title: Antimicrobial activities of benzoxazinorifamycin KRM-1648, clarithromycin and levofloxacin against intracellular Mycobacterium avium complex phagocytosed by murine peritoneal macrophages.
abstract: The in-vitro activities of KRM-1648, a new benzoxazinorifamycin, clarithromycin and levofloxacin against clinical isolates of Mycobacterium avium complex (MAC) were measured using various methods of assay and compared with their in-vivo therapeutic activities against MAC infection in mice. The MICs varied according to drug in the order KRM-1648 << clarithromycin < levofloxacin. However, KRM-1648 and clarithromycin 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 host mice. The values of Cmax (lung)/MBC were more closely related to the therapeutic efficacy of these drugs in mice than were MICs and MBCs alone. Potent microbicidal activity was observed with KRM-1648 and clarithromycin but not with levofloxacin against extracellularly growing 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 concentrations equivalent to Cmax (lung). The anti-EG-MAC bactericidal activity 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 effects of these agents against IG-MAC accurately reflected their therapeutic effects in mice, although the in-vivo activity of KRM-1648 was still overestimated using even this parameter.
authors.affiliation: Department of Microbiology and Immunology, Shimane Medical University, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: T
authors.initials: T
authors.lastname: Akaki
authors.forename: H
authors.initials: H
authors.lastname: Tomioka
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017291:Clarithromycin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D064704:Levofloxacin; D008168:Lung / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*; D015242:Ofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D010587:Phagocytosis; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D012294:Rifamycins; C068980:KRM 1648; D064704:Levofloxacin; D015242:Ofloxacin; D017291:Clarithromycin