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

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 kg). Interventions: The Aeroneb Pro nebulizer with an Idehaler vertical spacer was evaluated in a bench study. Amikacin was administered intravenously (15 mg/kg) and nebulized (40, 50, and 60 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 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 mg h(-1)l(-1), 122-143) than after nebulization (49 mg h(-1)l(-1), 39-55, at 40 mg/kg; 63, 53-67 at 50; 66, 50-71, at 60). Peak serum concentration was also higher after infusion: 48 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 h 24 min (2,07-2,45), 2 h 21 min (2,07-2,35), and 2 h 5 min (2,00-2,25), respectively. No side effect was observed. Conclusions: Nebulization of up to 60 mg/kg amikacin appears to be safe in healthy subjects and associated with lower serum concentrations than a 15 mg/kg infusion.