ANTIMICROBIAL ACTIVITIES OF BENZOXAZINORIFAMYCIN KRM-1648, CLARITHROMYCIN AND LEVOFLOXACIN AGAINST INTRACELLULAR MYCOBACTERIUM-AVIUM COMPLEX PHAGOCYTOSED BY MURINE PERITONEAL-MACROPHAGES

The in-vitro activities of KRM-1648, a new benzoxazinorifamycin, clari thromycin and levofloxacin against clinical isolates of Mycobacterium avium complex (MAC) were measured using various methods of assay and c ompared with their in-vivo therapeutic activities against MAC infectio n in mice. The MICs varied according to drug in the order KRM-1648 muc h less than clarithromycin < levofloxacin. However, KRM-1648 and clari thromycin but not levofloxacin had similar therapeutic outcomes in MAC -infected mice. KRM-1648 and clarithromycin given at clinical dosages caused 1 to 2 log unit reductions in bacterial loads in the lungs of h ost mice. The values of C-max (lung)/MBC were more closely related to the therapeutic efficacy of these drugs in mice than were MICs and MBC s alone. Potent microbicidal activity was observed with KRM-1648 and c larithromycin but not with levofloxacin against extracellularly growin g MAC (EG-MAC) in a liquid medium. These two agents caused more than 3 log unit killing of MAC during a 5 day incubation, when added at conc entrations equivalent to C-max (lung). The anti-EG-MAC bactericidal ac tivity of these drugs was greater than their efficacy in mice in vivo. KRM-1648 and clarithromycin but not levofloxacin caused respectively 2 and 0.5 log unit killing of intracellularly growing MAC (IG-MAC) in murine peritoneal macrophages. The profiles of bacterial killing effec ts of these agents against IG-MAC accurately reflected their therapeut ic effects in mice, although the in-vivo activity of KRM-1648 was stil l overestimated using even this parameter.