Acquired rifamycin resistance: pharmacology and biology.

The global emergence of multidrug-resistant and extensively drug-resistant TB has refocused attention on preventing acquired resistance. This article reviews basic science, pharmacology and public policy to understand the contribution of these factors to acquired rifamycin resistance (ARR), a critical factor in multidrug resistance. Directly observed therapy short course (DOTS) effectiveness requires that each drug's effects persist equally throughout the dosing interval. Although rifampin and isoniazid have similar pharmacokinetics, the postantibiotic effect of rifampin is several times greater than that of isoniazid. As a result, rifampin's effects may persist unopposed when standard multidrug regimens are administered at intervals longer than 24 h. ARR may occur in this setting when outgrowth is not otherwise contained by the host immune response. Most countries do not provide weekend therapy under DOTS. Limiting TB therapy to weekdays may promote the emergence of acquired drug resistance in patients with advanced AIDS and TB. A large, simple trial to examine this question is both warranted and feasible.