Michael Schleibinger1, Cathérine L Steinbach2, Christoph Töpper2, Alexander Kratzer3,4, Uwe Liebchen1, Frieder Kees5, Bernd Salzberger1, Martin G Kees2,6. 1. Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany. 2. Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany. 3. Hospital Pharmacy, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany. 4. Department of Pharmaceutical Biology, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany. 5. Department of Pharmacology, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany. 6. Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.
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.
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.
Authors: A A Pollock; P E Tee; I H Patel; J Spicehandler; M S Simberkoff; J J Rahal Journal: Antimicrob Agents Chemother Date: 1982-11 Impact factor: 5.191
Authors: I H Patel; S Chen; M Parsonnet; M R Hackman; M A Brooks; J Konikoff; S A Kaplan Journal: Antimicrob Agents Chemother Date: 1981-11 Impact factor: 5.191
Authors: Katharina Olbrisch; Tobias Kisch; Julia Thern; Evelyn Kramme; Jan Rupp; Tobias Graf; Sebastian G Wicha; Peter Mailänder; Walter Raasch Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2018-10-27 Impact factor: 3.000
Authors: Jan-Dirk Vermeij; Willeke F Westendorp; Yvo B Roos; Matthijs C Brouwer; Diederik van de Beek; Paul J Nederkoorn Journal: Cerebrovasc Dis Date: 2016-06-24 Impact factor: 2.762
Authors: Andrew Ackerman; Nathaniel R Zook; Jeremy F Siegrist; Charles F Brummitt; Margaret M Cook; Thomas J Dilworth Journal: Antimicrob Agents Chemother Date: 2020-05-21 Impact factor: 5.191