Despite controversies associated with forms and value of antibiotic therapy for cystic fibrosis patients, antibiotherapy remains a cornerstone in the management of those patients. Locally administered liposome-encapsulated antibiotics may offer advantages over free antibiotics, including sustained concentration of the antibiotic, minimal systemic absorption, reduced toxicity, and increased efficacy. We evaluated the efficacy of free and encapsulated tobramycin in fluid and rigid liposomal formulations administered to rats chronically infected with Pseudomonas aeruginosa. Chronic infection in lungs was established by intratracheal administration of 10(5) CFU of a mucoid variant of P. aeruginosa PA 508 prepared in agar beads. Antibiotic treatments were given intratracheally at time intervals of 16 h. After the last treatment, lung bacterial counts were determined and tobramycin levels in the lungs and kidneys were evaluated by high-performance liquid chromatographic analysis and microbiological assay. Two independent experiments showed that animals treated with encapsulated tobramycin in fluid liposomes had a number of CFU less than the minimal CFU number required to be statistically acceptable compared with > or = 10(6) CFU per pair of lungs for animals treated with encapsulated tobramycin in rigid liposomes, free antibiotic, or liposomes without tobramycin. Tobramycin measured in the lungs at 16 h after the last treatment following the administration of encapsulated antibiotic was still active, and its concentration was > or = 27 micrograms/mg of tissue. Low levels of tobramycin were detected in the kidneys (0.59 to 0.87 micrograms/mg of tissue) after the administration of encapsulated antibiotic, while 5.31 micrograms/mg of tissue was detected in the kidneys following the administration of free antibiotic. These results suggest that the local administration of fluid liposomes with encapsulated tobramycin could greatly improve the management of chronic pulmonary infection in cystic fibrosis patients.

In previous in-vivo studies, we demonstrated that liposomal entrapment of tobramycin resulted in an increased availability of the antibiotic in the lungs without increasing bactericidal efficacy (Omri et al. 1994). With the aim of developing liposomal formulations allowing more efficient liposome-bacteria interactions, we studied the influence of lipid composition on both drug release and pulmonary retention of encapsulated tobramycin. The phase transition temperatures of nine liposome-tobramycin formulations consisting of two synthetic phospholipids (distearoyl phosphatidylcholine (DPSC) or dipalmitoyl phosphatidylcholine (DPPC) with dimyristoyl phosphatidyl-glycerol (DPMG) or dimyristoyl phosphatidylcholine (DMPC) were determined by differential scanning calorimetry. Liposomes, varying in terms of membrane fluidity and charge were submitted to in-vitro and in-vivo kinetic studies while retention and release of tobramycin were measured by high-performance liquid chromatography (HPLC). Five less fluid liposome formulations showed absence or very low tobramycin release in in-vitro tests and long term pulmonary retention of tobramycin. Four fluid liposome formulations showed in vitro tests modulated tobramycin release while pulmonary retention of tobramycin was dependent of the presence of charged phospholipids. Administration of charged fluid liposomes in mice showed a low level of tobramycin in the kidneys; non-charged fluid liposomes exhibited a relatively high level of tobramycin retention in the kidneys.