title: 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 log10number of CFU of M. tuberculosis per milliliter of sputum, expressed as the change in log10number of CFU per milliliter of sputum per day. The mean 14-day activity of the combination of isoniazid, rifampin, ethambutol, and pyrazinamide (-0.163 log10CFU/ml sputum/day; 95% confidence interval [CI], -0.193, -0.133 log10CFU/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.).
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio, USA jjf38@case.edu.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Furin
authors.affiliation: Task Applied Science, Bellville, South Africa.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Du Bois
authors.affiliation: Task Applied Science, Bellville, South Africa.
authors.forename: Elana
authors.initials: E
authors.lastname: van Brakel
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: Phalkun
authors.initials: P
authors.lastname: Chheng
authors.affiliation: Division of Molecular Biology and Human Genetics, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.affiliation: Infectious Disease Pharmacokinetics Laboratory, University of Florida College of Pharmacy, and Emerging Pathogens Institute, Gainesville, Florida, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Infectious Disease Pharmacokinetics Laboratory, University of Florida College of Pharmacy, and Emerging Pathogens Institute, Gainesville, Florida, USA.|Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alsultan
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: Bonnie A
authors.initials: BA
authors.lastname: Thiel
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Debanne
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.affiliation: Task Applied Science, Bellville, South Africa.|Division of Molecular Biology and Human Genetics, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.affiliation: Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine, and University Hospitals Case Medical Center, Cleveland, Ohio, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D015169:Colony Count, Microbial; D004334:Drug Administration Schedule; D004338:Drug Combinations; D023381:Endpoint Determination; D004977:Ethambutol / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced / Q000175:diagnosis / Q000473:pathology; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D023303:Oxazolidinones / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011718:Pyrazinamide / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D013183:Sputum / Q000382:microbiology; D013921:Thrombocytopenia / Q000139:chemically induced / Q000175:diagnosis / Q000473:pathology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D004338:Drug Combinations; D023303:Oxazolidinones; D011718:Pyrazinamide; C453362:posizolid; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin