title: Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock.
abstract: BACKGROUND
  It has been proposed that doses of amikacin of >15 mg/kg should be used in conditions associated with an increased volume of distribution (Vd), such as severe sepsis and septic shock. The primary aim of this study was to determine whether 25 mg/kg (total body weight) of amikacin is an adequate loading dose for these patients.
  
  
  METHODS
  This was an open, prospective, multicenter study in four Belgian intensive care units (ICUs). All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom amikacin treatment was indicated, were included in the study.
  
  
  RESULTS
  In 74 patients, serum samples were collected before (t = 0 h) and 1 hour (peak), 1 hour 30 minutes, 4 hours 30 minutes, 8 hours, and 24 hours after the first dose of amikacin. Blood amikacin levels were measured by using a validated fluorescence polarization immunoassay method, and an open two-compartment model with first-order elimination was fitted to concentrations-versus-time data for amikacin (WinNonlin). In 52 (70%) patients, peak serum concentrations were >64 microg/ml, which corresponds to 8 times the clinical minimal inhibitory concentration (MIC) breakpoints defined by EUCAST for Enterobacteriaceae and Pseudomonas aeruginosa (S<8, R>16 microg/ml). Vd was 0.41 (0.29 to 0.51) L/kg; elimination half-life, 4.6 (3.2 to 7.8) hours; and total clearance, 1.98 (1.28 to 3.54) ml/min/kg. No correlation was found between the amikacin peak and any clinical or hemodynamic variable.
  
  
  CONCLUSIONS
  As patients with severe sepsis and septic shock have an increased Vd, a first dose of >or= 25 mg/kg (total body weight) of amikacin is required to reach therapeutic peak concentrations. However, even with this higher amikacin dose, the peak concentration remained below therapeutic target levels in about one third of these patients. Optimizing aminoglycoside therapy should be achieved by tight serum-concentration monitoring because of the wide interindividual variability of pharmacokinetic abnormalities.
authors.affiliation: Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, Bruxelles, Belgium. ftaccone@ulb.ac.be
authors.forename: Fabio Silvio
authors.initials: FS
authors.lastname: Taccone
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: Brice
authors.initials: B
authors.lastname: Layeux
authors.forename: Daniel
authors.initials: D
authors.lastname: De Backer
authors.forename: Xavier
authors.initials: X
authors.lastname: Wittebole
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: D000368:Aged; D000583:Amikacin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D001530:Belgium; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012720:Severity of Illness Index; D012772:Shock, Septic / Q000503:physiopathology*
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin