title: Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response.
abstract: Shiga toxin (Stx)-producing Escherichia coli (STEC) colonizes the human intestinal mucosa, produces Stx from phage, and causes the development of hemolytic-uremic syndrome via Stx-induced inflammatory cytokine production. Azithromycin exhibited strong in vitro activity against STEC without inducing Stx-converting phage, in marked contrast to norfloxacin. Azithromycin decreased the tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 production from Stx-treated human peripheral mononuclear cells or monocytes to a greater extent than did clarithromycin. In Stx-injected mice, azithromycin significantly suppressed Stx-induced TNF-alpha, IL-1beta, and IL-6 levels in serum and improved the outcome as assessed by survival rate. In the STEC oral infection experiment using immature mice immediately after weaning (weaned immature-mouse model), all mice died within 7 days postinfection. Azithromycin administration gave the mice 100% protection from killing, while ciprofloxacin administration gave them 67% protection. The data suggest that azithromycin (at least at higher concentrations) has a strong effect on Stx production by STEC and on the Stx-induced inflammatory host response and prevents death in mice. Azithromycin may have a beneficial effect on STEC-associated disease.
authors.affiliation: Division of Bacteriology, Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Ohara
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kojio
authors.forename: Ikue
authors.initials: I
authors.lastname: Taneike
authors.forename: Saori
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Gondaira
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tamura
authors.forename: Fumitake
authors.initials: F
authors.lastname: Gejyo
authors.forename: Hui-Min
authors.initials: HM
authors.lastname: Zhang
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology*; D001435:Bacteriophages / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D022621:Shiga Toxin / Q000096:biosynthesis* / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D022621:Shiga Toxin; D017963:Azithromycin