title: The activity of low-clearance liposomal amikacin in experimental murine tuberculosis.
abstract: Most of the amikacin in low-clearance liposomal amikacin is excreted very slowly, offering the possibility of maintaining effective treatment of pulmonary tuberculosis with widely separated supervised doses. As a preliminary to explorations in humans, its efficacy was assessed in acute experimental murine tuberculosis by weekly counts of viable bacilli in spleen and lungs over a 4 week period. Liposomal amikacin in dosages of 160, 80 and 40 mg/kg given iv three times a week was 2.4-5.0 times more active than free amikacin and 6.6-6.7 times more active than streptomycin with the non-liposomal drugs given im five times a week. When the free amikacin and the streptomycin were also given iv three times a week, liposomal amikacin was 2.7-2.9 times more active than free amikacin and 3.7-5.6 more active than streptomycin. In a model of chronic tuberculosis, initial BCG vaccination was followed by challenge with virulent Mycobacterium tuberculosis and a 2 week stabilization period. Thereafter, treatment with liposomal amikacin 160 and 80 mg/kg three times a week for the first 4 weeks and then once a week for a further 4 weeks, had greater initial bactericidal activity than free amikacin 160 mg/kg five times a week, but had less eventual sterilizing activity than five times a week oral isoniazid 25 mg/kg or rifampicin 15 mg/kg. Although low-clearance liposomes increased the safety, potency and dosing interval of amikacin in these models, all aminoglycosides, including liposomal amikacin, were only bactericidal in the presence of bacillary metabolism and growth.
authors.affiliation: Department of Medical Microbiology, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
authors.forename: J
authors.initials: J
authors.lastname: Dhillon
authors.forename: R
authors.initials: R
authors.lastname: Fielding
authors.forename: J
authors.initials: J
authors.lastname: Adler-Moore
authors.forename: R L
authors.initials: RL
authors.lastname: Goodall
authors.forename: D
authors.initials: D
authors.lastname: Mitchison
mesh_terms: D000583:Amikacin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D008081:Liposomes; D000583:Amikacin