INHALED TOBRAMYCIN IN YOUNG CYSTIC FIBROSIS PATIENTS

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The purpose of this proposal is to determine the short-term microbiologic efficacy and safety of an inhaled antibiotic, tobramycin solution for inhalation (TOBI), in infants and young children with cystic fibrosis (CF) and documented Pseudomonas aeruginosa (Pa) lower airway infection. Because initial colonization with Pa can occur in the first 5 years of life, there is growing interest in investigating anti-pseudomonal therapies in very young children with the long-term goal of delaying or preventing chronic infection that contributes to irreversible lung disease. To test anti- infective therapies in this age group, there is a need to assay the anti- microbial effect by direct lower airway sampling, and to compare these measures with surrogate markers. The current proposal is the first multicenter study of inhaled antibiotics in young children with CF and should serve as a paradigm for future anti-microbial therapeutic trials. TOBI has been selected because it is the only inhaled antibiotic with FDA approval. Although extensive animal toxicity and human safety data are available, no safety or efficacy data have been collected in children less than 6 years of age. Specifically, we hypothesize that administration of TOBI for inhalation twice daily for 28 days to children less than six years of age with CF who are culture positive for Pa in their lower airways will be safe and result in a significant reduction in the mean Pa density in lower airway cultures. Our secondary outcomes will evaluate the effect of antibiotic therapy on lower airway inflammation (cell count, % neutrophils, cytokines, elastase activity), surrogate markers of lower airway microbiology (oropharyngeal cultures, antibodies to Pa exotoxin A), and clinical status (weight gain, modified Shwachman scores, and lung function tests in subjects 3-5 years of age). We propose to conduct a multicenter, double blind, placebo-controlled randomized trial within the seven centers comprising the Cystic Fibrosis Foundation (CFF) funded Therapeutics Development Network (TDN). Ninety eight subjects with bronchoalveolar lavage (BAL) cultures positive for Pa will be randomized to receive TOBI or placebo twice daily for 28 days. At the end of treatment, a BAL will be repeated to quantitate Pa lower airway density. This study will provide valuable microbiologic efficacy and safety data for use of inhaled antibiotics in young children with CF, and will provide important data on surrogate markers of lower airway infection and inflammation.