title: Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis.
abstract: Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.
authors: Division of Physiology, Department of Medical Biochemistry, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa. ahd@sun.ac.za
authors: Andreas H
authors: AH
authors: Diacon
authors: Rodney
authors: R
authors: Dawson
authors: Florian
authors: F
authors: Von Groote-Bidlingmaier
authors: Gregory
authors: G
authors: Symons
authors: Amour
authors: A
authors: Venter
authors: Peter R
authors: PR
authors: Donald
authors: Almari
authors: A
authors: Conradie
authors: Ngozi
authors: N
authors: Erondu
authors: Ann M
authors: AM
authors: Ginsberg
authors: Erica
authors: E
authors: Egizi
authors: Helen
authors: H
authors: Winter
authors: Piet
authors: P
authors: Becker
authors: Carl M
authors: CM
authors: Mendel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use*; D013183:Sputum / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D011804:Quinolines; C493870:bedaquiline