Articles14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial
Introduction
Tuberculosis remains a major global health problem; although recently the global incidence has fallen slightly, the number of cases remains daunting and has overwhelmed the capabilities of many health systems, especially in countries with a concomitant HIV epidemic.1 Antituberculosis therapy relies on combinations of bactericidal and sterilising drugs that protect from development of resistance.2 Crucial to containing and defeating the tuberculosis epidemic are new, shorter, and safe treatment regimens, which are affordable and practical for use in low-resource settings. Ideally, such regimens would contain new drugs able to combat tuberculosis resistant to currently available drugs, especially multidrug-resistant (MDR) tuberculosis resistant to at least isoniazid and rifampicin, and free of interactions with antiretroviral regimens.
Since 2004 several new antituberculosis drugs have entered clinical assessment; among these drugs are bedaquiline, a diarylquinoline previously known as TMC207, and PA-824, a nitroimidazo-oxazine, which have completed initial dose-ranging monotherapy studies and have shown dose-related early bactericidal activity (EBA).3, 4, 5 Murine studies have provided evidence of the significant sterilising activity of both compounds.6, 7 Bedaquiline has also been studied in the first 6 months of MDR-TB treatment with promising early results.8, 9 In mouse experiments there is synergism between the first-line agent pyrazinamide and bedaquiline and between pyrazinamide and PA-824.10, 11 Moxifloxacin and other fluoroquinolones have shown bactericidal activity approaching that of isoniazid in EBA studies12, 13, 14 and murine studies have shown a powerful sterilising effect for moxifloxacin alone15, 16, 17 and when combined with PA-824 and pyrazinamide.18 Although formal interaction studies have not been completed, preclinical data suggest a low likelihood of clinically significant interactions of PA-824, moxifloxacin, and pyrazinamide with antiretroviral drugs.
EBA studies assess the fall in colony forming units (CFU) of Mycobacterium tuberculosis in sputum of patients with smear-microscopy-positive pulmonary tuberculosis in response to treatment. These studies are most often done with single drugs for proof of concept (ie, to confirm antimycobacterial activity of an agent on first use in patients with tuberculosis in closely monitored small patient groups, assess safety, and assist in identification of an appropriate dose for future studies19). Nonetheless, any new agent will be ultimately incorporated in multidrug regimens. This approach is usually assessed by substituting new agents one at a time for one constituent of the current standard treatment.20, 21, 22, 23 However, when many new agents are available this stepwise process is time consuming, costly, and requires substantial resources for clinical trials. New approaches are urgently needed to expedite progress from single drugs to new combination regimens.
We describe a 14-day EBA study in treatment naive patients with sputum-microscopy smear-positive fully drug-susceptible pulmonary tuberculosis, assessing various combinations of the new antituberculosis agents bedaquiline, PA-824, and moxifloxacin and the established agent pyrazinamide with a view to developing appropriate combinations for longer-term studies, leading to a tuberculosis regimen for management of drug-susceptible and MDR disease.
Section snippets
Trial design and patients
We did a phase 2A, partially double-blinded, randomised trial assessing EBA, safety, tolerability, and pharmacokinetics of bedaquiline alone, bedaquiline-PA-824, bedaquiline-pyrazinamide, PA-824-pyrazinamide, and PA-824-moxifloxacin-pyrazinamide over 14 days of treatment in groups of 15 treatment-naive patients with pulmonary tuberculosis without complicating factors. We also included a sixth group of ten patients who were randomised as a positive control to receive standard tuberculosis
Results
Most patients were male and of mixed ethnicity. Mean age was 30·00 (SD 9·13) years and mean body mass index 18·92 (2·80) kg/m2. These characteristics as well as baseline log10CFU and TTP values did not differ significantly between treatment groups. Six patients were co-infected with HIV (table 1).
One patient receiving bedaquiline-PA-824 was excluded from the analysis owing to very poor and inconsistent culture growth (figure 1). By contrast with previous EBA studies negative CFU results were
Discussion
Our study reports the first multiple agent combination EBA study for development of a next generation tuberculosis treatment regimen (panel 2). The study has at least three important findings. First, the new three-drug combination PA-824-moxifloxacin-pyrazinamide has a 14-day antituberculosis activity in sputum at least comparable with that of the current standard regimen for drug-susceptible tuberculosis. This drug combination relies neither on isoniazid nor rifampicin and thus has the
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