Efficacy of combination therapy in the Cynomolgus macaque model

Flynn, Joanne

Abstract

Tuberculosis remains a major threat worldwide, with significant morbidity and mortality. Although drug treatment is available, the regimen is lengthy with drugs that can have toxicity. The emergence of drug resistant strains of Mycobacterium tuberculosis leads to treatment with suboptimal second line therapy. New strategies are necessary for effectively combating tuberculosis. This project is the culmination of the other projects and cores in the Program Project, in that drug regimens identified and tested in smaller animal models and optimized by mathematical modeling will be tested for efficacy in a large animal model. The cynomolgus macaque model is arguably the closest to humans in terms of M. tuberculosis infection outcome, pathology and disease presentation. Our previous work demonstrated the utility of this model in testing drugs against tuberculosis, with similar outcomes in humans and macaques. We combine detailed necropsy and bacterial burden determinations with advanced serial imaging using Positron Emission Tomography and Computed Tomography (PET/CT) to identify successful regimens. Here we will compare two combinations identified, tested and optimized in the other projects and cores, for efficacy against TB in macaques. These combination regimens will be compared separately and sequentially, providing preclinical data that can be used to choose the best regimen to take into human clinical trials.