Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis.

Abstract

Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and computerized tomography ([18F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [18F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.

• Authors: Yingda L Xie, Veronique R de Jager, Ray Y Chen, Lori E Dodd, Praveen Paripati, Laura E Via, Dean Follmann, Jing Wang, Keith Lumbard, Saher Lahouar, Stephanus T Malherbe, Jenna Andrews, Xiang Yu, Lisa C Goldfeder, Ying Cai, Kriti Arora, Andre G Loxton, Naadira Vanker, Michael Duvenhage, Jill Winter, Taeksun Song, Gerhard Walzl, Andreas H Diacon, Clifton E Barry 3rd
• Journal: Science translational medicine (Sci Transl Med) Vol. 13 Issue 579 (02 03 2021) ISSN: 1946-6242 [Electronic] United States
• PMID: 33536283 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Antitubercular Agents
• Drug Combinations
• Fluorodeoxyglucose F18

Topics

• Antitubercular Agents (therapeutic use)
• Drug Combinations
• Drug Therapy, Combination
• Fluorodeoxyglucose F18
• Humans
• Positron Emission Tomography Computed Tomography
• Tuberculosis (diagnostic imaging, drug therapy)
• Tuberculosis, Pulmonary (diagnostic imaging, drug therapy)