title: Activities of bay Y 3118, levofloxacin, and ofloxacin alone or in combination with ethambutol against Mycobacterium avium complex in vitro, in human macrophages, and in beige mice.
abstract: Levofloxacin, ofloxacin, and Bay Y 3118 are new fluoroquinolones with variable in vitro bacteriostatic and bactericidal activities against the Mycobacterium avium complex (MAC). The potential therapeutic activities of these agents both alone and combined with ethambutol were evaluated in a human macrophage test system and in the beige mouse animal test system with MAC strain 101. Bay Y 3118 at a human-equivalent dose of 30 mg/kg/day for 4 weeks caused a significant reduction in mortality compared with that in untreated controls (P = 0.02). Bay Y 3118 also caused significant reductions in the number of MAC organisms in the blood, liver tissue, and spleen tissue compared with those in untreated controls. Levofloxacin at a human-equivalent dose of 200 mg/kg/day was associated with a significant reduction in mortality (10 versus 39%); however, treatment with either levofloxacin or ofloxacin (200 mg/kg/day) did not result in significant reductions in the numbers of MAC organisms in blood, liver, and spleen compared with those in untreated controls. When Bay Y 3118 was combined with ethambutol, there was no enhancement in therapeutic activity except in the spleen in terms of CFU per gram (reductions of 89% compared with the untreated control, 63% compared with Bay Y 3118 alone, and 72.5% compared with ethambutol alone). Levofloxacin in combination with ethambutol was more active than either drug alone in the reduction of organisms in blood, liver, and spleen. Bay Y 3118 was the most active fluoroquinolone for monotherapy of MAC infection in beige mice, and the combination of ethambutol plus either levofloxacin or ofloxacin was at least additive. In summary, this study demonstrates that quinolones, although active, are inhibitory against MAC in vivo and that there is little correlation between the activity of quinolones in vitro and the activity in mice.
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco 94115, US
authors.forename: L E
authors.initials: LE
authors.lastname: Bermudez
authors.forename: C B
authors.initials: CB
authors.lastname: Inderlied
authors.forename: P
authors.initials: P
authors.lastname: Kolonoski
authors.forename: M
authors.initials: M
authors.lastname: Wu
authors.forename: L
authors.initials: L
authors.lastname: Barbara-Burnham
authors.forename: L S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004338:Drug Combinations; D004977:Ethambutol / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy* / Q000382:microbiology; D015242:Ofloxacin / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D051381:Rats
chemical_list: D000890:Anti-Infective Agents; D004338:Drug Combinations; D024841:Fluoroquinolones; D015363:Quinolones; C079807:Bay Y3118; D064704:Levofloxacin; D004977:Ethambutol; D015242:Ofloxacin