World Health Organization group 5 drugs for the treatment of drug-resistant tuberculosis: unclear efficacy or untapped potential?

BACKGROUND: Treatment of multidrug-resistant or extensively drug-resistant tuberculosis (DR-tuberculosis) is challenging because commonly used second-line drugs are poorly efficacious and highly toxic. Although World Health Organization group 5 drugs are not recommended for routine use because of unclear activity, some may have untapped potential as more efficacious or better tolerated alternatives. METHODS: We conducted an exhaustive review of in vitro, animal, and clinical studies of group 5 drugs to identify critical research questions that may inform their use in current treatment of DR-tuberculosis and clinical trials of new DR-tuberculosis regimens. RESULTS: Clofazimine may contribute to new short-course DR-tuberculosis regimens. Beta-lactams merit further evaluation-specifically optimization of dose and schedule. Linezolid appears to be effective but is frequently discontinued due to toxicity. Thiacetazone is too toxic to warrant further evaluation. Mycobacterium tuberculosis has intrinsic inducible resistance to clarithromycin. CONCLUSIONS: Clofazimine and beta-lactams may have unrealized potential in the treatment of DR-tuberculosis and warrant further study. Serious toxicities or intrinsic resistance limit the utility of other group 5 drugs. For several group 5 compounds, better understanding of structure-toxicity relationships may lead to better-tolerated analogs.

Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis.

Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization-defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount.