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.

Figure 1. CONSORT flow diagram of study enrollment.

Figure 2. Bactericidal activity in sputum according to treatment arm as assessed by colony counts (left) and time to positivity in automated liquid culture (MGIT TTP, right).

Lines indicate prediction and shading 90% confidence interval (CI) as determined by mixed effects model repeated measures analysis, using day as a categorical variable. The vertical axis of the right hand figure is inverted to facilitate visual comparison with CFU findings. At 14 days, the 90% CI of all treatments excluded zero.

Figure 3. Bactericidal activity against M. tuberculosis H37Rv in whole blood culture (WBA) according to treatment arm, at discrete time points (left), and as cumulative effect (right).

Lines and shading indicate means and 90% confidence intervals (CI).

Figure 4. Distributions of minimal inhibitory concentrations (MICs) to sutezolid (PNU-100480) pre and post treatment (rows and columns, respectively), according to dosing schedule.

Values in each cell indicate numbers of patients. Cells shaded red are those in which MIC values increased, whereas they decreased in those shaded blue. No change was apparent in MIC values of the metabolite (PNU-101603, not shown).

Figure 5. Plasma concentrations of sutezolid (pink) and its major metabolite (yellow) at steady state (day 13–14) in patients treated with sutezolid 600 mg BID (left) or 1200 mg QD (right).

Solid lines indicate medians; shading indicates 90% CI. Lower and upper dotted lines indicate median pre-treatment MIC values for parent and metabolite, respectively.

Figure 6. Treatment-emergent ALT increases in sutezolid-treated subjects.