title: Mycobactericidal activity of sutezolid (PNU-100480) in sputum (EBA) and blood (WBA) of patients with pulmonary tuberculosis.
abstract: BACKGROUND
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01225640.
authors.affiliation: Formerly Pfizer Inc, Groton, Connecticut, United States of America.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wallis
authors.affiliation: University of Cape Town, Cape Town, South Africa.
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.affiliation: Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Sven O
authors.initials: SO
authors.lastname: Friedrich
authors.affiliation: Medical Research Council Centre for Molecular and Cellular Biology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Darcy
authors.initials: D
authors.lastname: Paige
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Annette
authors.initials: A
authors.lastname: Silvia
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Gobey
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Ellery
authors.affiliation: Pfizer, Groton, Connecticut, United States of America.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Eisenach
authors.affiliation: Formerly Pfizer Inc, Groton, Connecticut, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Miller
authors.affiliation: Division of Medical Physiology, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
mesh_terms: D000328:Adult; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001770:Blood Bactericidal Activity / Q000187:drug effects*; D015169:Colony Count, Microbial; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D023303:Oxazolidinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology*; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology*
chemical_list: D023303:Oxazolidinones; C543015:PNU-100480; D000410:Alanine Transaminase
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