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Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis

RATIONALE: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its f...

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Autores principales: Wallis, Robert S., Dawson, Rodney, Friedrich, Sven O., Venter, Amour, Paige, Darcy, Zhu, Tong, Silvia, Annette, Gobey, Jason, Ellery, Craig, Zhang, Yao, Eisenach, Kathleen, Miller, Paul, Diacon, Andreas H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986205/
https://www.ncbi.nlm.nih.gov/pubmed/24732289
http://dx.doi.org/10.1371/journal.pone.0094462
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author Wallis, Robert S.
Dawson, Rodney
Friedrich, Sven O.
Venter, Amour
Paige, Darcy
Zhu, Tong
Silvia, Annette
Gobey, Jason
Ellery, Craig
Zhang, Yao
Eisenach, Kathleen
Miller, Paul
Diacon, Andreas H.
author_facet Wallis, Robert S.
Dawson, Rodney
Friedrich, Sven O.
Venter, Amour
Paige, Darcy
Zhu, Tong
Silvia, Annette
Gobey, Jason
Ellery, Craig
Zhang, Yao
Eisenach, Kathleen
Miller, Paul
Diacon, Andreas H.
author_sort Wallis, Robert S.
collection PubMed
description RATIONALE: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. METHODS: Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. RESULTS: All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. CONCLUSIONS: The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01225640
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spelling pubmed-39862052014-04-15 Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis Wallis, Robert S. Dawson, Rodney Friedrich, Sven O. Venter, Amour Paige, Darcy Zhu, Tong Silvia, Annette Gobey, Jason Ellery, Craig Zhang, Yao Eisenach, Kathleen Miller, Paul Diacon, Andreas H. PLoS One Research Article RATIONALE: Sutezolid (PNU-100480) is a linezolid analog with superior bactericidal activity against Mycobacterium tuberculosis in the hollow fiber, whole blood and mouse models. Like linezolid, it is unaffected by mutations conferring resistance to standard TB drugs. This study of sutezolid is its first in tuberculosis patients. METHODS: Sputum smear positive tuberculosis patients were randomly assigned to sutezolid 600 mg BID (N = 25) or 1200 mg QD (N = 25), or standard 4-drug therapy (N = 9) for the first 14 days of treatment. Effects on mycobacterial burden in sputum (early bactericidal activity or EBA) were monitored as colony counts on agar and time to positivity in automated liquid culture. Bactericidal activity was also measured in ex vivo whole blood cultures (whole blood bactericidal activity or WBA) inoculated with M. tuberculosis H37Rv. RESULTS: All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% confidence intervals (CI) for bactericidal activity in sputum over the 14 day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious adverse events, premature discontinuations, or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven sutezolid-treated patients (14%) had transient, asymptomatic ALT elevations to 173±34 U/L on day 14 that subsequently normalized promptly; none met Hy's criteria for serious liver injury. CONCLUSIONS: The mycobactericidal activity of sutezolid 600 mg BID or 1200 mg QD was readily detected in sputum and blood. Both schedules were generally safe and well tolerated. Further studies of sutezolid in tuberculosis treatment are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01225640 Public Library of Science 2014-04-14 /pmc/articles/PMC3986205/ /pubmed/24732289 http://dx.doi.org/10.1371/journal.pone.0094462 Text en © 2014 Wallis et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wallis, Robert S.
Dawson, Rodney
Friedrich, Sven O.
Venter, Amour
Paige, Darcy
Zhu, Tong
Silvia, Annette
Gobey, Jason
Ellery, Craig
Zhang, Yao
Eisenach, Kathleen
Miller, Paul
Diacon, Andreas H.
Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title_full Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title_fullStr Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title_full_unstemmed Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title_short Mycobactericidal Activity of Sutezolid (PNU-100480) in Sputum (EBA) and Blood (WBA) of Patients with Pulmonary Tuberculosis
title_sort mycobactericidal activity of sutezolid (pnu-100480) in sputum (eba) and blood (wba) of patients with pulmonary tuberculosis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986205/
https://www.ncbi.nlm.nih.gov/pubmed/24732289
http://dx.doi.org/10.1371/journal.pone.0094462
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