Evaluation of Optimized Ceftazidime Dosing Regimen Versus Standard Regimen in Critical Care Patients with Sepsis

The primary objective of this study is to evaluate a **ceftazidime** regimen optimized for rapid attainment and maintenance of target concentration in critical care patients with **sepsis**, compared to the standard regimen. This is clinically relevant as achieving optimal drug concentrations swiftly can potentially improve patient outcomes in critical care settings, where timely and effective treatment is crucial.

Secondary objectives include evaluating the optimized dosing regimen versus the standard dosing regimen in terms of:

• Changes in patient severity between Day 0 and Day 7
• Mortality at Day 28
• Occurrence of adverse events
• Occurrence of overdose
• Estimation of renal function
• Delay in effective antibiotic therapy

The clinical trial involves participants diagnosed with **sepsis**, focusing on evaluating a ceftazidime regimen optimized for rapid attainment and maintenance of target concentration in critical care patients. The study population includes both male and female subjects, aged 18 years and older, who are hospitalized in critical care for an expected duration of at least 72 hours and have an infection for which ceftazidime therapy is being considered. Participants must have an arterial catheter for blood sampling and be affiliated with or entitled under a social security scheme. 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 an optimized **ceftazidime** regimen for rapid attainment and maintenance of target concentration in critical care patients with **sepsis**. This is a Phase 4, randomized, double-blind, controlled trial. The trial aims to compare the optimized dosing regimen against the standard regimen. The study is expected to commence on September 1, 2025, and conclude by October 31, 2026. Participants will be involved in the study for a maximum treatment period of one day, with the primary endpoint being the percentage of subjects achieving a ceftazidime concentration equal to or above the target threshold of 35 mg/L at both 3 hours and 24 hours post-administration, while remaining below the toxicity threshold of 100 mg/L.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (at least 18 years), hospitalization in critical care for at least 72 hours, and the presence of an arterial catheter for blood sampling. Follow-up visits will assess primary and secondary endpoints, including the Sepsis-related Organ Failure Assessment (SOFA) score at Day 0 and Day 7, death up to Day 28, and the occurrence of neurological adverse events. The end-of-study visit will finalize data collection and assess overall outcomes. Participants may be terminated early from the study if they experience severe adverse events or if they withdraw consent.

The trial will involve intravenous administration of ceftazidime, with a modified loading dose of 4g and maintenance doses adjusted based on the glomerular filtration rate (GFR). The maximum daily dose is set at 6 grams. The study will also monitor renal function using various estimators and track the time to reach pharmacokinetic/pharmacodynamic targets. The trial's design ensures rigorous assessment of the optimized regimen's efficacy and safety in a critical care setting.

The clinical trial involves the administration of **CEFTAZIDIME**, a **solution for injection** used as an **antibiotic**. The experimental medication is administered **intravenously**. The trial evaluates two dosing regimens of CEFTAZIDIME. The first regimen, designated as the test regimen, involves a modified loading dose of **4 grams** and a maintenance dose adjusted based on the patient's glomerular filtration rate (GFR). Specifically, the maintenance dose is **8 grams per day** if GFR is greater than 90, **6 grams per day** if GFR is between 40 and 90, and **4 grams per day** if GFR is between 15 and 30. The maximum daily dose is **6 grams**, and the maximum treatment period is **1 day**.

The comparator regimen involves the standard dosing of CEFTAZIDIME, also administered as a **solution for injection** via the **intravenous route**. The standard regimen maintains a maximum daily dose of **6 grams** and a maximum treatment period of **1 day**. Both regimens are designed to achieve rapid attainment and maintenance of target drug concentration in critical care patients. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of the ceftazidime dosing regimen in critical care will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the **percentage of subjects** achieving a ceftazidime concentration equal to or above the target concentration threshold of 35 mg/L at both 3 hours and 24 hours after the first administration, while remaining below the toxicity threshold of 100 mg/L. This measurement will help determine the effectiveness of the optimized dosing regimen in maintaining therapeutic drug levels.

Secondary endpoints include several parameters to further evaluate the regimen's impact. These include the assessment of patient severity using the SOFA (Sepsis-related Organ Failure Assessment) score at Day 0 and Day 7, which evaluates the function of six organ systems. Additional secondary endpoints are the occurrence of death up to Day 28, the incidence of neurological adverse events such as seizures or delirium, and the occurrence of an overdose defined by a concentration greater than 100 mg/L. Renal function will be assessed using creatinemia cystatin CKD-EPI, creatinuria/creatininemia ratio, and eGFR creat-cystatin. The time to reach pharmacokinetic/pharmacodynamic targets post-treatment introduction will also be measured.