Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis

Abstract

AZD5847 is an oxazolidinone antibiotic with in vitro activity against Mycobacterium tuberculosis The objective of this study was to evaluate the antimycobacterial activity, safety, and pharmacokinetics of AZD5847 in patients with pulmonary tuberculosis. Groups of 15 treatment-naive, sputum smear-positive adults with pulmonary tuberculosis were randomly assigned to receive AZD5847 at one of four doses (500 mg once daily, 500 mg twice daily, 1,200 mg once daily, and 800 mg twice daily) or daily standard chemotherapy. The primary efficacy endpoint was the mean daily rate of change in the log10 number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log10 number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (-0.163 log10 CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log10 CFU/ml sputum/day) was consistent with that found in previous studies. AZD5847 at 500 mg twice daily significantly decreased the number of CFU on solid medium (-0.039; 95% CI, -0.069, -0.009; P = 0.0048). No bactericidal activity was detected at doses of AZD5847 of 500 mg once daily (mean early bactericidal activity [EBA], 0.02 [95% CI, -0.01, 0.05]), 1,200 mg once daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]), and 800 mg twice daily (mean EBA, 0.02 [95% CI, -0.01, 0.05]). AZD5847 at doses of both 500 mg and 800 mg twice daily also showed an increase in the time to a positive culture in MGIT liquid culture medium. Two serious adverse events (grade 4 thrombocytopenia and grade 4 hyperbilirubinemia) occurred in patients receiving AZD5847 at higher doses. AZD5847 dosed twice daily kills tubercle bacilli in the sputum of patients with pulmonary tuberculosis and has modest early bactericidal activity. (This study has been registered at ClinicalTrials.gov under registration no. NCT01516203.).

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Disposition of study participants. 1, reasons for exclusion were sputum acid-fast bacillus negative (n = 16), CD4 count of ≤350/μl or antiretroviral treatment (n = 5), rifampin resistance (n = 3), prior anti-TB treatment (n = 4), hemoptysis (n = 1), or other medical illness (n = 7) (total n = 36, as some subjects were in >1 exclusion category); 2, one patient randomized to the arm with AZD5847 at 1,200-mg once daily was withdrawn due to adverse events consisting of a grade 3 elevated serum AST level and a grade 2 serum ALT level and completed only 7 days of the 14 days of study drug intake.

FIG 2

Change in the log10 number of CFU in sputum during the 14 days of study drug administration. The mean log10 number of CFU is plotted at the treatment time points for each treatment group to show the effect of treatment on the bacillary load. Error bars represent 95% confidence intervals for the mean estimate. AZD, AZD5847.

FIG 3

Change in the log10 number of CFU in sputum during the 14 days of study drug administration for the AZD5847 arms only. Repeated-measures analysis was used to determine the change in the log10 number of CFU in sputum over time by AZD5847 treatment group. The decline in CFU counts over time was significantly different from zero in the 500-mg-BID AZD5847 treatment arm. There was no significant difference in the fitted trajectories between AZD5847 treatment arms.

FIG 4

Change in time to detection in liquid medium (TTP) before and during 14 days of study drug administration for the AZD5847 arms only. Repeated-measures analysis was used to determine the change in TTP over time by AZD5847 treatment group. The increase in TTP was significantly different from zero in the 500-mg-BID and 800-mg-BID arms. There were no significant differences in the fitted trajectories between treatment arms.

FIG 5

Number of adverse events by severity and study arm.