TOBRAMYCIN ACCUMULATION IN THE RESPIRATORY SECRETIONS OF CF PATIENTS WITH REPE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The progressive obstructive pulmonary disease in most patients with cystic fibrosis (CF) is characterized by chronic endobronchial infection with Pseudomonas aeruginosa. Inhaled administration of anti-pseudomonal antibiotics is an attractive therapeutic option because of the ability to deliver high antibiotic concentrations to the site of infection in the endobronchial space while minimizing systemic absorption. The use of aerosolized aminoglycosides in patients with CF has been associated with improvement in lung function, decreased frequency of hospitalizations, and decreased endobronchial burden of Pseudomonas aeruginosa (1,2). Tobramycin solution for inhalation (TSI, TOBI , Chiron Corp., Seattle, WA) is approved by the U.S. Food and Drug Administration for the treatment of chronic Pseudomonas aeruginosa infection in patients with CF. It is generally prescribed for use in alternate monthly cycles, each cycle consisting of 300 mg of TSI twice daily for 28 days, followed by 28 days off therapy. The medication is delivered using a Pari LC Plus jet nebulizer with a Pulmo-aide compressor. This dosing regimen was employed in the pivotal Phase III studies of TOBI (2), and alternative dosing regimens have not been investigated. The objective of the proposed research is to assess whether tobramycin accumulates in the respiratory secretions of CF patients with mild to moderate lung disease with repeated dosing of TSI. This will be the first study to measure sputum tobramycin concentrations associated with repeated administration of TSI. Sputum induction will be utilized in order to non-invasively obtain more distal airway secretions than those produced by expectoration. Tobramycin concentrations will also be measured in expectorated sputum, as sputum expectoration is the standard means by which tobramycin concentrations have been measured in prior studies. The results of this study may lead to exploration of alternative dosing regimens for TSI. If there is evidence of accumulation of tobramycin with repeated dosing in these subjects, future studies may investigate dosing less frequently (e.g., daily) or for a shorter duration than 28 days. This is a prospective pilot study to measure tobramycin concentrations in induced and expectorated sputum at the beginning and end of a 28-day course of TSI, 300 mg twice daily.