title: Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy.
abstract: Data on the optimal amikacin regimen during continuous renal replacement therapy (CRRT) are scarce and the proposed loading dose of 10mg/kg may result in inadequate drug levels. The aim of this study was to describe the pharmacokinetics of a 25 mg/kg first dose of amikacin in septic shock patients treated with CRRT. Serum samples were collected before (t=0 h) and at 1 (peak), 1.5, 4.5, 8 and 24 h after a 30-min amikacin infusion in 13 consecutive patients treated with a combination of amikacin and β-lactam. Blood amikacin levels were measured using a validated fluorescence polarisation immunoassay method. In 9 patients (69%) the peak concentration was >64 mg/L, which corresponds to eight times the minimal inhibitory concentration breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Enterobacteriaceae and Pseudomonas aeruginosa (susceptible <8 mg/L, resistant >16 mg/L). The median (range) total volume of distribution was 0.50 L/kg (0.22-4.05 L/kg), the elimination half-life was 6.5h (4.5-279.6h) and total drug clearance (CL) was 1.26 mL/min/kg (0.1-3.30 mL/min/kg). Only three patients had drug concentrations at 24h (C(min)) of <5mg/L and the median predicted time needed to reach this value was 34 h (14-76 h). There was no correlation between CRRT parameters and C(min), CL or the time to C(min)<5mg/L. In septic shock patients treated with CRRT, a first dose of ≥ 25 mg/kg amikacin is therefore required to reach therapeutic peak concentrations. However, as drug clearance is reduced, amikacin concentrations remained above the threshold of renal toxicity at 24h. The therapeutic benefit of high-dose aminoglycoside therapy should be balanced with its potential renal effects in septic patients receiving CRRT.
authors.affiliation: Department of Intensive Care, Erasme Hospital, Brussels, Belgium.
authors.forename: Fabio Silvio
authors.initials: FS
authors.lastname: Taccone
authors.forename: Daniel
authors.initials: D
authors.lastname: de Backer
authors.forename: Pierre-François
authors.initials: PF
authors.lastname: Laterre
authors.forename: Herbert
authors.initials: H
authors.lastname: Spapen
authors.forename: Thierry
authors.initials: T
authors.lastname: Dugernier
authors.forename: Isabelle
authors.initials: I
authors.lastname: Delattre
authors.forename: Pierre
authors.initials: P
authors.lastname: Wallemacq
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vincent
authors.forename: Frédérique
authors.initials: F
authors.lastname: Jacobs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004755:Enterobacteriaceae / Q000187:drug effects; D005260:Female; D016231:Fluorescence Polarization Immunoassay / Q000379:methods; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D017582:Renal Replacement Therapy; D012772:Shock, Septic / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin