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Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-\u03b1 is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-\u03b1 appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although\n            <jats:italic>in vitro<\/jats:italic>\n            testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-\u03b1 resistance appears to be lower than for many other antibiotics. Rifaximin-\u03b1 has been used for many years for traveler\u2019s diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-\u03b1 retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-\u03b1 may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-\u03b1 not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-\u03b1 resistance between bacterial species. Reported emergence of vancomycin-resistant\n            <jats:italic>Enterococcus<\/jats:italic>\n            in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between\n            <jats:italic>in vitro<\/jats:italic>\n            resistance and rifaximin-\u03b1 efficacy.\n          <\/jats:p>","DOI":"10.1128\/cmr.00039-23","type":"journal-article","created":{"date-parts":[[2023,11,16]],"date-time":"2023-11-16T14:03:44Z","timestamp":1700143424000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["The potential for development of clinically relevant microbial resistance to rifaximin-\u03b1: a narrative review"],"prefix":"10.1128","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1652-7168","authenticated-orcid":true,"given":"Herbert L.","family":"DuPont","sequence":"first","affiliation":[{"name":"School of Public Health and McGovern Medical School, Baylor College of Medicine, Kelsey Research Foundation, University of Texas Health Science Center Houston, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2014.106"},{"key":"e_1_3_2_3_2","volume-title":"Rifaximin, StatPearls","author":"Robertson KD","year":"2021","unstructured":"Robertson KD, Nagalli S. 2021. 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