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; Sang Nae Cho; Clifton E. Barry; Jo Anne L. Flynn

doi:10.1126/scitranslmed.3009500

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, Sang Nae Cho, Clifton E. Barry, Jo Anne L. Flynn

Department of Microbiology

Research output: Contribution to journal › Article › peer-review

98 Citations (Scopus)

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 language	English
Article number	265ra167
Journal	Science Translational Medicine
Volume	6
Issue number	265
DOIs	https://doi.org/10.1126/scitranslmed.3009500
Publication status	Published - 2014 Dec 3

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© 2014; American Association for the Advancement of Science. All rights reserved.

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Medicine(all)

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10.1126/scitranslmed.3009500

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Coleman, M. T., Chen, R. Y., Lee, M., Lin, P. L., Dodd, L. E., Maiello, P., Via, L. E., Kim, Y., Marriner, G., Dartois, V., Scanga, C., Janssen, C., Wang, J., Klein, E., Cho, S. N., Barry, C. E., & 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

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title = "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-[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.",

author = "Coleman, {M. Teresa} and Chen, {Ray Y.} and Myungsun Lee and Lin, {Philana Ling} and Dodd, {Lori E.} and Pauline Maiello and Via, {Laura E.} and Youngran Kim and Gwendolyn Marriner and Veronique Dartois and Charles Scanga and Christopher Janssen and Jing Wang and Edwin Klein and Cho, {Sang Nae} and Barry, {Clifton E.} and Flynn, {Jo Anne L.}",

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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, SN, 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

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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, Sang Nae

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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JO - Science Translational Medicine

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ER -

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

Abstract

Bibliographical note

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UN SDGs

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