Emerging preclinical and clinic evidence described herein suggests that the mechanism of action of
rifaximin is not restricted to direct antibacterial effects within the gastrointestinal tract. Data from this study were derived from general and clinical trial-specific PubMed searches of English-language articles on
rifaximin available through December 3, 2014. Search terms included
rifaximin alone and in combination (using the Boolean operation "AND") with travelers'
diarrhea,
hepatic encephalopathy,
liver cirrhosis,
irritable bowel syndrome,
inflammatory bowel disease, and
Crohn's disease.
Rifaximin appears to reduce bacterial virulence and pathogenicity by inhibiting bacterial translocation across the gastrointestinal epithelial lining.
Rifaximin was shown to decrease bacterial adherence to epithelial cells and subsequent internalization in a bacteria- and cell type-specific manner, without an alteration in bacterial counts, but with a down-regulation in epithelial proinflammatory
cytokine expression.
Rifaximin also appears to modulate gut-immune signaling. In animal models of
inflammatory bowel disease,
rifaximin produced
therapeutic effects by activating the
pregnane X receptor and thereby reducing levels of the proinflammatory
transcription factor nuclear factor κB. Therefore, for a given disease state,
rifaximin may act through several mechanisms of action to exert its
therapeutic effects. Clinically,
rifaximin 600 mg/d significantly reduced symptoms of travelers'
diarrhea (eg, time to last unformed stool vs placebo [32.0 hours vs 65.5 hours, respectively; P=.001]). For the prevention of
hepatic encephalopathy recurrence, data indicate that treating 4 patients with
rifaximin 1100 mg/d for 6 months would prevent 1 episode of
hepatic encephalopathy. For
diarrhea-predominant
irritable bowel syndrome, a significantly greater percentage (40.7%) of patients treated with
rifaximin 1650 mg/d for 2 weeks experienced adequate global
irritable bowel syndrome symptom relief vs placebo (31.7%; P<.001).
Rifaximin may be best described as a gut microenvironment modulator with cytoprotection properties, and further studies are needed to determine whether these putative mechanisms of action play a direct role in clinical outcomes.