolated from blood or another normally sterile site, such as joint fluid or tissue, using conventional culture methods.