Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Abstract

Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

Probability of pharmacological target attainment with flucloxacillin in Staphylococcus aureus bloodstream infection: a prospective cohort study of unbound plasma and individual MICs

“…Previously, more aggressive dosing recommendations have been made based on total flucloxacillin concentrations or the oxacillin ECOFF. 10 , 20 , 22 The present data showing high target achievement with the use of the strain-specific MIC, as well as the lack of association between outcome and target achievement with the use of MSSA ECOFF, challenge current flucloxacillin dosing recommendations. In addition, dosages should only be adjusted according to the measured unbound flucloxacillin concentration in patients with MSSA-BSI, 20 as models that are able to accurately predict the unbound concentration from the total measured flucloxacillin concentration are lacking.…”

“…Using this approach, we observed that 90% of all patients and 100% of critically ill patients attained the optimal target (100% fT >MIC ), whereas, with 100% fT >ECOFF, only 38% of critically ill patients attained the target. In pharmacokinetic/pharmacodynamic studies, the ECOFF 20 or the EUCAST clinical species-specific breakpoint value 14 for the targeted bacterium is applied to define the target concentration of the antibacterial drug. In our study, measured flucloxacillin MICs ranged from <0.06 to 0.25 mg/L with a median value of 0.125 mg/L.…”

“…The infective endocarditis guidelines of the BSAC recommend the use of lower flucloxacillin dosages than what was administered in our cohort, even in patients with confirmed infective endocarditis. 4 Others have recommended evaluating a dosage reduction in patients with moderate AKI after 48–72 h 20 and argue against maintaining the dosage as long as the creatinine clearance is above 10 mL/min/1.73 m 2 . 29…”

Pharmacokinetic/Pharmacodynamic Target Attainment Based on Measured versus Predicted Unbound Ceftriaxone Concentrations in Critically Ill Patients with Pneumonia: An Observational Cohort Study

“…Serum albumin was the only plasma protein taken into account as ceftriaxone is known to bind predominantly to albumin [ 27 ]. Protein binding PK parameters were, in case of linear protein binding, the linear protein binding constant and in case of nonlinear protein binding, the maximum binding capacity (Bmax), the Hill coefficient (h) and the dissociation constant (B50) ( File S2, Supplementary Materials ) [ 35 ]. Between-patient variability (BPV) was estimated for the protein binding kinetics parameters.…”

Hypoalbuminemia as Surrogate and Culprit of Infections

“…Hypoalbuminemia is a risk factor for treatment failure with cefotiam in bacteremia caused by gram-negative bacteria [ 194 ]. It has also been recommended that because of the high prevalence of hypoalbuminemia in critically ill patients, dose adjustments of flucloxacillin should be based on monitoring unbound concentrations to account for non-linear protein binding [ 195 ].…”