New drugs for TB

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. This study, published in The Lancet, investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development.

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 7 October 2010 and 19 August 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 milliliter of sputum in daily overnight sputum collections. Clinical staff were partially masked but laboratory personnel were fully masked.

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 (10; 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 One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria pre-specified in the protocol.

PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multi-agent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens.

Diacon AH, et al. The Lancet, Early Online Publication, 23 July 2012.

[http://dx.doi.org/10.1016/S0140-6736(12)61080-0]