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Chronic pulmonary infections are a significant cause of morbidity and mortality in patients with cystic fibrosis. The traditional approach to managing patients with cystic fibrosis is to treat acute exacerbations with antimicrobial, airway clearance, and nutritional therapies. Advances in the understanding of the pharmacodynamics of antibiotics have led to the development of new dosing strategies to maximize the antibiotics’ activity. Recent data on the use of aerosolized tobramycin as chronic maintenance therapy have demonstrated that it improves pulmonary function significantly and reduces hospitalization days. New insights into the pathogenesis of pulmonary disease have led to the development of novel therapies, including salt-insensitive antimicrobial peptides and rBPI21, as adjunctive therapy to increase the sensitivity of current antibiotics. In addition, macrolide antibiotics are being investigated for their anti-inflammatory effects as chronic maintenance therapy. Until effective therapies are available to correct the basic genetic defect that causes cystic fibrosis, antibacterial and anti-inflammatory agents will continue to be the mainstay of treatment.