Effects of azithromycin on shiga toxin production by Escherichia coli and subsequent host inflammatory response.
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.
Ohara
Tatsuki
T
Division of Bacteriology, Department of Infectious Disease Control and International Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Kojio
Seiichi
S
Taneike
Ikue
I
Nakagawa
Saori
S
Gondaira
Fumio
F
Tamura
Yukiko
Y
Gejyo
Fumitake
F
Zhang
Hui-Min
HM
Yamamoto
Tatsuo
T
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
D000900:Anti-Bacterial Agents; D016207:Cytokines; D022621:Shiga Toxin; D017963:Azithromycin