Marked increases in case rates of
drug-resistant tuberculosis and nontuberculous mycobacterial
infections have brought renewed urgency to the development of new treatment regimens for mycobacterial
infections. Preclinical data, such as in vitro measures of
drug activity and pharmacokinetics, are used in the design of new treatment regimens. This review surveys the extensive published clinical experience concerning the treatment of
drug-susceptible
tuberculosis to evaluate the use of these preclinical measures in predicting clinical outcomes of antimycobacterial
therapy. In vitro measures of
drug activity predict the potency of a
drug to prevent the emergence of resistance to other antimycobacterial drugs but do not predict the sterilizing activity of a
drug or the activity of
drug combinations. In vitro measures of
drug activity do not allow reliable predictions of the level at which an organism should be considered resistant. Assays of
drug penetration in tissues and activity against intracellular bacilli add modestly to the predictive value of in vitro measures of
drug activity but still do not predict sterilizing activity. In contrast, animal models of
tuberculosis have predicted relative
drug potency (including sterilizing activity), the efficacy of multidrug regimens, and the
duration of therapy needed. Despite pharmacokinetic parameters that would suggest the need for multiple doses per day, all of the first-line antituberculous drugs are active when given as infrequently as twice weekly. It is difficult to predict the efficacy of
therapy for an intracellular pathogen that has the capacity for dormancy. Better in vitro models are needed, particularly ones that predict sterilizing activity.