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

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, Sangnae Cho, Clifton E. Barry, Jo Anne L. Flynn

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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-[18F]-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 subjectswere similar inmagnitude to those observed inmacaques, 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.

Original languageEnglish
Article number265ra167
JournalScience Translational Medicine
Volume6
Issue number265
DOIs
Publication statusPublished - 2014 Dec 3

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Linezolid
Oxazolidinones
Macaca
Tuberculosis
Tomography
Therapeutic Uses
Extensively Drug-Resistant Tuberculosis
Lung
Bacterial Load
Fluorodeoxyglucose F18
Therapeutics
Mycobacterium tuberculosis
Human Activities
Positron-Emission Tomography
Rodentia
Theoretical Models
Pathology
Anti-Bacterial Agents
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Coleman, M. T., Chen, R. Y., Lee, M., Lin, P. L., Dodd, L. E., Maiello, P., ... Flynn, J. A. L. (2014). PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. Science Translational Medicine, 6(265), [265ra167]. https://doi.org/10.1126/scitranslmed.3009500
Coleman, M. Teresa ; Chen, Ray Y. ; Lee, Myungsun ; Lin, Philana Ling ; Dodd, Lori E. ; Maiello, Pauline ; Via, Laura E. ; Kim, Youngran ; Marriner, Gwendolyn ; Dartois, Veronique ; Scanga, Charles ; Janssen, Christopher ; Wang, Jing ; Klein, Edwin ; Cho, Sangnae ; Barry, Clifton E. ; Flynn, Jo Anne L. / PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. In: Science Translational Medicine. 2014 ; Vol. 6, No. 265.
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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-[18F]-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 subjectswere similar inmagnitude to those observed inmacaques, 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.",
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Coleman, MT, Chen, RY, Lee, M, Lin, PL, Dodd, LE, Maiello, P, Via, LE, Kim, Y, Marriner, G, Dartois, V, Scanga, C, Janssen, C, Wang, J, Klein, E, Cho, S, Barry, CE & Flynn, JAL 2014, 'PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis', Science Translational Medicine, vol. 6, no. 265, 265ra167. https://doi.org/10.1126/scitranslmed.3009500

PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis. / Coleman, M. Teresa; Chen, Ray Y.; Lee, Myungsun; Lin, Philana Ling; Dodd, Lori E.; Maiello, Pauline; Via, Laura E.; Kim, Youngran; Marriner, Gwendolyn; Dartois, Veronique; Scanga, Charles; Janssen, Christopher; Wang, Jing; Klein, Edwin; Cho, Sangnae; Barry, Clifton E.; Flynn, Jo Anne L.

In: Science Translational Medicine, Vol. 6, No. 265, 265ra167, 03.12.2014.

Research output: Contribution to journalArticle

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T1 - PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis

AU - Coleman, M. Teresa

AU - Chen, Ray Y.

AU - Lee, Myungsun

AU - Lin, Philana Ling

AU - Dodd, Lori E.

AU - Maiello, Pauline

AU - Via, Laura E.

AU - Kim, Youngran

AU - Marriner, Gwendolyn

AU - Dartois, Veronique

AU - Scanga, Charles

AU - Janssen, Christopher

AU - Wang, Jing

AU - Klein, Edwin

AU - Cho, Sangnae

AU - Barry, Clifton E.

AU - Flynn, Jo Anne L.

PY - 2014/12/3

Y1 - 2014/12/3

N2 - 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-[18F]-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 subjectswere similar inmagnitude to those observed inmacaques, 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.

AB - 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-[18F]-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 subjectswere similar inmagnitude to those observed inmacaques, 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.

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