Flucloxacillin plasma and urinary concentrations with and without probenecid and urinary biomarker profiles in healthy volunteers

Aim Oral flucloxacillin is widely used for methicillin‐susceptible Staphylococcus aureus (MSSA) infections, but its recommended 6‐hourly dosing may limit adherence. Probenecid inhibits renal tubular secretion of β‐lactams and enhances flucloxacillin exposure, allowing less frequent dosing. This study aimed to determine the effect of repeated dosing of probenecid on serum and urinary concentrations of flucloxacillin and its impact on pharmacodynamic target attainment. Methods Ten healthy adults participated. Flucloxacillin was administered intravenously and orally. Oral flucloxacillin was administered with and without probenecid. Rich plasma sampling was undertaken, with analysis by UHPLC–MS/MS. A population PK model was developed and evaluated, followed by Monte Carlo simulations to assess the probability of target attainment (PTA; target of at least 50% fT > MIC at MIC 0.5 mg/L). Urinary biomarkers (NGAL, KIM‐1, glycosaminoglycans), urinary flucloxacillin concentrations and serum creatinine concentrations were monitored. Results Across 307 plasma samples, unbound steady state flucloxacillin concentrations were higher with probenecid (median 0.74 mg/L) than without (median 0.30 mg/L; p = .002). Probenecid reduced flucloxacillin clearance from 143 to 46.9 L/h. Simulations showed markedly improved PTA for flucloxacillin 1 g 8 hourly with probenecid (84%) compared with 1 g 6 hourly alone (6%). Urinary flucloxacillin concentrations were reduced with probenecid, consistent with decreased renal clearance. Serum creatinine concentrations and urinary biomarkers remained stable, and only non‐serious adverse events were reported. Conclusion Co‐administration of probenecid significantly enhanced flucloxacillin exposure, without serious adverse effects. These findings warrant evaluation in a clinical trial of patients with MSSA infection. Trial Registration Clinical trial registered with ANZCTR: ACTRN12623001155684.