Evaluation of eGFR as a Predictor for Dose Adjustment in Staphylococcus aureus Bacteremia Using Therapeutic Drug Monitoring of Cloxacillin Concentrations

The primary objective of this study is to evaluate the extent to which the treatment goal of 100% **fT>MICECOFF** is achieved with standard dosing of **cloxacillin** in patients with **Staphylococcus aureus bacteremia** (SAB). Additionally, the study aims to determine if the initial renal function, as estimated by the **glomerular filtration rate (eGFR)**, can predict which patients are at risk of being under- or overdosed. This is clinically relevant as it may inform dosing adjustments to optimize therapeutic outcomes and minimize adverse effects in patients with varying renal function.

The clinical trial involves participants diagnosed with **Staphylococcus aureus bacteremia**. The study population includes both male and female subjects aged 18 years and older. The participants are generally in a stable health condition, as the trial does not focus on a vulnerable population. The total number of participants is not provided by the sponsor. Selection criteria include individuals who have provided written consent, have a primary blood culture positive for S. aureus taken within 72 hours prior to inclusion, and have commenced treatment with cloxacillin either at inclusion or within the preceding 72 hours. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **cloxacillin** in patients with **Staphylococcus aureus bacteremia**. The study is a randomized, double-blind, controlled trial with an estimated duration from January 8, 2024, to June 30, 2026. The primary objective is to assess whether the estimated glomerular filtration rate (eGFR) can predict the need for adjusted dosing via therapeutic drug monitoring (TDM) of cloxacillin concentrations in plasma. The trial will involve intravenous administration of cloxacillin, with a maximum daily dose of 12 grams and a total dose not exceeding 360 grams over a 30-day treatment period.

Participants will be involved in the study for a period of up to 30 days, with the possibility of early termination if they experience adverse effects or if they withdraw consent. The inclusion criteria require participants to be 18 years or older, have a primary blood culture positive for S. aureus taken within 72 hours before inclusion, and be undergoing treatment with cloxacillin initiated at inclusion or within the preceding 72 hours. The study will exclude any participants who do not meet these criteria.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits on days 2 and 7 post-inclusion to monitor the achievement of the treatment goal of 100% fT>MIC and to assess potential toxic levels in relation to renal function. Secondary endpoints will evaluate elevated levels of urinary markers for tubular damage and clinical signs of CNS impact, measured daily from days 2 to 7. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

The clinical trial involves the administration of **Cloxacillin**, a chemical-origin antibiotic, as the experimental medication. **Cloxacillin** is provided in a pharmaceutical form identified as PHF675. The medication is administered intravenously, with a maximum daily dose of 12 grams and a total maximum dose of 360 grams over a treatment period of up to 30 days. The primary objective of the trial is to evaluate the achievement of the treatment goal, specifically 100% fT>MICECOFF, with standard dosing of **Cloxacillin** in patients with Staphylococcus aureus bacteremia (SAB). The study also aims to determine if initial renal function, as estimated by glomerular filtration rate (eGFR), can predict the risk of under- or overdosing.

In addition to the experimental treatment, the study may involve standard-of-care therapy as a non-experimental treatment. However, no specific details regarding the use of a placebo or comparator treatment are provided. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve a pediatric formulation, and **Cloxacillin** is not classified as an orphan drug in this study. The trial's design does not include any devices, and all substances used are of chemical origin.

Efficacy in this clinical trial will be assessed by evaluating the achievement of the treatment goal of 100% **fT>MIC** at standard dosing of cloxacillin in patients with **Staphylococcus aureus** bacteremia (SAB). The primary endpoints include the proportion of patients reaching the treatment goal in relation to renal function, as well as the proportion of patients reaching potentially toxic levels (free fraction > 5 mg/L or total concentration > 50 mg/L) in relation to renal function. These measurements will be taken at specific timepoints, namely day 2 and day 7 after inclusion in the study.

Secondary endpoints will involve assessing elevated levels relative to the normal population/reference values of urinary markers for tubular damage, such as cystatin C, KIM-1, NAG, NGAL, and α1-Microglobulin, in relation to cloxacillin concentrations (peak and trough) on day 2 and day 7. Additionally, acute kidney injury, defined according to KDIGO (creatinine-based), will be measured daily from day 1 to day 7. Clinical signs of new-onset CNS effects, including decreased consciousness measured by the Glasgow Coma Scale, seizures, confusion, and tremor, will be evaluated daily from day 2 to day 7 and related to cloxacillin concentrations (peak and trough) on day 2 and day 7.

Other variables such as gender, age, weight, height, renal function, comorbidity measured by the Charlson comorbidity index, concurrent medications at inclusion, severity of infection (NEWS), proportion of complicated or uncomplicated infections according to established criteria (IDSA), duration of bacteremia (days), and 30-day mortality will also be considered. Exploratory biomarker levels in urine and plasma will be measured on day 2 and day 7. The study will also include semi-structured interviews to describe participants' experiences, analyzed using qualitative methods.