Infection Dynamics and Response to Chemotherapy in a Rabbit Model of Tuberculosis using [ 18 F]2-Fluoro-Deoxy- d -Glucose Positron Emission Tomography and Computed Tomography

Abstract

With a host of new antitubercular chemotherapeutics in development, methods to assess the activity of these agents beyond mouse efficacy are needed to prioritize combinations for clinical trials. Lesions in Mycobacterium tuberculosis -infected rabbits are hypoxic, with histopathologic features that closely resemble those of human tuberculous lesions. Using [ ¹⁸ F]2-fluoro-deoxy- d -glucose ([ ¹⁸ F]FDG) positron emission tomography–computed tomography (PET-CT) imaging, we studied the dynamics of tuberculosis infection in rabbits, revealing an initial inflammatory response followed by a consolidative chronic disease. Five weeks after infection, as much as 23% of total lung volume was abnormal, but this was contained and to some extent reversed naturally by 9 weeks. During development of this chronic state, individual lesions in the same animal had very different fates, ranging from complete resolution to significant progression. Lesions that remained through the initial stage showed an increase in volume and tissue density over time by CT. Initiation of chemotherapy using either isoniazid (INH) or rifampin (RIF) during chronic infection reduced bacterial load with quantitative changes in [ ¹⁸ F]FDG uptake, lesion density and total lesion volume measured by CT. The [ ¹⁸ F]FDG PET uptake in lesions was significantly reduced with as little as 1 week of treatment, while the volume and density of lesions changed more slowly. The results from this study suggest that rabbits may be a useful surrogate species for evaluating novel chemotherapies and understanding changes in both PET and CT scans in human clinical trials.