Rifaximin Mechanism of Action
Rifaximin inhibits bacterial RNA synthesis by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase, thereby blocking transcription and preventing bacterial protein synthesis. 1, 2
Primary Molecular Mechanism
Rifaximin binds specifically to the beta-subunit of bacterial DNA-dependent RNA polymerase, which blocks one of the steps in transcription and suppresses the initiation of RNA chain formation. 2
This binding mechanism results in inhibition of bacterial protein synthesis, producing a bactericidal effect against susceptible organisms. 3, 1
The antimicrobial effect is relatively specific to bacterial organisms at usual doses—mammalian RNA synthesis is not affected, making it selective for bacterial targets. 3, 1
Resistance to rifaximin occurs primarily through mutations in the rpoB gene, which alters the binding site on DNA-dependent RNA polymerase and decreases rifaximin's binding affinity. 2
Spectrum of Antimicrobial Activity
Rifaximin demonstrates broad antimicrobial activity against both aerobic and anaerobic gram-positive and gram-negative bacteria. 1, 4
The drug shows good activity against Escherichia coli (including enterotoxigenic and enteroaggregative strains), species of Staphylococcus, Streptococcus, and Enterococcus. 2, 5
Activity is more limited against species of Enterobacteriaceae and invasive pathogens such as Campylobacter, Salmonella, and Shigella species, which explains why rifaximin is not appropriate for treatment of dysentery or invasive diarrhea. 3, 1, 5
Unique Pharmacological Properties
Rifaximin is virtually unabsorbed after oral administration (less than 0.4% systemic absorption), maintaining high concentration levels in the intestine where it remains in an active form until excreted. 1, 6, 2
After three days of therapy, the average fecal level reaches approximately 8000 μg/g of stool, providing sustained local antimicrobial activity. 7
The non-absorbable nature results in minimal systemic exposure, which translates to an excellent safety profile with minimal drug interactions and very low risk of systemic adverse effects. 3, 1
Cross-resistance between rifaximin and other classes of antimicrobials has not been observed. 2
Clinical Implications of the Mechanism
The mechanism allows rifaximin to reduce ammonia-producing bacteria in the gut, which is the basis for its efficacy in hepatic encephalopathy. 1
The intestinal-specific action and lack of systemic absorption provide superior tolerability compared to systemically absorbed antibiotics, with adverse event rates comparable to placebo in clinical trials. 3
The drug has minimal impact on the intestinal microbiome and negligible effect on colonic flora despite its antimicrobial activity, likely because it acts primarily in the small bowel. 7, 8
Rifaximin does not significantly affect intestinal or hepatic CYP3A4 activity, minimizing potential drug-drug interactions. 2