Scientific Publication

14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial

author(s) Donald, P.R.. - Diacon, A.H.. - Spigelman, M.K.. - van Niekerk, C.. - Becker, P.. - Dawson, R.. - Everitt, D.. - Mendel, C.M.. - Symons, G.. - Venter, A.. - von Groote-Bidlingmaier, F.. - Winter, H.
from UK Foreign, Commonwealth & Development Office (FCDO)
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themes
regions
  • Southern Africa
  • Sub-Saharan Africa
  • Africa
  • World
citation

Diacon, A.H.; Dawson, R.; von Groote-Bidlingmaier, F.; Symons, G.; Venter, A.; Donald, P.R.; van Niekerk, C.; Everitt, D.; Winter, H.; Becker, P.; Mendel, C.M.; Spigelman, M.K. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet (2012) : (DOI: 10.1016/S0140-6736(12)61080-0)

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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. Findings: 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. Interpretation: 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

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