Total flucloxacillin plasma concentrations poorly reflect unbound concentrations in hospitalized patients with Staphylococcus aureus bacteraemia.

Aims: Flucloxacillin dosing may be guided by measurement of its total plasma concentrations. Flucloxacillin is highly protein bound with fraction unbound in plasma (f ) of around 0.04 in healthy individuals. The utility of measuring unbound flucloxacillin concentrations for patients outside the intensive care unit (ICU) is not established. We aimed to compare flucloxacillin f in non-ICU hospitalised patients against healthy volunteers, and to examine the performance of a published model for predicting unbound concentrations, using total flucloxacillin and plasma albumin concentrations.

Methods: Data from 12 healthy volunteers (248 samples) and 47 hospitalized patients (61 samples) were examined. Plasma flucloxacillin concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Flucloxacillin f for the two groups was compared using a generalized estimating equation model to account for clustered observations. The performance of the single protein binding site prediction model in hospitalized patients was compared with measured unbound concentrations using Bland-Altman plots.

Results: The median (range) flucloxacillin f for healthy (median albumin 45 g l ) and hospitalized individuals (median albumin 30 g l ) were 0.04 (0.02-0.07) and 0.10 (0.05-0.37), respectively (P < 0.0001). The prediction model underpredicted unbound flucloxacillin concentrations with a mean bias (95% limits of agreement) of -54% (-137%, +30%).

Conclusions: The flucloxacillin f values observed in our cohort of hospitalized patients had a wide range and were greater than those of healthy individuals. Unbound flucloxacillin plasma concentrations were predicted poorly by the model. Instead, unbound concentrations should be measured to guide dosing.