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

C uring drug-sensitive tuberculosis (TB) takes 6 to 9 months of combination therapy despite the availability of antibiotics with potent in vitro activity, yet other pulmonary infectious diseases can be cured with single drugs that have similar mechanisms of action with only 3 to 14 days of treatment. One hypothesis used to explain the extended duration required with TB therapy is that subpopulations of bacteria become phenotypically drug tolerant in response to specific local microenvironmental conditions determined by the pathology of individual lesions (37). Understanding the features of these microenvironments and the conditions that generate tolerance may allow a rational design of drug regimens capable of shortening the time required to achieve a durable TB cure, but the methods used to evaluate new regimens have changed little and rely heavily on murine models of tuberculosis that typically have less complex lung pathology than human lesions. Premature discontinuation of treatment in humans results in disease relapse and the presence of cavities, and advanced lung pathology is strongly correlated with relapse (7,19,23). Only the rabbit and nonhuman primate models of pulmonary tuberculosis develop similar heterogeneous pathology, including the formation of cavitary disease. Guinea pigs, and some newer mouse models, develop more highly organized lesions, but these do not progress to cavities (for a comprehensive review of the comparative pathology of tuberculosis animal models, see reference 2).Nonterminal monitoring procedures, such as live imaging modalities, are increasingly being applied during TB drug efficacy experiments in animals and in human clinical trials (12,32,40,52). Structural and/or functional features observed in imaging modalities such as computed tomography (CT) and positron emission tomography (PET) are particularly attractive because they can be measured serially in a single subject at many time points during treatment. Computed tomography (CT) can add highly detailed information to the characteristic features of pulmonary tuberculosis visualized using conventional chest X-rays (1). CT scanning is typically used to monitor patients, assist in diagnosis, and assess surgical options for drug-resistant cases of disease (26), but there have been few examinations of the rate of change in CT findings during chemotherapy. The most detailed study of TB chemotherapy in patients (25) examined high-resolution CT scans from patients undergoing TB chemotherapy for up to 20 months. Old fibrotic lesions could be distinguished from active lesions, and criteria for the state of metabolic activity of lesions were proposed. However, that study did not sequentially

Early Changes by 18 Fluorodeoxyglucose Positron Emission Tomography Coregistered with Computed Tomography Predict Outcome after Mycobacterium tuberculosis Infection in Cynomolgus Macaques

“…This phenomenon was also seen during low-dose infection among both active-disease and latent animals. We and others reported a loose correlation between bacterial burden and SUV and size of individual granulomas in active TB and latently infected animals at necropsy (3,14). This range of lesional dynamics within the same host, and even lung lobe, likely accounts for the variety of granuloma types seen in our model and in humans (5,15).…”

“…A region of interest was drawn on the PET image in the axial view to measure metabolic activity (FDG avidity) by SUV (standard uptake volume ratio adjusted by size and normalized to muscle to reduce the variability between scans) as described previously (4). Scans were performed at baseline and 3,6,8,12,16,20, and 24 weeks postinfection. All CT/PET measurements were made by the same imaging analyst (M. T. Coleman).…”

“…Tuberculous lesions can be detected by 18 F-fluorodeoxyglucose with positron emission tomography coregistered with computed tomography (FDG PET/CT) in several animal models of tuberculosis, including the nonhuman primate, although this has mostly been reported in the context of drug efficacy studies (2)(3)(4). The use of PET/CT facilitates real-time, serial in vivo assessments of disease progression without the need for sacrificing experimental animals.…”

Radiologic Responses in Cynomolgus Macaques for Assessing Tuberculosis Chemotherapy Regimens

“…In our previous studies in a rabbit model, the increase in FDG avidity in INH-treated animals was not observed at 4 weeks of treatment. There was a significant decrease in the SUVR in individual lesions at as early as 1 week and also by 2 months of treatment (19). The macaque develops a variety of lesion types, and it may be that some granuloma types respond to INH more quickly than other lesion types and these lesion types are more prominent in rabbits.…”

“…More recently, small pilot studies have been conducted to determine whether this method might be feasible in humans undergoing TB treatment (14)(15)(16), although validation data are limited. PET-CT has also been used in experimental animal models (e.g., mice and rabbits) to identify tuberculous disease and monitor the treatment response (17)(18)(19).…”