Rip Van Winkle wakes up: development of tuberculosis treatment in the 21st century.

The increase in drug-resistant tuberculosis and the global pandemic of human immunodeficiency virus infection-related tuberculosis threaten global tuberculosis control. There are needs for improved therapy in all aspects of tuberculosis treatment: treatment of latent infection, active drug-susceptible disease, and particularly, drug-resistant disease. Fortunately, at this time of great need, the field of tuberculosis drug development has reemerged after >30 years of inactivity. I review the specific needs for new treatment regimens, the pathways of tuberculosis drug development, and the agents that are currently in clinical development. There is renewed interest in the rifamycin class; studies in the mouse model suggest that higher doses of rifampin or rifapentine may markedly improve the treatment of drug-susceptible disease. Fluoroquinolones may allow shorter treatment durations for drug-susceptible disease, though initial phase 2B trials have shown inconsistent activity. Novel drugs, such as TMC207, OPC-67683, PA824, SQ109, and PNU-100480, may improve the treatment of drug-resistant and drug-susceptible tuberculosis.