Aerosol Therapy in Cystic Fibrosis: DNase, Tobramycin

Recurrent and chronic endobronchial infections are the major cause of morbidity and mortality in patients with cystic fibrosis (CF), with Pseudomonas aeruginosa being a significant pathogen contributing to progressive obstructive airway disease. Antipseudomonal therapy has been delivered intravenously, inhaled, and more recently by mouth with the development of the quinolone derivatives. Patients receive intravenous therapy most commonly when they are experiencing an exacerbation of pulmonary symptoms. Patients require relatively high doses of intravenous aminoglycosides to reach adequate concentration, in part due to these patients' increased clearance of antibiotics and in part because these drugs penetrate endobronchial secretions poorly. Associated with these higher required doses are concerns of nephrotoxity and ototoxicity. Intravenous therapy may require a prolonged hospital stay at great financial and emotional expense to the patient and family. As an alternative to in-hospital intravenous therapy, many centers have set up home intravenous programs for the medically stable patient with good venous access. The fluoroquinolones, including ciprofloxacin, norfloxacin, and ofloxacin, have excellent oral absorption, are effective against P. aeruginosa, and are widely used in adults with cystic fibrosis. However, these oral antibiotics have not been approved for use in prepubescent children in the United States, due to the potential risk of arthropathy. In light of the considerations, inhaled aminoglycosides are increasingly promising as a means by which to deliver antibiotics in high concentration to the site of infection, while decreasing the risk of systemic absorption and toxicity. Multiple studies have been done in the past decade in an attempt to document safety and efficacy of these inhaled agents. Hodson et al performed a randomized double-blind crossover trial in which 20 patients with CF received 6 months of treatment with aerosolized carbenicillin and gentamicin and 6 months of treatment with placebo. With aerosolized antibiotics, patients experienced subjective improvement in symptoms, objective improvement in lung function as measured by forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and peak expiratory flow rate (PEFR), and decreased frequency of acute hospital admissions (although this finding was not statistically significant due to small patient numbers). Steinkamp et al studied 14 patients with CF who received tobramycin aerosol therapy (80 mg/dose) for up to 38 months in an open, noncontrolled study. Compared to the year prior to the study, patients had a lower frequency of hospital admissions. The clinical benefit, including improved weight gain and growth, appeared to be better in moderately ill patients; patients with mild or severe disease had less response. No ototoxicity, nephrotoxicity, or topical side effects were found. MacLusky et al studied 28 patients with CF assigned alternately to an aerosol tobramycin (80 mg) or control (2 mL of saline) group. Patients were followed over a mean duration of 32 months. The rate of decline of FVC, FEV1, and forced expiratory flow between 25 and 75% vital capacity (FEF25-75%) was significantly less in the treatment group compared with the control group. Although there appeared to be decreased frequency and duration of hospitalization in the treatment group, the difference was not significant. There was no ototoxicity nor nephrotoxicity reported. Smith et al studied 22 patients with CF