Evaluation of Optimized Initial Dosing of Beta-Lactam Antibiotics in Critically Ill ICU Patients with Sepsis: A Study of Flucloxacillin, Amoxicillin, and Ceftriaxone

The primary objective of the study titled "Beta-Lactam antibiotics initiaL expoSure optimisEd in criticallY ill patients with sEpsis (BuLLSEYE)" is to determine if using a new dosing strategy improves the clinical outcome of patients with **sepsis** in the intensive care unit (ICU). This is clinically relevant as optimizing antibiotic dosing in critically ill patients can potentially enhance treatment efficacy, reduce mortality, and minimize the development of antibiotic resistance. No secondary objectives are specified for this study.

The clinical trial focuses on patients diagnosed with **sepsis** and aims to evaluate a new dosing strategy to improve clinical outcomes in the ICU. The study population includes both male and female participants aged 18 years and older. Participants are required to be receiving intravenous antibiotic therapy, specifically targeting beta-lactam antibiotics, and must have a primary infection. Additionally, they must be admitted to the ICU and meet the Sepsis-3 criteria for septic shock, which includes sepsis with shock necessitating vasopressors to maintain a mean arterial pressure of 65 mm Hg or greater, alongside a serum lactate level exceeding 2.0 mmol/L after adequate fluid resuscitation. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of a new dosing strategy for **sepsis** patients in the intensive care unit (ICU). This is a Phase IV, randomized, double-blind, controlled trial. The trial is expected to commence on December 2, 2024, and conclude by December 2, 2026. The primary objective is to assess whether the new dosing strategy improves clinical outcomes, with the primary endpoint being 28-day mortality. Secondary endpoints include blood levels of antibiotics at 24, 48, and 72 hours, infection parameters, and various mortality and length of stay metrics.

Participants will be involved in the study for a maximum treatment period of 3 days, with the possibility of early termination if they no longer meet the inclusion criteria or experience adverse events. The inclusion criteria require participants to be 18 years or older, admitted to the ICU, and receiving intravenous antibiotic therapy for a primary infection, meeting the Sepsis-3 criteria for septic shock. The study will exclude individuals who do not meet these criteria.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular monitoring visits to assess the primary and secondary endpoints. The end-of-study visit will occur after the treatment period to evaluate the final outcomes and collect data on any adverse events. The trial will utilize intravenous administration of beta-lactam antibiotics, including **flucloxacillin**, **amoxicillin**, **ceftriaxone sodium**, **piperacillin sodium**, **tazobactam sodium**, **meropenem**, **cefotaxime**, **ceftazidime pentahydrate**, and **cefuroxime**. The study aims to provide comprehensive data on the effectiveness of the dosing strategy in improving patient outcomes in a critical care setting.

The clinical trial involves the administration of several **beta-lactam antibiotics** to critically ill patients with sepsis. The experimental medication **Floxapen** is a powder for solution for injection, available in dosages of 250 mg, 500 mg, and 1 g. The active substance is **flucloxacillin**, and it is administered intravenously. The maximum daily dose is 12 g, with a total maximum dose of 36 g over a treatment period of up to 3 days.

**Amoxicilline CF** is another experimental medication used in the trial. It is a powder for solution for injection or infusion, available in dosages of 125 mg, 250 mg, 500 mg, and 1000 mg. The active substance is **amoxicillin**, administered intravenously. The maximum daily dose is 12 g, with a total maximum dose of 36 g over a 3-day treatment period.

**Ceftriaxon Fresenius Kabi** is provided as a 1 g powder for solution for injection or infusion. The active substance is **ceftriaxone sodium**, administered intravenously. The maximum daily dose is 4 g, with a total maximum dose of 12 g over a 3-day treatment period.

**Piperacilline/Tazobactam Fresenius Kabi** is a combination product available as a 2 g/0.25 g powder for solution for infusion. The active substances include **piperacillin sodium** and **tazobactam sodium**, administered intravenously. The maximum daily dose is 24 g, with a total maximum dose of 72 g over a 3-day treatment period.

**Meropenem CF** is a 1000 mg powder for solution for injection or infusion. The active substance is **meropenem**, administered intravenously. The maximum daily dose is 6 g, with a total maximum dose of 18 g over a 3-day treatment period.

**Cefotaxim 1000 mg PCH** is a powder for solution for injection. The active substance is **cefotaxime**, administered intravenously. The maximum daily dose is 12 g, with a total maximum dose of 36 g over a 3-day treatment period.

**Amoxicilline/Clavulaanzuur Sandoz** is a combination product available as a 2000 mg/200 mg powder for solution for intravenous infusion. The active substances include **amoxicillin** and **clavulanic acid**, administered intravenously. The maximum daily dose is 8 g, with a total maximum dose of 24 g over a 3-day treatment period.

**Ceftazidim Fresenius Kabi** is a 500 mg powder for solution for injection. The active substance is **ceftazidime pentahydrate**, administered intravenously. The maximum daily dose is 12 g, with a total maximum dose of 36 g over a 3-day treatment period.

**Meropenem Fresenius Kabi** is a 1 g powder for solution for injection or infusion. The active substance is **meropenem trihydrate**, administered intravenously. The maximum daily dose is 6 g, with a total maximum dose of 18 g over a 3-day treatment period.

**Cefuroxim Hikma** is a 1500 mg powder for solution for injection or infusion. The active substance is **cefuroxime**, administered intravenously. The maximum daily dose is 9 g, with a total maximum dose of 27 g over a 3-day treatment period.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to optimize the initial exposure of beta-lactam antibiotics in critically ill patients with sepsis to improve clinical outcomes.

The efficacy of the clinical trial titled "Beta-Lactam antibiotics initiaL expoSure optimisEd in criticallY ill patients with sEpsis (BuLLSEYE)" will be assessed using both primary and secondary endpoints. The primary endpoint is the 28-day mortality rate, which will serve as a direct measure of the clinical outcome in patients with **sepsis**. Secondary endpoints include a range of parameters that provide additional insights into the treatment's effectiveness and patient outcomes. These parameters are blood levels of antibiotics measured at 24, 48, and 72 hours after the start of therapy, infection parameters such as C-reactive protein (CRP), procalcitonin, and white blood cell count, as well as 90-day and 365-day mortality rates. Other secondary endpoints include hospital and ICU length of stay, post-study cost calculations in both study groups, and the EQ5D questionnaire administered 3 and 12 months after admission. The number of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) will also be recorded, along with the delta Sequential Organ Failure Assessment (SOFA) score from baseline to day 3.