Adenosine A sub(2A) receptor activation reduces recurrence and mortality from Clostridium difficile infection in mice following vancomycin treatment

• Published in: BMC infectious diseases 2012-01, Vol.12 (1), p.342-342
• Main Authors: Li, Yuesheng, Figler, Robert A, Kolling, Glynis, Bracken, Tara C, Rieger, Jayson, Stevenson, Ralph W, Linden, Joel, Guerrant, Richard L, Warren, Cirle Alcantara
• Format: Article
• Language: English
• Subjects: Clostridium difficile
• ISSN: 1471-2334; 1471-2334
• DOI: 10.1186/1471-2334-12-342

Background: Activation of the A sub(2A) adenosine receptor (A sub(2A)AR) decreases production of inflammatory cytokines, prevents C. difficile toxin A-induced enteritis and, in combination with antibiotics, increases survival from sepsis in mice. We investigated whether A sub(2A)AR activation improves and A sub(2A)AR deletion worsens outcomes in a murine model of C. difficile (strain VPI10463) infection (CDI). Methods: C57BL/6 mice were pretreated with an antibiotic cocktail prior to infection and then treated with vancomycin with or without an A sub(2A)AR agonist. A sub(2A)AR super(-/-) and littermate wild-type (WT) mice were similarly infected, and IFN[gamma] and TNF[alpha] were measured at peak of and recovery from infection. Results: Infected, untreated mice rapidly lost weight, developed diarrhea, and had mortality rates of 50-60%. Infected mice treated with vancomycin had less weight loss and diarrhea during antibiotic treatment but mortality increased to near 100% after discontinuation of antibiotics. Infected mice treated with both vancomycin and an A sub(2A)AR agonist, either ATL370 or ATL1222, had minimal weight loss and better long-term survival than mice treated with vancomycin alone. A sub(2A)AR KO mice were more susceptible than WT mice to death from CDI. Increases in cecal IFN[gamma] and blood TNF[alpha] were pronounced in the absence of A sub(2A)ARs. Conclusion: In a murine model of CDI, vancomycin treatment resulted in reduced weight loss and diarrhea during acute infection, but high recurrence and late-onset death, with overall mortality being worse than untreated infected controls. The administration of vancomycin plus an A sub(2A)AR agonist reduced inflammation and improved survival rates, suggesting a possible benefit of A sub(2A)AR agonists in the management of CDI to prevent recurrent disease.