There is a growing interest in early intervention in CF pulmonary disease, with the goal of delaying or preventing irreversible lung damage. Aerosolized antibiotics are an attractive potential therapy, theoretically providing high airway concentrations while minimizing the risk of systemic toxicity. The first step in adapting an inhaled antibiotic to the youngest age range is determination of an optimal dose. The objective of the proposed research is to formulate doses of inhaled antibiotics that produced lower airway concentrations adequate to kill bacteria (effective) while minimizing systemic absorption (safe). The applicant proposes a logical series of investigations to arrive at this dose. First, the antibiotic concentration necessary for effective bacterial killing in CF sputum, which is known to inhibit antibiotic bioactivity, will be determined. Next, the applicant will ascertain whether this target antibiotic concentration is achieved in the lower respiratory tract secretions of young children after aerosol dosing. Lastly, the pharmacokinetics of the inhaled antibiotic will be determined, as a measure of toxicity due to systemic absorption. Through these aims, the proposed research will attempt to develop an integrated systems model for the rational dosing of inhaled antibiotics in very young children. The initial development of proposed model will be conducted utilizing aerosolized tobramycin, which has been shown to be safe and effective in the treatment of CF patients over six years of age and was recently licensed for use by the FDA. The methodologies will then be further developed and refined by applying them to the study of polymyxin E1, a promising alternative inhaled agent currently in pre-clinical development. The goal of this two-phase development is to yield model systems applicable to the study of a broad variety of inhaled agents. The results and experience gained by the proposed studies may aid in the rigorous conduct of future clinical trials of inhaled agents in infants both with and without CF.
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| Kulich, Michal; Rosenfeld, Margaret; Goss, Christopher H et al. (2003) Improved survival among young patients with cystic fibrosis. J Pediatr 142:631-6 |
| Mayer-Hamblett, Nicole; Rosenfeld, Margaret; Emerson, Julia et al. (2002) Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med 166:1550-5 |
