Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol.

Abstract

Ethambutol is used for the treatment of tuberculosis in cases where there is isoniazid resistance. We examined the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies of a hollow-fiber system. Dose-effect and dose-scheduling studies were performed with ethambutol and log-phase growth Mycobacterium tuberculosis to identify exposures and schedules linked to optimal kill and resistance suppression. In one study, after 7 days of daily ethambutol, 300 mg isoniazid per day was administered to each system to determine its early bactericidal activity. Efflux-pump blockage reduced the mutation frequency to ethambutol 64-fold. In dose-effect studies, ethambutol had a maximal early bactericidal activity of 0.22 log10 colony-forming units/mL/day, as is encountered in patients. By day 7, resistance to both ethambutol and isoniazid had increased. Previous exposure to ethambutol halted isoniazid early bactericidal activity. Daily therapy, as opposed to more intermittent therapy, was associated with the least proportion of efflux-pump-driven resistance, consistent with a time-driven effect. Microbial kill was best explained by the ratio of area under the concentration-time curve to minimum inhibitory concentration (r2 = 0.90). The induction of an efflux pump that reduces the effect of multiple drugs provides an alternative pathway to sequential acquisition of mutations in the development of multiple drug resistance.