Protein Binding of -Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?

The use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentra-tions. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respec-tively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and un-bound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentra-tions were marked for all antibiotics, with significant differences being present betweenmeasured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P< 0.05). The predictive performance for calcu-lating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound con-centrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R2 0.81 to 1.00; P< 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albu-min concentration were also found to be linearly correlated (R2 0.776; P< 0.01). In conclusion, significant differences be-tweenmeasured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftri