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

• Published in: Journal of antimicrobial chemotherapy Vol. 52; no. 2; pp. 247 - 252
• Main Authors: Marier, J. F., Brazier, J. L., Lavigne, J., Ducharme, M. P.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-08-2003; Oxford Publishing Limited (England)
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; efficacy; Injections, Spinal; liposomal tobramycin; Liposomes; Lung - drug effects; Lung - metabolism; Lung - microbiology; Male; Medical sciences; P. aeruginosa; pharmacokinetics; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - metabolism; Rats; Rats, Sprague-Dawley; Respiratory Tract Infections - drug therapy; Respiratory Tract Infections - metabolism; Respiratory Tract Infections - microbiology; Tobramycin - administration & dosage; Tobramycin - pharmacokinetics; Pseudomonadales; Rat; Lung; Multiple dose; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Lung disease; Respiratory disease; Treatment efficiency; Rodentia; Single dose; Liposome; Infection; Antibiotic; Vertebrata; Chemotherapy; Mammalia; Treatment; Aminoglycoside; Animal; Bacteriosis; Dosage form; Tobramycin; Antibacterial agent; Pharmacokinetics; Intratracheal administration
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkg317

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 P. 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 falling 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.