Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis

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dc.contributor.authorWallis, Robert Sen_ZA
dc.contributor.authorDawson, Rodneyen_ZA
dc.contributor.authorFriedrich, Sven Oen_ZA
dc.contributor.authorVenter, Amouren_ZA
dc.contributor.authorPaige, Darcyen_ZA
dc.contributor.authorZhu, Tongen_ZA
dc.contributor.authorSilvia, Annetteen_ZA
dc.contributor.authorGobey, Jasonen_ZA
dc.contributor.authorEllery, Craigen_ZA
dc.contributor.authorZhang, Yaoen_ZA
dc.date.accessioned2016-01-02T05:08:11Z
dc.date.available2016-01-02T05:08:11Z
dc.date.issued2014en_ZA
dc.description.abstractRationale: 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 NCT01225640en_ZA
dc.identifier.apacitationWallis, R. S., Dawson, R., Friedrich, S. O., Venter, A., Paige, D., Zhu, T., ... Zhang, Y. (2014). Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. <i>PLoS One</i>, http://hdl.handle.net/11427/16182en_ZA
dc.identifier.chicagocitationWallis, Robert S, Rodney Dawson, Sven O Friedrich, Amour Venter, Darcy Paige, Tong Zhu, Annette Silvia, Jason Gobey, Craig Ellery, and Yao Zhang "Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis." <i>PLoS One</i> (2014) http://hdl.handle.net/11427/16182en_ZA
dc.identifier.citationWallis, R. S., Dawson, R., Friedrich, S. O., Venter, A., Paige, D., Zhu, T., ... & Eisenach, K. (2014). Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PloS one, 9(4), e94462. doi:10.1371/journal.pone.0094462en_ZA
dc.identifier.ris TY - Journal Article AU - Wallis, Robert S AU - Dawson, Rodney AU - Friedrich, Sven O AU - Venter, Amour AU - Paige, Darcy AU - Zhu, Tong AU - Silvia, Annette AU - Gobey, Jason AU - Ellery, Craig AU - Zhang, Yao AB - 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 DA - 2014 DB - OpenUCT DO - 10.1371/journal.pone.0094462 DP - University of Cape Town J1 - PLoS One LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis TI - Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis UR - http://hdl.handle.net/11427/16182 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/16182
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pone.0094462
dc.identifier.vancouvercitationWallis RS, Dawson R, Friedrich SO, Venter A, Paige D, Zhu T, et al. Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis. PLoS One. 2014; http://hdl.handle.net/11427/16182.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis 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 credited.en_ZA
dc.rights.holder© 2014 Wallis et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLoS Oneen_ZA
dc.source.urihttp://journals.plos.org/plosoneen_ZA
dc.subject.otherBlooden_ZA
dc.subject.otherMycobacterium tuberculosisen_ZA
dc.subject.otherSputumen_ZA
dc.subject.otherTuberculosisen_ZA
dc.subject.otherDrug metabolismen_ZA
dc.subject.otherMetabolitesen_ZA
dc.subject.otherAdverse eventsen_ZA
dc.subject.otherConfidence intervalsen_ZA
dc.titleMycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosisen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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