The effect of ethambutol on tubercle bacilli within cultured human macrophages

Ethambutol (EMB) generally is believed to be clinically mycobacteriostatic. This concept was reexamined in an in vitro model of human tuberculosis that has direct relevance to in vivo effects in human subjects. Cultured human monocyte-derived macrophages infected with virulent Erdman tubercle bacilli were treated with EMB, and the resulting antimycobacterial consequences were measured by counts of acid-fast bacilli and bacterial colony-forming units. When added immediately after infection of the macrophages, EMB inhibited and killed tubercle bacilli within the cells at the same concentrations as it did in bacteriologic culture medium. When added 2 days after infection, it first appeared to increase the viable bacillary count above control culture levels, then killed intramacrophage bacilli at lower concentrations than in bacteriologic culture medium. We speculate that this occurs because macrophages enhance EMB effectiveness by killing tubercle bacilli, which have defective cell walls due to the effects of the drug. The concentrations of EMB that proved mycobactericidal in human macrophages are readily achieved clinically. The purported lesser antituberculosis effectiveness of EMB when compared to other bactericidal agents may be due to its less direct and efficient mode of killing tubercle bacilli, and the necessity therefore, for stricter maintenance of effective drug concentrations in vivo.