New drugs for the treatment of tuberculosis: hope and reality [State of the Art Series. New tools. Number 2 in the series]

Jul 6, 2012The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease

New tuberculosis drugs: promise and actual results

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Abstract

Rifapentine, while showing potential in mice, did not confirm its efficacy in a recent short-term clinical trial.

Moxifloxacin improved the effectiveness of standard TB treatment when substituted for ethambutol.
Clofazimine, historically used for leprosy, requires further study after showing success in a 9-month regimen for multidrug-resistant TB.
The diarylquinoline TMC207 demonstrated the highest promise among new TB drugs due to its rate of culture conversion.
Daily doses of 200 mg of nitroimidazo-oxazine PA-824 and nitro-dihydro-imidazooxazole OPC-67683 were safe and showed bactericidal effects.
New oxazolidinones PNU-100480 and AZD-5847 may be as effective as linezolid but with lower toxicity.
Benzothiazinones and dinitrobenzamides exhibited significant in vitro anti-microbial activity and warrant further investigation.

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The objective of this review is to report evidence about the efficacy and potential of currently licensed drugs and new molecules beyond pre-clinical development for improving the chemotherapy of tuberculosis (TB). Rifapentine, a rifamycin with low minimum inhibitory concentration, long half-life and potent sterilizing activity in mice did not confirm its potential in a recent short-term clinical trial and is being extensively re-evaluated. Moxifloxacin, a fluoroquinolone, improved the activity of the standard drug regimen when substituted for ethambutol (EMB). It is being studied to shorten the duration of treatment for fully drug-susceptible TB (Remox study). Clofazimine, a fat-soluble dye with experimental activity against TB, but used only for leprosy in the last 50 years, requires further study because it has been included in a successful short 9-month combined drug regimen for the treatment of multidrug-resistant TB. The diarylquinoline TMC207 is the most promising among the new TB drugs because of its experimental and clinical rate of culture conversion. Also exciting, 200 mg daily doses in humans of the nitroimidazo-oxazine PA-824 and the nitro-dihydro-imidazooxazole OPC-67683 were safe and induced a bactericidal effect of respectively 0.098 ± 0.072 log(10) and 0.040 ± 0.056 log(10) per day. The new oxazolidinones PNU-100480 and AZD-5847 might be at least as active as linezolid and much less toxic. SQ109 is an EMB analogue that does not have cross-resistance with EMB and might have synergistic activity in combined regimens. Benzothiazinones and dinitrobenzamides show exciting in vitro anti-microbial activity and deserve careful attention.

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