title: In vitro and in vivo antibacterial activities of KRM-1648 and KRM-1657, new rifamycin derivatives.
abstract: The in vitro and in vivo antibacterial activities of the new rifamycin derivatives KRM-1648 and KRM-1657 were compared with those of rifampin. Rifabutin, ciprofloxacin, and clarithromycin were also tested for reference. The respective MICs of KRM-1648 and KRM-1657 for 90% of the strains tested (MIC90S) were 0.016 and 0.0078 microgram/ml, respectively, for methicillin-susceptible Staphylococcus aureus, 0.016 and 0.0039 microgram/ml, respectively, for methicillin-resistant S. aureus, and 0.0625 and 0.016 microgram/ml, respectively, for methicillin- and quinolone-resistant S. aureus. These MIC90S of KRM-1657 were equal to or 2- to 64-fold lower than those of rifampin. KRM-1648 and KRM-1657 with MIC90S of between 0.002 and 0.078 microgram/ml were 2- to 128-fold more active than rifampin against Staphylococcus epidermidis and Streptococcus species, including Streptococcus pneumoniae and Streptococcus pyogenes. The MIC90S of KRM-1657 for Haemophilus influenzae and Neisseria gonorrhoeae were 0.25 and 0.1 microgram/ml, respectively; KRM-1657 was almost as active as rifampin and was 8- to 16-fold more active than KRM-1648 against these strains. The frequency of occurrence of spontaneous mutations to resistance to KRM-1648 and KRM-1657 was equal to that to rifampin. Against systemic infection with S. aureus in mice, the efficacies of KRM-1648 and KRM-1657 were comparable to that of rifampin.
authors.affiliation: Department of Microbiology, Toho University School of Medicine, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Fujii
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.forename: K
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: S
authors.initials: S
authors.lastname: Goto
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology* / Q000627:therapeutic use; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D004352:Drug Resistance, Microbial; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D012293:Rifampin / Q000494:pharmacology; D012294:Rifamycins / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics
chemical_list: D000904:Antibiotics, Antitubercular; D012294:Rifamycins; C068980:KRM 1648; C068981:KRM 1657; D012293:Rifampin