Clinically important interaction between statin drugs and Clostridium difficile toxin?
Clostridium difficile associated disease (CDAD), a common type of antibiotic associated diarrhea, is increasing in frequency and affecting patients outside of traditional populations. At one time CDAD exclusively occurred in hospitalized patients or frail elderly patients receiving antibiotic therapy. It is now occurring more commonly in younger patients who are relatively healthy and may not be receiving antibiotics. Co-factors that might explain this increase incidence and changing demographic are of great public health interest. Recent investigations have identified gastric acid suppression, particularly via proton pump inhibitors, as a risk factor for the development of CDAD by mechanisms which are not entirely clear. C. difficile toxin comes as two major forms that are closely related, toxin A and toxin B and both are able to produce CDAD. These toxins have a glucosyltransferase domain that glucosylates actived Rho, a small GTP binding protein involved in multiple cellular signaling pathways. Glucosylation inactivates Rho and modifies cell cycle, cytoskeletal and inflammatory pathways. The lipid lowering drugs called statins also inhibit Rho but at an earlier step in the Rho pathway. Statins inhibit the isoprenylation of Rho and therefore inhibits membrane anchoring a key step in Rho signaling. We propose that statins potentiate C. difficile toxin effects on colonic epithelium which leads to an increased risk of CDAD. We present preliminary data from a retrospective cohort which demonstrated an increased rate of CDAD in patients receiving statins compared to non-statin controls. The weight of the evidence leads to our hypothesis that statins interact with C difficile toxin A and B causing an increase in the rate and severity of CDAD.
McGuire
Timothy
T
College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-6045, United States. trmcguir@unmc.edu
Dobesh
Paul
P
Klepser
Don
D
Rupp
Mark
M
Olsen
Keith
K
D000368:Aged; D001427:Bacterial Toxins / Q000378:metabolism*; D016360:Clostridioides difficile / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008962:Models, Theoretical
D001427:Bacterial Toxins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors