PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.

Abstract

Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human phase 2 trials. We show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in Mycobacterium tuberculosis-infected cynomolgus macaques with active TB. This effect coincided with a decline in 2-deoxy-2-[(18)F]-fluoro-d-glucose positron emission tomography (FDG PET) imaging avidity in the lungs of these animals and with reductions in pulmonary pathology measured by serial computed tomography (CT) scans over 2 months of monotherapy. In a parallel phase 2 clinical study of linezolid in patients infected with XDR-TB, we also collected PET/CT imaging data from subjects receiving linezolid that had been added to their failing treatment regimens. Quantitative comparisons of PET/CT imaging changes in these human subjects were similar in magnitude to those observed in macaques, demonstrating that the therapeutic effect of these oxazolidinones can be reproduced in this model of experimental chemotherapy. PET/CT imaging may be useful as an early quantitative measure of drug efficacy against TB in human patients.

• Authors: M Teresa Coleman, Ray Y Chen, Myungsun Lee, Philana Ling Lin, Lori E Dodd, Pauline Maiello, Laura E Via, Youngran Kim, Gwendolyn Marriner, Veronique Dartois, Charles Scanga, Christopher Janssen, Jing Wang, Edwin Klein, Sang Nae Cho, Clifton E Barry 3rd, JoAnne L Flynn
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 265 Pg. 265ra167 (Dec 03 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 25473035 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• Acetamides
• Anti-Bacterial Agents
• Oxazolidinones
• Fluorodeoxyglucose F18
• posizolid
• Linezolid

Topics

• Acetamides (administration & dosage)
• Algorithms
• Animals
• Anti-Bacterial Agents (therapeutic use)
• Extensively Drug-Resistant Tuberculosis (diagnostic imaging, drug therapy)
• Fluorodeoxyglucose F18
• Humans
• Linezolid
• Lymph Nodes (pathology)
• Macaca
• Multimodal Imaging
• Oxazolidinones (administration & dosage, therapeutic use)
• Positron-Emission Tomography
• Stem Cells
• Tomography, X-Ray Computed
• Treatment Outcome