Current tools for monitoring response to tuberculosis treatments have several limitations. Noninvasive biomarkers could accelerate tuberculosis drug development and clinical studies, but to date little progress has been made in developing new imaging technologies for this application. In this study, we developed pulmonary single-photon emission computed tomography (SPECT) using radioiodinated DPA-713 to serially monitor the activity of tuberculosis treatments in live mice, which develop necrotic granulomas and cavitary lesions. C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered either a standard or a highly active bedaquiline-containing drug regimen.
Recognizing that tuberculosis (TB) is still a leading cause of human death from a curable disease, the international health community has set an ambitious target to eliminate TB by 2050. However, using mathematical modeling, Dye and Williams at the World Health Organization have shown that while most TB patients can be cured with current drug treatments, the 2050 target cannot be achieved with current tools and requires a combination of new diagnostics, shorter TB drug treatments, and new vaccines (1). However, current tools for evaluating TB therapeutics have several limitations. Conventional preclinical studies are limited to analysis of serial postmortem samples using microbiologic methods that take 3 to 4 weeks for results. Moreover, different groups of animals are sacrificed over several time points during the study, and therefore, assessments of disease in the same animal can never be made. Similar limitations exist for monitoring TB treatments in humans. The standard 8-week sputum culture conversion is not available in real time, taking several weeks for results. Even though nucleic acid amplification tests such as GeneXpert provide results rapidly (2), both sputum culture and GeneXpert are subject to sampling bias and provide information only about the lesions communicating with the airways. Noncommunicating pulmonary or extrapulmonary lesions are often never assessed. Similarly, assessment for relapse can require monitoring hundreds of patients for up to 2 years after treatment completion. With increasing rates of multidrug-resistant, extensively drug-resistant, and totally drug-resistant TB (3, 4), it is imperative to develop even better tools to monitor treatment responses and predict relapse.Noninvasive imaging provides rapid, three-dimensional views of the whole body, as well as the ability to monitor disease in the same individual. Real-time, longitudinal assessments can also provide new insights into the pathophysiology of disease, which may be difficult to assess with current technologies. Computed tomography (CT) and 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET) are being increasingly used to monitor TB (5-8), in both preclinical and clinical settings. However, both CT and 18 F-FDG PET lack specificity, and 18 F-FDG is taken up by all glycolytically active tissues (9-11). Since activated m...