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Background: Direct aerosol delivery of aminoglycosides such as tobramycin to the lower airways of patients with cystic fibrosis may control infection with Pseudomonas aeruginosa and improve pulmonary function, with low systemic toxicity. We conducted a randomized crossover study to evaluate the safety and efficacy of aerosolized tobramycin in patients with cystic fibrosis and P. aeruginosa infections., Methods: Seventy-one patients with stable pulmonary status were recruited from seven U.S. centers for the treatment of cystic fibrosis and randomly assigned to one of two crossover regimens. Group 1 received 600 mg of aerosolized tobramycin for 28 days, followed by half-strength physiologic saline (placebo) for two 28-day period. Group 2 received placebo for 28 days, followed by tobramycin for two 28-day periods. Pulmonary function, the density of P. aeruginosa in sputum, ototoxicity, nephrotoxicity, and the emergence of tobramycin-resistant P. aeruginosa were monitored., Results: In the first 28-day period, treatment with tobramycin was associated with an increase in the percentage of the value predicted for forced expiratory volume in one second (9.7 percentage points higher than the value for placebo; P < 0.001), forced vital capacity (6.2 percentage points higher than the value for placebo; P = 0.014), and forced expiratory flow at the midportion of the vital capacity (13.0 percentage points higher than the value for placebo; P < 0.001). A decrease in the density of P. aeruginosa in sputum by a factor of 100 (P < 0.001) was found during all periods of tobramycin administration. Neither ototoxicity nor nephrotoxicity was detected. The frequency of the emergence of tobramycin-resistant bacteria was similar during both tobramycin and placebo administration., Conclusions: The short-term aerosol administration of a high dose of tobramycin in patients with clinically stable cystic fibrosis is an efficacious and safe treatment for endobronchial infection with P. aeruginosa.