THE VALUE OF IN-VITRO DRUG ACTIVITY AND PHARMACOKINETICS IN PREDICTING THE EFFECTIVENESS OF ANTIMYCOBACTERIAL THERAPY - A CRITICAL-REVIEW

Marked increases in case rates of drug-resistant tuberculosis and nont uberculous mycobacterial infections have brought renewed urgency to th e development of new treatment regimens for mycobacterial infections, Preclinical data, such as in vitro measures of drug activity and pharm acokinetics, are used in the design of new treatment regimens. This re view surveys the extensive published clinical experience concerning th e treatment of drug-susceptible tuberculosis to evaluate the use of th ese preclinical measures in predicting clinical outcomes of antimycoba cterial therapy, In vitro measures of drug activity predict the potenc y of a drug to prevent the emergence of resistance to other antimycoba cterial 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 s hould be considered resistant, Assays of drug penetration in tissues a nd activity against intracellular bacilli add modestly to the predicti ve value of in vitro measures of drug activity but still do not predic t sterilizing activity, In contrast, animal models of tuberculosis hav e predicted relative drug potency (including sterilizing activity), th e efficacy of multidrug regimens, and the duration of therapy needed, Despite pharmacokinetic parameters that would suggest the need for mul tiple doses per day, all of the first-line antituberculous drugs are a ctive when given as infrequently as twice weekly, It is difficult to p redict the efficacy of therapy for an intracellular pathogen that has the capacity for dormancy, Better in vitro models are needed, particul arly ones that predict sterilizing activity.