Liposomal tobramycin against pulmonary infections of Pseudomonas aeruginosa: A pharmacokinetic and efficacy study following single and multiple intratracheal administrations in rats

Abstract

Objective: To determine the pharmacokinetics and efficacy of tobramycin against pulmonary infections of Pseudomonas aeruginosa in rats after intratracheal administration of conventional and liposomal formulations. Methods: Male Sprague-Dawley rats were inoculated with 106 cfu of a mucoid variant of A aeruginosa (MIC of tobramycin for PA 508 = 1 mg/L) and tobramycin (conventional or liposomal formulations) was administered in single (490 μg) and multiple dose (490 μg during 4 days) experiments. Rats were killed at multiple time points to determine the residual cfu of P. aeruginosa and tobramycin amounts in lungs. Pharmacokinetic parameters were calculated using a two-compartment model with NONMEM. Results: Mean (±S.D.) elimination half-life (t1/2β) and pulmonary exposure (AUC) of the conventional formulation were 14.0±4.0 h and 663±89 μg ·h/lungs, respectively. The pharmacokinetic profile of liposomal tobramycin was markedly different, with a longer t1/2β (34.4±5 h, P < 0.05), resulting in an increased AUC (3890 ±560 μg·h/lungs, P < 0.05). χ2 analyses were carried out on cfu data distributed in the following categories: below 103, 103-105, and above 105 cfu. In the single dose experiments, approximately 90% of the observations were above 105 cfu for both formulations. Significant differences in cfu distribution were observed after multiple treatments, with approximately 10% of the observations failing below 103 cfu of P. aeruginosa for the conventional formulation versus 30% for the liposomal formulation. Conclusion: The liposomal formulation of tobramycin promoted drug retention in lungs and improved its efficacy after multiple treatments.