The Case for Using Higher Doses of First Line Anti-Tuberculosis Drugs to Optimize Efficacy

Apart from new anti-tuberculosis drug development, another approach for tuberculosis (TB) treatment optimization is to derive maximum benefit from current agents. However, the dosage of current anti-TB drug regimens has never been optimized according to the exposure-effect relationships of each drug. The objective of this article is to review the latest pharmacokinetic, pharmacodynamic, experimental, and clinical data concerning the use of higher doses of first-line anti-TB drugs to improve the efficacy of pulmonary tuberculosis treatment. Exposure-effect relationships have been described for all first-line anti-TB agents. There is convincing evidence that patients would benefit from higher rifamycin exposure. This could be achieved by using higher daily doses of rifampin, or more frequent dosing of rifapentine. The dose-dependent activity of pyrazinamide observed in hollow-fiber and animal models suggests that higher doses of pyrazimamide might be more efficacious, but the tolerability of such higher doses needs to be investigated in humans. It is likely that higher doses of ethambutol would be associated with higher antibacterial effect, but the dose-related ocular toxicity of the drug precludes such practice. For isoniazid, dose individualization is required to optimize patient care. The use of higher than standard doses of isoniazid in fast acetylators should result in greater early bactericidal activity. To conclude, the use of higher doses for some of the firstline anti-TB agents has definite potential for shortening or improving TB treatment.