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.
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