Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients

Abstract

Aims: The aim of the present study was to assess the pharmacokinetics of total and unbound ceftriaxone in intensive care unit (ICU) patients and its protein binding characteristics.

Methods: Twenty patients (m/f 15/5, age 25-86 years, body weight 60-121 kg, APACHE II 7-40, estimated glomerular filtration rate 19-157 ml min(-1) , albumin 11.7-30.1 g l(-1) , total bilirubin <0.1-36.1 mg dl(-1) ) treated with intravenous ceftriaxone were recruited from two ICUs. Timed plasma samples were obtained using an opportunistic study protocol. Ceftriaxone concentrations were determined by high-performance liquid chromatography; unbound concentrations were determined after ultrafiltration using a new method which maintains physiological pH and temperature. The pharmacokinetics was described by a one-compartment model, the protein-binding characteristics by Michaelis-Menten kinetics.

Results: For total drug, the volume of distribution was 20.2 l (median; interquartile range 15.6-24.5 l), the half-life 14.5 h (10.0-25.5 h) and the clearance 0.96 l h(-1) (0.55-1.28 l h(-1) ). The clearance of unbound drug was 1.91 l h(-1) (1.46-6.20 l h(-1) ) and linearly correlated with estimated glomerular filtration rate (slope 0.85, y-intercept 0.24 l h(-1) , r(2) = 0.70). The unbound fraction was higher in ICU patients (33.0%; 20.2-44.5%) than reported in healthy volunteers, particularly when renal impairment or severe hyperbilirubinaemia was present. In all patients, unbound concentrations during treatment with ceftriaxone 2 g once daily remained above the EUCAST susceptibility breakpoint (≤1 mg l(-1) ) throughout the whole dosing interval.

Conclusions: Protein binding of ceftriaxone is reduced and variable in ICU patients due to hypoalbuminaemia, but also to altered binding characteristics. Despite these changes, the pharmacokinetics of unbound ceftriaxone is governed by renal function. For patients with normal or reduced renal function, standard doses are sufficient.

Keywords: HPLC; albumin; cystatin C; dosing; pharmacodynamics; ultrafiltration.

© 2015 The British Pharmacological Society.

Figures

Figure 1

Agreement between observed concentrations and those predicted by a one-compartment model for (A) total ceftriaxone and (B) unbound ceftriaxone

Figure 2

Simulated concentration–time courses of unbound ceftriaxone in 17 intensive care unit patients on days 1 and 6 of therapy (2 g i.v. once daily over 30 min), and in three virtual patients with a clearance of 6 l h–1 and a varying volume of distribution (V). Vertical reference line: mid-interval; horizontal reference lines: susceptibility (≤1 mg l–1), resistance (>2 mg l–1) and 4 × resistance (>8 mg l–1) breakpoints for Enterobacteriaceae according to European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Figure 3

Unbound fraction vs. total concentration of ceftriaxone in plasma from healthy volunteers and from intensive care unit patients

Figure 4

Scatchard plot of ceftriaxone binding in plasma from healthy volunteers. cbound, cunbound, calbumin: molar concentrations of bound and unbound ceftriaxone and of albumin

Figure 5

Michaelis–Menten analysis of ceftriaxone binding to plasma from healthy volunteers and intensive care unit patients. cbound, cunbound, calbumin: molar concentrations of bound and unbound ceftriaxone and of albumin