IN-VITRO AND EX-VIVO ACTIVITIES OF ANTIMICROBIAL AGENTS USED IN COMBINATION WITH CLARITHROMYCIN, WITH OR WITHOUT AMIKACIN, AGAINST MYCOBACTERIUM-AVIUM

MICs of clarithromycin, amikacin, isoniazid, rifabutin, ciprofloxacin, sparfloxacin, ethambutol, and clofazimine were determined for six iso lates of Mycobacterium avium complex (MAC) from AIDS patients both by the radiometric method and by an ex vivo model of infection in human m acrophages. The median MICs in macrophages were similar or slightly lo wer than values found in broth, except for amikacin, which had slightl y higher MICs inside the cells. Combinations of clarithromycin with ot her antimicrobial agents showed that clarithromycin-clofazimine and cl arithromycin-rifabutin were synergistic on five of sis strains while c larithromycin-amikacin and clarithromycin-isoniazid were antagonistic on one and two strains, respectively, The addition of amikacin made th e combinations of clarithromycin-clofazimine and clarithromycin-ethamb utol synergistic against all the MAC strains. In the macrophage model, the combination of clarithromycin clofazimine (mean survival, 21%) an d clarithromycin-rifabutin (mean survival, 29%) showed a strong reduct ion in viable counts compared with single drugs, while clarithromycin- amikacin,vas less active than single drugs alone. In general, the addi tion of amikacin did not improve the activity of the combinations, exc ept for clarithromycin-isoniazid-amikacin (mean survival, 19%), which was significantly more active than either clarithromycin-isoniazid or clarithromycin-amikacin. The use of the macrophage model can suggest n ew combinations of antimicrobial agents with anti-MAC activity which, on the basis of their in vitro effectiveness, would probably be disreg arded for assay in animal models.