We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270？mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90？mg/kg and ethambutol (EMB) at 100 to 1000？mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000？mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90？mg/kg, INH 30？mg/kg, EMB 300？mg/kg, and PZA 300？mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development. 1. Introduction Tuberculosis remains a leading cause of death worldwide [1] despite unprecedented interest in the scientific community to better understand the pathobiology and development of newer interventional therapies. In this process, animal models of infection have been a corner stone in understanding complex pathology and immunology of tuberculosis. Guinea pigs were the first animal models used to demonstrate tuberculosis disease by Koch in 1882 [2]. Since then, a variety of animal models including mice, rabbits, and nonhuman primates [3–5] have been investigated to simulate tubercular disease and associated host responses. However, none of the models can mimic the complex pathobiology seen in humans. The mouse continues to be a preferred species for modeling tuberculosis infection as well as for screening novel anti-TB drug candidates due to practical reasons [6, 7]. Guinea pigs, rabbits, and nonhuman primates are known to be better representatives of late human disease [4, 5] but pose a challenge for drug screening due to large compound requirements and prohibitive costs. Rats have significantly contributed to modeling of variety of human pulmonary bacterial [8], fungal [9] and viral infections [10, 11] due to an increasing availability of rat immunological reagents.
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