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Early Bactericidal Activity of AZD5847 in Patients with Pulmonary Tuberculosis.

Authors :: Furin JJ
Du Bois J
van Brakel E
Chheng P
Venter A
Peloquin CA
Alsultan A
Thiel BA
Debanne SM
Boom WH
Diacon AH
Johnson JL
Source :: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2016 Oct 21; Vol. 60 (11), pp. 6591-6599. Date of Electronic Publication: 2016 Oct 21 (Print Publication: 2016).
Publication Year :: 2016
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 log <subscript>10</subscript> number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log <subscript>10</subscript> 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 log <subscript>10</subscript> CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log <subscript>10</subscript> 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.).<br /> (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)