Journal of Antimicrobial Chemotherapy (2001) 48, 869-876
© 2001 The British Society for Antimicrobial Chemotherapy
The activity of low-clearance liposomal amikacin in experimental murine tuberculosis
a Department of Medical Microbiology, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK; b NeXstar Pharmaceuticals Inc., Boulder, CO 80301, USA; c Medical Research Council Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK
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.
* Corresponding author. Tel: +44-20-8725-5704; Fax: +44-20-8672-0234; E-mail: dmitchis{at}sghms.ac.uk
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  P. R. Donald, F. A. Sirgel, A. Venter, E. Smit, D. P. Parkin, B. W. Van de Wal, and D. A. Mitchison The early bactericidal activity of a low-clearance liposomal amikacin in pulmonary tuberculosis J. Antimicrob. Chemother., December 1, 2001; 48(6): 877 - 880. [Abstract] [Full Text] [PDF]
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