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

ABSTRACT Tools for monitoring response to tuberculosis (TB) treatment are time-consuming and resource intensive. Noninvasive biomarkers have the potential to accelerate TB drug development, but to date, little progress has been made in utilizing imaging technologies. Therefore, in this study, we used noninvasive imaging to monitor response to TB treatment. BALB/c and C3HeB/FeJ mice were aerosol infected with Mycobacterium tuberculosis and administered bactericidal (standard and highly active) or bacteriostatic TB drug regimens. Serial pulmonary [18F]-2-fluoro-deoxy-d-glucose (FDG) positron emission tomography (PET) was compared with standard microbiologic methods to monitor the response to treatment. [18F]FDG-PET correctly identified the bactericidal activity of the drug regimens. Imaging required fewer animals; was available in real time, as opposed to having CFU counts 4 weeks later; and could also detect TB relapse in a time frame similar to that of the standard method. Lesion-specific [18F]FDG-PET activity also broadly correlated with TB treatment in C3HeB/FeJ mice that develop caseating lesions. These studies demonstrate the application of noninvasive imaging to monitor TB treatment response. By reducing animal numbers, these biomarkers will allow cost-effective studies of more expensive animal models of TB. Validated markers may also be useful as “point-of-care” methods to monitor TB treatment in humans.

[1]  G I Bell,et al.  Structure and function of mammalian facilitative sugar transporters. , 1993, The Journal of biological chemistry.

[2]  Sanjay Jain,et al.  Management and Outcomes of Intracranial Tuberculomas Developing During Antituberculous Therapy: Case Report and Review , 2005, Clinical pediatrics.

[3]  Takeshi Ishizaki,et al.  Usefulness of 18F-fluorodeoxyglucose positron emission tomography for diagnosing disease activity and monitoring therapeutic response in patients with pulmonary mycobacteriosis , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[4]  Gary D Luker,et al.  Applications of bioluminescence imaging to the study of infectious diseases , 2007, Cellular microbiology.

[5]  Nicholas A. Be,et al.  Bacterial Thymidine Kinase as a Non-Invasive Imaging Reporter for Mycobacterium tuberculosis in Live Animals , 2009, PloS one.

[6]  D. Kernodle,et al.  Monitoring therapeutic efficacy by real-time detection of Mycobacterium tuberculosis mRNA in sputum. , 2009, Clinical chemistry.

[7]  Abass Alavi,et al.  18-fluorodeoxyglucose positron emission tomographic imaging in the detection and monitoring of infection and inflammation. , 2002, Seminars in nuclear medicine.

[8]  N. Tamaki,et al.  FDG uptake and glucose transporter subtype expressions in experimental tumor and inflammation models. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[9]  Martin Pomper,et al.  Antibiotic Treatment of Tuberculosis: Old Problems, New Solutions With tuberculosis and drug resistance surging, the search is on for new drugs along with better and faster ways of evaluating them , 2008 .

[10]  G. Rook,et al.  The role of gamma-interferon, vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis. , 1987, Immunology.

[11]  J. Gerberding,et al.  Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs--worldwide, 2000-2004. , 2006, MMWR. Morbidity and mortality weekly report.

[12]  Abass Alavi,et al.  Positron emission tomography imaging in nonmalignant thoracic disorders. , 2002, Seminars in nuclear medicine.

[13]  L. Culp,et al.  Induction of monocyte expression of tumor necrosis factor alpha by the 30-kD alpha antigen of Mycobacterium tuberculosis and synergism with fibronectin. , 1996, The Journal of clinical investigation.

[14]  K. Kinzler,et al.  Imaging bacterial infections with radiolabeled 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[15]  T. Karayel,et al.  Computed tomography and bronchoscopy in endobronchial tuberculosis. , 2003, Canadian respiratory journal.

[16]  Michael E. Phelps,et al.  Molecular imaging of lymphoid organs and immune activation using positron emission tomography with a new 18F-labeled 2′-deoxycytidine analog , 2008, Nature Medicine.

[17]  Kyung-Han Lee,et al.  Augmented 18F-FDG uptake in activated monocytes occurs during the priming process and involves tyrosine kinases and protein kinase C. , 2004, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[18]  R. Chaisson,et al.  Daily Dosing of Rifapentine Cures Tuberculosis in Three Months or Less in the Murine Model , 2007, PLoS medicine.

[19]  W. Bishai,et al.  Weekly moxifloxacin and rifapentine is more active than the denver regimen in murine tuberculosis. , 2005, American journal of respiratory and critical care medicine.

[20]  Kyung-Han Lee,et al.  Augmented 18 F-FDG Uptake in Activated Monocytes Occurs During the Priming Process and Involves Tyrosine Kinases and Protein Kinase C , 2003 .

[21]  S. Gillespie,et al.  Biomarkers of treatment response in clinical trials of novel antituberculosis agents. , 2007, The Lancet. Infectious diseases.

[22]  Sanjay Jain.  Monitoring Disease in Animal Models of TB - The 21st Century: Non-Invasive, Real-Time, in Live Animals , 2008 .

[23]  M. Daly,et al.  Ipr1 gene mediates innate immunity to tuberculosis , 2005, Nature.

[24]  J. Flynn,et al.  Lessons from experimental Mycobacterium tuberculosis infections. , 2006, Microbes and infection.

[25]  Laurent Younes,et al.  Template registration with missing parts: Application to the segmentation of M. tuberculosis infected lungs , 2009, 2009 IEEE International Symposium on Biomedical Imaging: From Nano to Macro.

[26]  J. Goo,et al.  Pulmonary tuberculoma evaluated by means of FDG PET: findings in 10 cases. , 2000, Radiology.

[27]  T Ido,et al.  Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. , 1992, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[28]  T. Shim,et al.  Evaluation of Therapeutic Response of Tuberculoma Using F-18 FDG Positron Emission Tomography , 2008, Clinical nuclear medicine.

[29]  G. Kaplan,et al.  Selective increase in plasma tumor necrosis factor-alpha and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis. , 1998, The Journal of infectious diseases.

[30]  V. R. McCready,et al.  FDG accumulation and tumor biology. , 1998, Nuclear medicine and biology.