Experimental drugs and combination therapy.

The worldwide increase in tuberculosis, the additional problem of increasing multiple drug resistance (MDR) and the primary resistance of Mycobacterium avium requires new strategies in drug development and in therapy. The reason for development of MDR is manifold. One important factor is the change in cell wall construction which limits the penetration of the drug to the target receptor. This is supported by the observation that within a class of tuberculostatic drugs (identical mode of action) the more lipophilic derivative is more effective. In addition, it has been shown that mycobacteria within macrophages are able to synthesize additional multilamellar cell wall components. Several possibilities exist to overcome MDR. Besides improving the permeation properties of drugs, the development of synergistic drug combinations based on their special mode of action is a promising approach. This is illustrated with the highly synergistic combination of newly developed hydrazones and thiacetazone respectively with rifampicin. Chance combinations which may even lead to antagonism have to be avoided. Examples of antagonistic behavior of the combinations clofazimine-dapsone and ofloxacin-rifampicin are discussed. An optimization procedure has been developed based on the determination of the specific resistance of patient-derived mycobacteria against single drugs and their combinations. With its use, an individual optimal treatment becomes feasible. Preliminary clinical experience is encouraging.