title: In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis.
abstract: The in vitro and in vivo activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis H37Rv were compared with those of rifampin. Bactericidal activity was evaluated by using a silicone-coated slide culture method. The MBC of KRM-1648 was 0.15 to 0.3 microgram/ml for 24 h of exposure, while that of rifampin was > 160 microgram/ml under the same conditions. Against experimental murine tuberculosis, KRM-1648 exhibited significant therapeutic effects, in terms of prolonged survival times for mice compared with those with rifampin treatment, even at lower doses, such as 1 and 3 mg/kg. At a dose of 3 mg/kg, KRM-1648 was at least as effective as rifampin at 10 mg/kg. The combination of KRM-1648 (3 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg) exhibited much more activity than did rifampin (10 mg/kg) plus isoniazid (3 mg/kg) plus ethambutol (10 mg/kg). These findings suggest that KRM-1648 is a promising candidate for the treatment of tuberculosis.
authors.affiliation: Department of Infection and Inflammation, Kyoto University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamamoto
authors.forename: R
authors.initials: R
authors.lastname: Amitani
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: E
authors.initials: E
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Murayama
authors.forename: F
authors.initials: F
authors.lastname: Kuze
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004977:Ethambutol / Q000008:administration & dosage; D007538:Isoniazid / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D012293:Rifampin / Q000494:pharmacology / Q000627:therapeutic use; D012294:Rifamycins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D004338:Drug Combinations; D012294:Rifamycins; C068980:KRM 1648; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin