Recent advances in tuberculosis: New drugs and treatment regimens

Abstract

The current treatment regimen against drug susceptible tuberculosis (DS-TB) was defined by the 1980s. Since then the emergence of the global HIV pandemic and the escalation of drug resistant (DR-) forms of TB have presented new challenges for therapeutic research. Priority goals include shortening DS-TB treatment, improving DR-TB treatment and making combined TB-HIV therapy easier. To help achieve these goals, a range of new drugs and treatment strategies are currently being evaluated. Phase IIb and III clinical trials are ongoing to assess combinations involving the high-dose rifamycins, the 8-methoxyquinolones, a diarylquinoline (bedaquiline) and the nitroimidazoles. Other compounds (e.g. novel oxazolidinones and ethylenediamines) are at earlier stages of clinical development. Overall, there are grounds for optimism that recent advances will contribute towards achievement of new treatment regimens in the foreseeable future. However, long-term investment, political commitment and scientific endeavour are crucial to ensure that progress is sustained and the benefits of recent advances reach those in the greatest need.

Keywords: Bedaquiline (TMC-207); Delamanid (OPC-67683); Gatifloxacin; Moxifluxacin; PA-824; Rifampicin; Rifapentine; Sterilising activity.

Fig. (1)

Bacillary sub-populations theory of bacillary response to chemotherapy. A: Schematic diagram demonstrating probable response of distinct bacillary sub-populations during DS-TB therapy. During the Early Bactericidal Phase (first 5-7 days), isoniazid is key to killing metabolically active and replicating organisms. After day 7, the majority of viable bacilli are likely to be metabolically quiescent persisters, which are eradicated more slowly by sterilising drugs (especially rifampicin). The overall bacillary load falls in a biphasic manner, reflecting elimination of different bacillary populations at different times in therapy. B: Sputum colony counting data from 3 patient cohorts, demonstrating biphasic bacillary elimination in clinical practice, adapted from [39] and [95].

Fig. (2). The Global Tuberculosis Drug Pipeline

Schematic of the global drug development pipeline from the Working Group on New Drugs, Stop TB Partnership adapted from [36]. Drug names are followed by details of the relevant drug class in parenthesis. Drug classes are coded as follows: R=rifamycin, Q=fluoroquinolone, D=diarylquinoline, N=nitroimidazoles, Ed=ethylenediamine, O=oxazolidine. Compounds discussed in specific detail in this review are listed in bold and underlined.