Noninvasive Pulmonary [
            <sup>18</sup>
            F]-2-Fluoro-Deoxy-
            <scp>d</scp>
            -Glucose Positron Emission Tomography Correlates with Bactericidal Activity of Tuberculosis Drug Treatment

Davis, S. Lindsey; Nuermberger, Eric L.; Um, Peter; Vidal, Carol; Jedynak, Bruno; Pomper, Martin G.; Bishai, William R.; Jain, Sanjay

doi:10.1128/aac.00789-09

Cited by 127 publications

(148 citation statements)

References 23 publications

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“…Using an animal model and TB infection model, it has been shown that quantitative 18 F-FDG uptake can be used to monitor the effectiveness of treatment. 115,140 In this study, there was a clear correlation between the fall in 18 F-FDG uptake in the lungs and successful administration of a bactericidal drug. In contrast, uptake of 18 F-FDG increased when an ineffective drug was given and in the control group.…”

Section: Therapy Monitoring Of Tbmentioning

confidence: 84%

FDG-PET Imaging in HIV Infection and Tuberculosis

Sathekge

Maes

Wiele

2013

Seminars in Nuclear Medicine

100

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Section: Therapy Monitoring Of Tbmentioning

confidence: 84%

FDG-PET Imaging in HIV Infection and Tuberculosis

Sathekge

Maes

Wiele

2013

Seminars in Nuclear Medicine

100

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“…C3HeB/FeJ mice are highly susceptible to M. tuberculosis infection, and develop necrotic granulomas in which the bacilli are exposed to hypoxic conditions (33,34). In contrast, C3H/HeJ mice do not develop necrosis, and the majority of bacilli appear to reside intracellullarly by histologic assessment.…”

Section: Discussionmentioning

confidence: 99%

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

Gupta

Tyagi

Almeida

et al. 2013

Am J Respir Crit Care Med

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151

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Rationale: A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Objectives: Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/ pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Methods: Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. Measurements and Main Results: We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone.Conclusions: These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.Keywords: human equivalent doses; verapamil; efflux; Mycobacterium tuberculosis Tuberculosis (TB), a disease affecting millions of people worldwide, requires treatment of patients with multiple drugs for several months. The complexity and length of therapy has led to the emergence of extensively drug-resistant Mycobacterium tuberculosis, which poses a global threat (1). The limited number of new antimicrobials in the TB drug development pipeline further emphasizes the need for fresh approaches in TB therapy. Repurposing existing approved drugs that may serve as treatmentshortening adjuvants is a promising and relatively efficient approach (2). Efflux pump inhibitors (EPIs) are potential agents in this category, and there have been initial promising reports for licensed agents, such as verapamil, reserpine, and piperine (3).Recently, Adams and colleagues (4) showed that the bacterial efflux pump-encoding gene, Rv1258c promotes intracellular bacterial survival, and may mediate drug tolerance. Addition of verapamil reduced tolerance to rifampin in both M. tuberculosis and Mycobacterium marinum, and incubation of M. marinuminfected macrophages with verapamil reduced intracellular bacterial growth. When verapamil was added to isoniazidand rifampin-treated M. marinum-infected macrophages, it restored antibiotic killing by red...

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“…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.…”

mentioning

confidence: 99%

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

et al. 2014

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Cynomolgus macaques infected with low-dose Mycobacterium tuberculosis develop both active tuberculosis and latent infection similar to those of humans, providing an opportunity to study the clinically silent early events in infection.18 Fluorodeoxyglucose radiotracer with positron emission tomography coregistered with computed tomography (FDG PET/CT) provides a noninvasive method to measure disease progression. We sought to determine temporal patterns of granuloma evolution that distinguished active-disease and latent outcomes. Macaques (n ‫؍‬ 10) were infected with low-dose M. tuberculosis with FDG PET/CT performed during infection. At 24 weeks postinfection, animals were classified as having active disease (n ‫؍‬ 3) or latent infection (n ‫؍‬ 6), with one "percolator" monkey. Imaging characteristics (e.g., lesion number, metabolic activity, size, mineralization, and distribution of lesions) were compared among active and latent groups. As early as 3 weeks postinfection, more pulmonary granulomas were observed in animals that would later develop active disease than in those that would develop latent infection. Over time, new lesions developed in active-disease animals but not in latent animals. Granulomas and mediastinal lymph nodes from active-disease but not latent animals consistently increased in metabolic activity at early time points. The presence of fewer lesions at 3 weeks and the lack of new lesion development in animals with latent infection suggest that innate and rapid adaptive responses are critical to preventing active tuberculosis. A greater emphasis on innate responses and/or rapid recruitment of adaptive responses, especially in the airway, should be emphasized in newer vaccine strategies.

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Noninvasive Pulmonary [ ¹⁸ F]-2-Fluoro-Deoxy- d -Glucose Positron Emission Tomography Correlates with Bactericidal Activity of Tuberculosis Drug Treatment

Cited by 127 publications

References 23 publications

FDG-PET Imaging in HIV Infection and Tuberculosis

FDG-PET Imaging in HIV Infection and Tuberculosis

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

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

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Noninvasive Pulmonary [ 18 F]-2-Fluoro-Deoxy- d -Glucose Positron Emission Tomography Correlates with Bactericidal Activity of Tuberculosis Drug Treatment

Cited by 127 publications

References 23 publications

FDG-PET Imaging in HIV Infection and Tuberculosis

FDG-PET Imaging in HIV Infection and Tuberculosis

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

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

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Product

Resources

About

Noninvasive Pulmonary [ ¹⁸ F]-2-Fluoro-Deoxy- d -Glucose Positron Emission Tomography Correlates with Bactericidal Activity of Tuberculosis Drug Treatment

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