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Observational Study
. 2013 Dec;57(12):6165-70.
doi: 10.1128/AAC.00951-13. Epub 2013 Sep 30.

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

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Free PMC article
Observational Study

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

Gloria Wong et al. Antimicrob Agents Chemother. .
Free PMC article

Abstract

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 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.

Figures

Fig 1
Fig 1
Linear correlation between measured and predicted unbound trough concentrations of ceftriaxone (a) and cefazolin (b) (R2 = 0.96; P = 0.003). The x = y plots are shown as gray dashed lines.
Fig 2
Fig 2
Bland-Altman plots of relative difference (percentage of measured unbound concentrations) against the mean of predicted and measured unbound concentrations for piperacillin (n = 94; ρ = −0.51; P < 0.01) (a), ampicillin (n = 8; ρ = 0.42; P = 0.30) (b), benzylpenicillin (n = 11; ρ = −0.92; P < 0.01) (c), meropenem (n = 49; ρ = 0.02; P = 0.91) (d), ceftriaxone (n = 19; ρ = −0.43; P = 0.07) (e), cefazolin (n = 5; ρ = −0.80; P < 0.01) (f), and flucloxacillin (n = 11; ρ = −0.81; P < 0.01) (g). The biases and 95% limits of agreement are shown as solid and broken horizontal lines, respectively.

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