High unbound flucloxacillin fraction in critically ill patients

Abstract

Objectives: To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies.

Patients and methods: Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR.

Results: The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L).

Conclusions: Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.

Figure 1.

Unbound fraction flucloxacillin versus unbound flucloxacillin concentrations.

Figure 2.

Unbound fraction flucloxacillin versus serum albumin.

Figure 3.

Goodness-of-fit diagnostics for the final pharmacokinetic model of unbound flucloxacillin in critically ill patients. The population and individual predicted concentrations are in concordance with the observed concentrations; the discrepancy between predictions and observations is small. Furthermore, the conditional weighted residuals indicate no model misspecification, the distribution is homogeneous and the majority of the data lie within the (−2 to +2) interval.

Figure 4.

Visual predictive check (VPC) for the final pharmacokinetic model stratified for total (FF = 1) and unbound (FF = 2) concentrations. Prediction-corrected simulated (shaded) areas and observed (open circles) concentrations versus time after dose. The upper and lower lines connect the 5th and 95th percentiles of the observations. Light grey shaded areas are the 95% CIs of the 5th and 95th percentiles. Dark grey shaded areas indicate the CI of the median. The distribution of observed concentrations was consistent with the distribution of the predicted concentrations, suggesting a good internal validity of the model to the data.

Figure 5.

Boxplots showing the simulated flucloxacillin unbound concentrations for ICU patients on dosing regimens of 6, 8 and 12 g/24 h at steady-state for different CL_CR categories. The boxplots present the 5th, 25th, median, 75th and 95th percentiles of data. The grey dashed horizontal lines at 0.5, 2.5 and 10 mg/L correspond to a target of 100% fT>MIC, assuming an MIC of 0.5 mg/L, and 100% fT>5×MIC, assuming an MIC of 0.5 and 2 mg/L, respectively. The red dashed horizontal line represents the upper limit of 20 mg/L. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.