The hallmark of cystic fibrosis (CF), and the cause of death in over 90% of patients, is progressive pulmonary disease. Pseudomonas aeruginosa (Pa) is the most significant pathogen in CF lung disease. Over 80% of CF patients eventually become colonized with Pa. Recent studies in infants and young children with CF have demonstrated that Pa colonization begins far earlier than previously recognized, often before the onset of symptoms. There is growing recognitiion of the need to target therapy to young children before irreversible lung damage has occurred. There have been no published studies of treatment with antipseudomonal agents in infants or very young children. Antipseudomonal therapy in early childhood could potentially delay the progressive obstructive lung disease that is the major cause of morbidity and mortality at all ages in patients with CF. The standard therapy for Pa endobronchial infections is 14 to 21 days of parenteral antipseudomonal antibiotics, typically including an aminoglycoside. parenteral aminoglycosides, penetrate poorly into the endobronchial space. Local concentrations 10-to 25-fold the minimal inhibitory concentration (MIC) are required to overcome sputum antagonism of aminoglycoside bioavailability. To obtain adequate drug concentrations at the site of infection with parenteral administration, serum levels approaching those associated with nephro-, vestibulo-, and ototoxicity are required. Aerosolized administration of aminoglycosides offers an attractive alternative, delivering high concentrations of antibiotic directly to the site of infection in the endobronchial space while minimizing systemic bioavailability. Tobramycin is a logical choice for a prototypical aerosolized antibiotic in young children, as its safety and efficacy in older subjects is the most thoroughly documented of all inhaled antibiotics. The primary objectives of this study are: 1) To determine the lower respiratory tract (ELF) tobramycin concentration [T] produced after completion of a single 300 mg dose of inhaled tobramycin. 2) To determine the proportion of subjects in whom ELF [T] is at least 10-fold greater than the tobramycin MIC90(2 ug/mL) for this age range. 3) To determine whether a single 300 mg dose of inhaled tobramycin delivered by jet nebulizer is safe and well tolerated in young children with CF. 4) To determine the association between peak serum [T] and ELF [T]. 5) To measure the apparent concentration of bioactive tobramycin in BAL fluid after completion of a single 300 mg dose of inhaled tobramycin, using a bioassay of antipseudomonal activity. This is a multicenter study designed to study a total of 12 children with CF who are >6 months and <6 years of age. A single 300 mg dose of inhaled tobramycin will be administered by Pari LC Plus jet nebulizer and PulmoAide compressor, using a facemask. Bronchoalveolar lavage (BAL) fluid will be obtained by flexible bronchoscopy. Bacterial cultures of BAL fluid will be performed for clinical purposes. Serum will be obtained for [T] at 30, 60, and 120 minutes after initiation of the dose. Subjects will be monitored for clinical evidence of acute bronchospasm or respiratory distress.
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