title: Time- and dose-dependent effect of fosfomycin on suppression of infection-induced endotoxin shock in mice.
abstract: Therapeutic effects of fosfomycin (FOF) and imipenem (IPM) were investigated in a novel model for endotoxin shock that was caused by intraperitoneal (i.p.) infection with 10(8) colony forming units of attenuated Salmonella typhimurium. Acute lethal shock was observed in BALB/c and ddY but not in lipopolysaccharide (LPS)-nonresponder BALB/lps(d) mice. Effects of FOF, but not its enantiomer, and IPM were dose- and time-dependent, since therapeutic efficacy was demonstrated in mice injected i.p. or orally at doses of more than 20 mg/kg 15 min before or 1 h after infection. Treatment with FOF 1 h postinfection (p.i.) resulted in significant decreases in bacterial numbers in spleen and liver, suggesting that the antimicrobial activity of FOF seems to closely correlate to suppression of infection-induced lethal shock. Regarding coagulation systems, FOF inhibited increase in the prothrombin time but upregulated fibrinogen concentration. Plasma levels of LPS released from bacilli were significantly higher in FOF- than IPM-treated mice and infection controls, but both antibiotics showed similar efficacy in protection.
authors.affiliation: Medicinal Plant Garden, School of Pharmaceutical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Kawaguchi
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Hasunuma
authors.forename: Sei-ichi
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Roland
authors.initials: R
authors.lastname: Ryll
authors.forename: Keiko
authors.initials: K
authors.lastname: Morikawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kumazawa
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005578:Fosfomycin / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D012481:Salmonella Infections, Animal / Q000097:blood / Q000188:drug therapy*; D012486:Salmonella typhimurium; D012772:Shock, Septic / Q000097:blood / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D005578:Fosfomycin