title: Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia.
abstract: OBJECTIVE
  Modifications of antimicrobials' pharmacokinetic parameters have been reported in critically ill patients, resulting in a risk of treatment failure. We characterized amikacin pharmacokinetic variability in critically ill patients with ventilator-associated pneumonia (VAP) and evaluated several dosing regimens.
  
  
  METHODS
  We conducted a prospective multicenter study in critically ill patients with presumptive diagnosis of Gram-negative bacilli (GNB) VAP. Patients empirically received imipenem and a single-dose of amikacin, which was administered as a 30-min infusion (20 mg/kg). Concentrations were measured 0.5, 1, 8, 16, and 24 h after beginning of infusion. Pharmacokinetic parameters were estimated using a population approach. Main pharmacodynamic target was a ratio ≥ 10 between the concentration achieved 1 h after beginning of infusion (C 1h) and the minimal inhibitory concentration of the liable bacteria (MIC). We simulated individual C 1h for several dosing regimens by Monte Carlo method and computed C 1h/MIC ratios for MICs from 0.5 to 64 mg/L.
  
  
  RESULTS
  Sixty patients (47 males), median (range) age, and body weight, 61.5 years (28-84) and 78 kg (45-126), respectively, were included. Amikacin median C 1h was 45 mg/L (22-87). Mean value (between-patients variability) for CL, V1, Q, and V2 were 4.3 L/h (31 %), 15.9 L (22 %), 12.1 L/h (27 %), and 21.4 L (47 %), respectively. CL increased with CrCL (p<0.001) and V1 with body weight (p<0.001) and PaO2/FIO2 ratio (p<0.001). With a 25 mg/kg regimen, the pharmacodynamic target was achieved in 20 and 96 % for a MICs of 8 and 4 mg/L, respectively.
  
  
  CONCLUSIONS
  Amikacin clearance was decreased and its volume of distribution was increased as previously reported. A ≥ 25 mg/kg single-dose is needed for empirical treatment of GNB-VAP.
authors.affiliation: INSERM, IAME, UMR 1137, 75018, Paris, France, charles.burdet@inserm.fr.
authors.forename: C
authors.initials: C
authors.lastname: Burdet
authors.forename: O
authors.initials: O
authors.lastname: Pajot
authors.forename: C
authors.initials: C
authors.lastname: Couffignal
authors.forename: L
authors.initials: L
authors.lastname: Armand-Lefèvre
authors.forename: A
authors.initials: A
authors.lastname: Foucrier
authors.forename: C
authors.initials: C
authors.lastname: Laouénan
authors.forename: M
authors.initials: M
authors.lastname: Wolff
authors.forename: L
authors.initials: L
authors.lastname: Massias
authors.forename: F
authors.initials: F
authors.lastname: Mentré
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000583:Amikacin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016638:Critical Illness; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D016905:Gram-Negative Bacterial Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D000583:Amikacin