Killing of macrophage-ingested mycobacteria by rifampicin, pyrazinamide, and pyrazinoic acid alone and in combination.

A study was undertaken with the aim of assessing the killing capacity of rifampicin, pyrazinamide, and pyrazinoic acid on macrophage-ingested, live Mycobacterium tuberculosis. The 3 drugs were used at concentrations corresponding to the average peak levels observed in humans after administration of therapeutic doses that had been found to penetrate into macrophages in a previous study. The degree of killing was studied after exposure of the cell cultures to the individual drugs and their combinations for 3, 18, 24, 48, and 72 h. Comparing the degree of killing in the control, drug-free cultures with that observed in the drug-containing systems, over a period of 3 to 24 h, indicated that in these a greater, more rapid, although not statistically significant, killing of intracellular mycobacteria took place. At 48 h the degree of killing was similar in the control and in the drug-containing cell cultures. Between 48 and 72 h, however, a marked growth of intracellular mycobacteria was observed in the control cultures. This phenomenon was much less evident in the drug-containing cultures. No major increase in the killing effect with respect to that observed with the individual drugs was found after exposure of the macrophages to all possible combinations of the 3 drugs.