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

Abstract

cThe 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 concentrations. 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, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P < 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations 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 (R 2 ‫؍‬ 0.81 to 1.00; P < 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (R 2 ‫؍‬ 0.776; P < 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.

Dose optimization of piperacillin/tazobactam in critically ill children

“…However, this simplification was previously found to be acceptable for β-lactam antibiotics with low protein binding like piperacillin and tazobactam. 50 Third, MIC values were not prospectively determined in order to be able to calculate individual target drug concentrations in culture-proven infections.…”

The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients

“…A comparison between estimating the free drug concentrations from total values versus direct determination of the free unbound concentration was performed by Wong et al on seven antibiotics that differ in their known percent of protein binding [82]. In their study Wong et al [82] found that while estimation of the free drug concentration is not significantly different for meropemen, known to have a low fraction of protein binding, significant differences were noted for the highly protein-bound antibiotics such as ceftriaxone and flucloxacillin. Consequently, it was recommended to directly measure, instead of estimating, the free unbound concentrations [82].…”

“…In their study Wong et al [82] found that while estimation of the free drug concentration is not significantly different for meropemen, known to have a low fraction of protein binding, significant differences were noted for the highly protein-bound antibiotics such as ceftriaxone and flucloxacillin. Consequently, it was recommended to directly measure, instead of estimating, the free unbound concentrations [82]. However, it is worth mentioning that from all the currently published analytical methods only one method used ultracentrifugation for the analysis of free drug concentrations of β-lactam antibiotics [57].…”

“…The reported protein binding data for the antibiotics are made on analysis done in noncritically ill patients. Consequently, the estimation of the free unbound concentration from the total amount analyzed might result in over or under prediction of the true values especially that hypoalbuminemia is very common in critically ill patients [80][81][82]. A comparison between estimating the free drug concentrations from total values versus direct determination of the free unbound concentration was performed by Wong et al on seven antibiotics that differ in their known percent of protein binding [82].…”

“…Consequently, the estimation of the free unbound concentration from the total amount analyzed might result in over or under prediction of the true values especially that hypoalbuminemia is very common in critically ill patients [80][81][82]. A comparison between estimating the free drug concentrations from total values versus direct determination of the free unbound concentration was performed by Wong et al on seven antibiotics that differ in their known percent of protein binding [82]. In their study Wong et al [82] found that while estimation of the free drug concentration is not significantly different for meropemen, known to have a low fraction of protein binding, significant differences were noted for the highly protein-bound antibiotics such as ceftriaxone and flucloxacillin.…”