EFFECTS OF CLARITHROMYCIN AND RIFABUTIN ALONE AND IN COMBINATION ON INTRACELLULAR AND EXTRACELLULAR REPLICATION OF MYCOBACTERIUM-AVIUM

The combined effect of clarithromycin and rifabutin against Mycobacter ium avium multiplying either within human monocyte-derived macrophages or extracellularly in a liquid medium was additive: both MICs and MBC s were twofold lower for the combination than they were for each drug alone. Prolonged exposure for 4 weeks of M. avium-infected macrophages to combined concentrations that were only twofold greater than the MI Cs resulted in a 100-fold decrease in the number of viable bacteria, w hile in the drug-free controls a 100-fold or greater increase in compa rison with the initial viable counts took place. Comparison of this ef fect with the results of the prolonged exposure to each drug alone sug gested that under these experimental conditions rifabutin enhanced the antimicrobial activity of clarithromycin against intracellular bacter ia. At the same time, inhibition of intracellular growth by a 2-h puls ed exposure of the infected macrophages to the combination of the two drugs was not different from the effect induced by clarithromycin alon e. In conclusion, clarithromycin played the major role in the antimicr obial activity of the tested combination, while rifabutin may have enh anced this effect during a prolonged exposure of the intracellular bac teria to these two agents.