pa-824 and Latent-Tuberculosis

The bicyclic nitroimidazole-like molecule PA-824 has activity both against replicating and hypoxic non-replicating Mycobacterium tuberculosis, raising the possibility that it may have a role in the treatment of latent tuberculosis infection (LTBI). This study aimed to examine the bactericidal and sterilising activities of PA-824 against LTBI in C3HeB/FeJ mice, which develop hypoxic, necrotic granulomas histologically resembling their human counterparts. Female 5-6-week-old C3HeB/FeJ mice were immunised via the aerosol route with a recombinant BCG strain overexpressing the 30-kDa major secretory protein (rBCG30) and were aerosol-infected 6 weeks later with virulent M. tuberculosis H37Rv. Six weeks after M. tuberculosis infection, separate groups of mice were left untreated (negative controls) or were treated with either rifampicin, isoniazid (INH) or PA-824. Culture-positive relapse was assessed in subgroups of mice after 2 months and 4 months of treatment. Human-equivalent doses of PA-824 given five times weekly showed similar bactericidal activity as INH at Months 1, 2 and 4 of treatment, and 15/15 mice treated with either PA-824 or INH showed lung-culture relapse 3 months after completion of treatment. To the best of our knowledge, this is the first report examining the sterilising activity of PA-824 in an animal model of LTBI. This model may be useful for screening the efficacy of novel drugs against LTBI, particularly those with specific activity against bacilli residing within necrotic lung granulomas.

Topics: Animals; Antitubercular Agents; Disease Models, Animal; Female; Isoniazid; Latent Tuberculosis; Lung; Mice; Mice, Inbred C3H; Mycobacterium tuberculosis; Nitroimidazoles; Rifampin

Novel treatments for multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), or latent TB are needed urgently. Recently, we reported the formulation and characterization of the nitroimidazo-oxazine PA-824 for efficient aerosol delivery as dry powder porous particles and the subsequent disposition in guinea pigs after pulmonary administration. The objective of the present study was to evaluate the effects of these PA-824 therapeutic aerosols on the extent of TB infection in the low-inoculum aerosol infection guinea pig model. Four weeks after infection by the pulmonary route, animals received daily treatment for 4 weeks of either a high or a low dose of PA-824 dry powder aerosol. Animals received PA-824 cyclodextrin/lecithin suspensions orally as positive controls, and those receiving placebo particles or no treatment were negative controls. The lungs and spleens of animals receiving the high dose of inhaled PA-824 particles exhibited a lower degree of inflammation (indicated by wet tissue weights), bacterial burden, and tissue damage (indicated by histopathology) than those of untreated or placebo animals. Treatment with oral PA-824 cyclodextrin/lecithin suspension resulted in a more significant reduction in the bacterial burden of lungs and spleen, consistent with a dose that was larger than inhaled doses (eight times the inhaled low dose and four times the inhaled high dose). However, histopathological analysis revealed that the extent of tissue damage was comparable in groups receiving the oral or either inhaled dose. The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB.

Topics: Administration, Inhalation; Administration, Oral; Aerosols; Animals; Antitubercular Agents; Chemistry, Pharmaceutical; Colony Count, Microbial; Disease Models, Animal; Extensively Drug-Resistant Tuberculosis; Guinea Pigs; Humans; Latent Tuberculosis; Lung; Male; Nitroimidazoles; Particle Size; Powders; Spleen; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary