title: Multidrug-resistant tuberculosis and culture conversion with bedaquiline.
abstract: BACKGROUND
  Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks.
  
  
  METHODS
  In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline.
  
  
  RESULTS
  Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.
  
  
  CONCLUSIONS
  The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).
authors.affiliation: The authors' affiliations are provided in the Appendix.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.forename: Alexander
authors.initials: A
authors.lastname: Pym
authors.forename: Martin P
authors.initials: MP
authors.lastname: Grobusch
authors.forename: Jorge M
authors.initials: JM
authors.lastname: de los Rios
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gotuzzo
authors.forename: Irina
authors.initials: I
authors.lastname: Vasilyeva
authors.forename: Vaira
authors.initials: V
authors.lastname: Leimane
authors.forename: Koen
authors.initials: K
authors.lastname: Andries
authors.forename: Nyasha
authors.initials: N
authors.lastname: Bakare
authors.forename: Tine
authors.initials: T
authors.lastname: De Marez
authors.forename: Myriam
authors.initials: M
authors.lastname: Haxaire-Theeuwes
authors.forename: Nacer
authors.initials: N
authors.lastname: Lounis
authors.forename: Paul
authors.initials: P
authors.lastname: Meyvisch
authors.forename: Els
authors.initials: E
authors.lastname: De Paepe
authors.forename: Rolf P G
authors.initials: RP
authors.lastname: van Heeswijk
authors.forename: Brian
authors.initials: B
authors.lastname: Dannemann
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D064687:Diarylquinolines / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification*; D013183:Sputum / Q000382:microbiology; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; C493870:bedaquiline