Human Tuberculosis. III. Current and Prospective Approaches in Anti-Tubercular Therapy

Ineffectively treated tuberculosis (TB) is associated with substantial morbidity and mortality. Cure of TB patients is hampered by the development of multidrug resistance in M. tuberculosis and the need of long-term treatment. The diarylquinoline derivative bedaquiline was approved in December 2012 under the accelerated-approval regulations of FDA as part of a combination therapy for treating adults with pulmonary MDR-TB for whom effective cures are not otherwise available. The bicyclic nitroimidazoles delamanid and its companion pretomanid inhibit mycolic acid synthesis via an unknown mechanism. In November 2013, delamanid received conditional approval by the European Medicines Agency for MDR-TB treatment. Use of both drugs, however, is limited owing to toxicity issues. If the aim to reduce treatment duration is pursued in order to limit costs and improve patient adherence, it is mandatory to demonstrate their noninferiority with fewer months of therapy. In three phase III clinical trials the efficacy of the most recent fluoroquinolones, gatifloxacin and moxifloxacin, has been investigated in a four-month treatment regimen of drug-susceptible TB. In all three studies, after two months the culture conversion rates of observed sputum indicated that fluoroquinolone-based therapies were likely to be superior. However, this feature did not reliably predict sterilizing activity or a risk of relapse. In other words, the shortened treatments were not noninferior to standard treatments. To counteract mycobacterial survival strategies and reduce the timelength of treatment with anti-TB drugs, other novel and powerful agents, as well as tuberculosis vaccines, are under intense clinical investigation for safety and efficacy assessment.