title: Bactericidal activity of pyrazinamide and clofazimine alone and in combinations with pretomanid and bedaquiline.
abstract: BACKGROUND
  New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis.
  
  
  OBJECTIVE
  To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B.
  
  
  METHODS
  Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling.
  
  
  RESULTS
  Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe.
  
  
  CONCLUSIONS
  B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).
authors.affiliation: 1 Division of Medical Physiology, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.forename: Florian
authors.initials: F
authors.lastname: von Groote-Bidlingmaier
authors.forename: Gregory
authors.initials: G
authors.lastname: Symons
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Donald
authors.forename: Christo
authors.initials: C
authors.lastname: van Niekerk
authors.forename: Daniel
authors.initials: D
authors.lastname: Everitt
authors.forename: Jane
authors.initials: J
authors.lastname: Hutchings
authors.forename: Divan A
authors.initials: DA
authors.lastname: Burger
authors.forename: Robert
authors.initials: R
authors.lastname: Schall
authors.forename: Carl M
authors.initials: CM
authors.lastname: Mendel
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use; D002991:Clofazimine / Q000627:therapeutic use*; D064687:Diarylquinolines / Q000627:therapeutic use*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D009593:Nitroimidazoles / Q000627:therapeutic use*; D011718:Pyrazinamide / Q000627:therapeutic use*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*; D018088:Tuberculosis, Multidrug-Resistant / Q000150:complications / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D064687:Diarylquinolines; D009593:Nitroimidazoles; C410767:pretomanid; D011718:Pyrazinamide; C493870:bedaquiline; D002991:Clofazimine
keywords: antitubercular agents; drug evaluation; tuberculosis