title: 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial.
abstract: BACKGROUND
  New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development.
  
  
  METHODS
  In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851.
  
  
  RESULTS
  The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.
  
  
  CONCLUSIONS
  PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.
  
  
  BACKGROUND
  The Global Alliance for TB Drug Development (TB Alliance).
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: Christo
authors: C
authors: van Niekerk
authors: Daniel
authors: D
authors: Everitt
authors: Helen
authors: H
authors: Winter
authors: Piet
authors: P
authors: Becker
authors: Carl M
authors: CM
authors: Mendel
authors: Melvin K
authors: MK
authors: Spigelman
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001372:Aza Compounds / Q000009:adverse effects / Q000627:therapeutic use; D015169:Colony Count, Microbial; D064687:Diarylquinolines; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D050296:Microbial Viability / Q000187:drug effects; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D009593:Nitroimidazoles / Q000009:adverse effects / Q000627:therapeutic use; D011446:Prospective Studies; D011718:Pyrazinamide / Q000009:adverse effects / Q000627:therapeutic use; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use; D013183:Sputum / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D064687:Diarylquinolines; D024841:Fluoroquinolones; D009593:Nitroimidazoles; D011804:Quinolines; C410767:pretomanid; D011718:Pyrazinamide; C493870:bedaquiline; D000077266:Moxifloxacin