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  • Use of Aerosolized Antibiotics in Patients With Cystic Fibrosis: Inhalation Toxicology

How Should Patients Receiving Aerosolized Antibiotics Be Monitored?
Background: Toxicology of Aerosolized Antibiotics
Although numerous antibiotics have been studied as inhaled antibiotics, with few exceptions, the safety profiles of these drugs as delivered by aerosol are largely unknown. The potential for systemic exposure is great because the surface area of the lung far exceeds the surface area of the skin or GI tract. Long-term consequences of administering high doses of drug may be related to drug-specific toxic-ities, nonspecific irritation to the airways, and preservatives in the dosing formulations.
Inhalation Toxicology for Tobramycin in Rats and Guinea Pigs: Three inhalation toxicology studies of preservative-free aerosolized tobramycin were conducted in rats and guinea pigs at 3 to 109 times the estimated clinical dose in humans, for as long as 2 years, to evaluate the local effects on the respiratory tract. This was assessed mainly by histopathology and monitoring systemic exposure. These studies demonstrated that preservative-free tobramycin has a high safety margin with no irreversible toxicity observed at 12 times the intended human dose. birth control

The predominant exposure-related change in the respiratory tract was the appearance of minimal to moderate microscopic lesions in the larynx and lungs of animals treated with multiples > 12 times the human clinical dose. These changes are typical of aerosols and are considered adaptive responses to nonspecific irritation from treatments with high concentration aerosols. Many of the lesions resolved during the 4-week recovery period, which supports the 28-day on/off dosing regimen proposed for preservative-free tobramycin.
Background: Safety Evaluation of Aerosolized Antibiotics
Determining the safety of an aerosolized antibiotic requires assessment of patients for both expected and unexpected effects. Expected effects, which are derived from the known toxicities of an agent previously characterized in animals or humans, are generally derived from toxicities associated with the parenteral form of an antibiotic. Thus, the known ototoxicity and nephrotoxicity of tobramycin should be evaluated as well as local effects on airway reactivity. To capture unexpected effects, many diverse end points must be examined and analyzed in a descriptive fashion.

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