Unbound cloxacillin plasma concentrations in relation to toxicity and renal function: protocol for a prospective, observational clinical trial in a real-world <i>Staphylococcus aureus</i> bacteraemia population

Introduction Staphylococcus aureus bacteraemia (SAB) is a common and severe infection, with a 90-day mortality of 24%–32%. Cloxacillin is regarded as a first-line antibiotic treatment in SAB in Sweden. However, exposure to cloxacillin in real-world hospitalised patients with SAB, most of whom are elderly patients treated outside the intensive care unit, is not well described. There are also limited data on the role of unbound cloxacillin exposure in relation to renal function or drug-induced toxicity. Methods and analysis This multicentre, prospective, observational clinical trial will include 95 adult patients with methicillin-susceptible S. aureus bacteraemia, treated with cloxacillin. Patients with endocarditis, polymicrobial bacteraemia or those considered unsuitable for cloxacillin treatment are excluded. Trough and peak total and unbound cloxacillin concentrations will be measured at steady state at days 2 and 7. Blood cultures will be obtained at days 2, 3, 4 and 7 to assess time to negative culture. Renal function will be assessed daily for plasma creatinine and at days 1 and 6 for cystatin C and for 12-hour urine creatinine clearance. In a novel approach to detecting nephrotoxicity, renal tubular damage biomarkers will be measured at days 1 and 6 (KIM-1, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, urine cystatin C, alpha-1-microglobulin). Detection of neurologic symptoms such as confusion, tremor, hallucinations and convulsions, as well as consciousness, will be monitored daily using a structured evaluation form. We aim to investigate to which extent target attainment (100% of the dosing interval during which the free (unbound) drug concentration exceeds the minimum inhibitory concentration) is achieved with standard dosing of cloxacillin in a real-world cohort of hospitalised patients with SAB, and whether initial renal function can predict who is at risk for underdosing or overdosing. We will also explore whether neurological or renal damage is prevalent and associated with cloxacillin levels. Ethics and dissemination Ethics approval has been granted by the Swedish Ethical Review Authority (EUCT 2023-505148-20-00) as part of a low-intervention clinical trial approval according to EU regulation 536/2014. Results will be disseminated in a peer-reviewed journal and at academic conferences. Trial registration number EUCT 2023-505148-20-00.