title: Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients.
abstract: OBJECTIVE
  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: Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
authors: Michael
authors: M
authors: Schleibinger
authors: Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
authors: Cathérine L
authors: CL
authors: Steinbach
authors: Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
authors: Christoph
authors: C
authors: Töpper
authors: Hospital Pharmacy, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.|Department of Pharmaceutical Biology, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany.
authors: Alexander
authors: A
authors: Kratzer
authors: Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
authors: Uwe
authors: U
authors: Liebchen
authors: Department of Pharmacology, University of Regensburg, Universitätsstr. 31, 93053, Regensburg, Germany.
authors: Frieder
authors: F
authors: Kees
authors: Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauß Allee 11, 93053, Regensburg, Germany.
authors: Bernd
authors: B
authors: Salzberger
authors: Department of Anaesthesiology and Intensive Care, Charité Universitätsmedizin Berlin - Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.|Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Kelchstr. 31, 12169, Berlin, Germany.
authors: Martin G
authors: http://orcid.org/0000-0003-1708-0265
authors: MG
authors: Kees
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D002443:Ceftriaxone / Q000008:administration & dosage / Q000097:blood* / Q000627:therapeutic use; D003198:Computer Simulation; D016638:Critical Illness / Q000628:therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D012709:Serum Albumin; D002443:Ceftriaxone
keywords: HPLC; albumin; cystatin C; dosing; pharmacodynamics; ultrafiltration