Abstrait

Therapeutic efficacy of aerosolized liposome-encapsulated nubiotic against pulmonary Pseudomonas aeruginosa infection

RMK Dale, G Schnell, RJD Zhang and JP Wong

Respiratory tract infection caused by Pseudomonas aeruginosa is one of the major causes of mortality and morbidity in cystic fibrosis patients. However, physicians treating cystic fibrosis patients are confronting the growing problem of multiple-drug resistance in P. aeruginosa. Nubiotics are a novel class of nucleotide-based drugs that have the potential to improve clinical outcome against pulmonary infection by multidrug resistant P. aeruginosa. In this study, therapeutic efficacy of liposome-encapsulated nubiotic (Nu-3, a protonated deoxyribonucleotide-based antibiotic) was evaluated using a rat model of pulmonary P. aeruginosa infection. Nu-3 was loaded into small unilamellar vesicles using a remote loading procedure. Groups of Sprague–Dewley rats were infected intratracheally with cystic fibrosis strains of P. aeruginosa, which were enmeshed in agar beads (2–10 × 106 enmeshed bacteria/animal). At 2 weeks postinfection, the infected rats were treated with a single-exposure dose of liposome-encapsulated Nu-3 or phosphate-buffered saline, given either by intratracheal administration (150 μl of 2600 A/ml) or by aerosol inhalation using nebulization (50-min exposure, nebulized volume 16 ml of 1300 A/ml). At 4 days post-treatment, the rats were euthanized and the lungs were aseptically harvested, homogenized and cultured for P. aeruginosa. Intratracheal administration of liposome-encapsulated Nu-3 showed a modest approximately 1–2 log10 reduction of colony-forming units in the treated group compared with untreated controls. Treatment with a single aerosol exposure of liposome-encapsulated Nu-3 resulted in complete eradication of P. aeruginosa from the lung homogenates of 67% of the treated rats, while the other 33% showed significant colony-forming unit reductions compared with the phosphate-buffered saline-treated group (p < 0.05). In a parallel study, aerosolized liposome-encapsulated Nu-3 resulted in complete eradication in 90% of the mice infected with a ciprofloxacin-resistant strain of P. aeruginosa (p < 0.05). These results suggest that aerosolized liposome-encapsulated Nu-3 may represent a promising therapy for chronic pulmonary P. aeruginosa infection.