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The potential for development of clinically relevant microbial resistance to rifaximin-α: a narrative review

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CLINICAL MICROBIOLOGY REVIEWS
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AMER SOC MICROBIOLOGY
DOI: 10.1128/cmr.00039-23

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antibiotics; clinical resistance; mechanism of action; microbial resistance; rifaximin-alpha efficacy

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Rifaximin-alpha is a gut-targeted antibiotic with multifaceted mechanism of action that not only exhibits direct antimicrobial effects but also improves gut permeability and reduces inflammation. It has low systemic drug levels and low risk of resistance compared to other antibiotics. Its efficacy and safety have been observed in chronic gastrointestinal disorders and traveler's diarrhea.
Rifaximin-alpha is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. 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-alpha 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-alpha appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-alpha resistance appears to be lower than for many other antibiotics. Rifaximin-alpha has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-alpha 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-alpha may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-alpha not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-alpha resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-alpha efficacy.

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