Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects.

摘要

OBJECTIVE: Nebulized amikacin may be an attractive option for the treatment of lung infections. Low systemic absorption may permit the use of high doses, leading to high lung concentrations without systemic toxicity. We evaluated the pharmacokinetics and safety of an optimized high-dose amikacin nebulization technique. DESIGN: in vitro and in vivo pharmacokinetic study. PATIENTS AND PARTICIPANTS: Six healthy volunteers (age 21-30 years, weight 49-68[Symbol: see text]kg). INTERVENTIONS: The Aeroneb Pro nebulizer with an Idehaler vertical spacer was evaluated in a bench study. Amikacin was administered intravenously (15[Symbol: see text]mg/kg) and nebulized (40, 50, and 60[Symbol: see text]mg/kg) during noninvasive pressure-support ventilation through a mouthpiece. MEASUREMENTS AND RESULTS: Median (interquartile range) in vitro inhaled fraction was 31% (30-32) and inhalable output was 681[Symbol: see text]mg/h (630-743). Serum concentrations after nebulization were less than or equal to those after infusion. The area under the serum concentration curve was significantly higher after infusion (138[Symbol: see text]mg[Symbol: see text]h(-1)l(-1), 122-143) than after nebulization (49[Symbol: see text]mg[Symbol: see text]h(-1)l(-1), 39-55, at 40[Symbol: see text]mg/kg; 63, 53-67 at 50; 66, 50-71, at 60). Peak serum concentration was also higher after infusion: 48[Symbol: see text]mg/l (45-49) after infusion compared to 8.2 (5.6-8.7), 9.2 (7.6-10.2), and 9.2 (5.2-10.3), respectively. Mean absorption times after nebulization were 2[Symbol: see text]h 24[Symbol: see text]min (2,07-2,45), 2[Symbol: see text]h 21[Symbol: see text]min (2,07-2,35), and 2[Symbol: see text]h 5[Symbol: see text]min (2,00-2,25), respectively. No side effect was observed. CONCLUSIONS: Nebulization of up to 60[Symbol: see text]mg/kg amikacin appears to be safe in healthy subjects and associated with lower serum concentrations than a 15[Symbol: see text]mg/kg infusion.