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

Abstract

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.

• Authors: Robert S Wallis, Rodney Dawson, Sven O Friedrich, Amour Venter, Darcy Paige, Tong Zhu, Annette Silvia, Jason Gobey, Craig Ellery, Yao Zhang, Kathleen Eisenach, Paul Miller, Andreas H Diacon
• Journal: PloS one (PLoS One) Vol. 9 Issue 4 Pg. e94462 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24732289 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Oxazolidinones
• PNU-100480
• Alanine Transaminase

Topics

• Adult
• Alanine Transaminase (metabolism)
• Animals
• Blood Bactericidal Activity (drug effects)
• Colony Count, Microbial
• Female
• Humans
• Male
• Mice
• Microbial Sensitivity Tests
• Mycobacterium tuberculosis (drug effects, growth & development)
• Oxazolidinones (blood, pharmacokinetics, pharmacology, therapeutic use)
• Sputum (microbiology)
• Tuberculosis, Pulmonary (blood, drug therapy, microbiology)