Search

Summary 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 One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.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. Funding The Global Alliance for TB Drug Development (TB Alliance).

whether one is a clinician or a health administrator attempting to control tuberculosis. In developed communities tuberculosis occurs mainly in older adults; in developing communities tuberculosis occurs at all ages, albeit with differing manifestations. In developing communities a high disease incidence is encountered in young children. A large proportion of the population is aged less than 15 years and as many as 40% of tuberculosis notifications may be children; tuberculosis may be responsible for 10% or more of childhood hospital admissions and 10% or more of hospital deaths. Furthermore, with an annual risk of infection of 2–3%, close to 40% of the population may be infected by age 15 y e a r s . The figure illustrates schematically the age-related population pyramids in the process of infection (B) and disease development (C). The figure also shows, by way of contrast, the shape of the broad-based population pyramid in a hypothetical developing community (A). The high incidence of disease among the relatively small population of infected infants is noteworthy as is the rapid rise in incidence among teenagers. While those concerned with tuberculosis control will focus upon patients with cavitating disease who are spreading infection, the clinician will be concerned with the varying manifestations of disease occurring from infancy through to adolescence. Against this background and with HIV-seroprevalence rates among the sexually active population approaching 30% in much of sub-Saharan Africa, what opportunities exist for protecting the next generation against the ravages of tuberculosis? First, it is unlikely that a new vaccine or new antituberculosis agents will become available in the foreseeable future. In the absence of any better vaccine BCG vaccination of newborn babies should continue and may offer protection against disseminated disease. Even in developing communities a significant proportion of adulttype disease may arise from lymphohaematogenous dissemination to the lung apices, and later endogenous reactivation rather than recent infection. Adolescent BCG vaccination may therefore theoretically help prevent adulttype pulmonary tuberculosis in the older adolescent. If this Children and tuberculosis: protecting the next generation?