Capreomycin is used for the treatment of
multidrug-resistant tuberculosis (MDR-TB), but it is limited therapeutically by its severe side effects. The objectives of the present studies were (i) to design low-density porous
capreomycin sulfate particles for efficient pulmonary delivery to improve local and systemic
drug bioavailability and capacity to reduce the bacillary load in the lungs in a manner similar to that achieved with
intramuscular injections; (ii) to determine pharmacokinetic parameters after pulmonary administration of these
capreomycin particles; and (iii) to evaluate the efficacy of these particles in treating animals in a small-
aerosol-inoculum guinea pig model of TB.
Capreomycin particles were manufactured by spray drying and characterized in terms of size and
drug content. Pharmacokinetic parameters were determined by noncompartmental methods with healthy guinea pigs after administration of
capreomycin particles by insufflation. The efficacy of the particles was evaluated by histopathological analysis and in terms of wet organ weight and bacterial burden in TB-infected animals. Lungs of animals receiving a 14.5-mg/kg dose of
capreomycin particles showed significantly lower wet weights and smaller bacterial burdens than those of animals receiving any other treatment. These results were supported by histopathological analysis. The feasibility of inhaling
capreomycin in a novel
powder form, with the ultimate objective of the treatment of MDR-TB, is demonstrated by pharmacokinetic and pharmacodynamic studies with guinea pigs. If applied to humans with MDR-TB, such a therapeutic approach might simplify
drug delivery by eliminating
injections and might reduce adverse effects through lowering the dose.