TABLE 2.

Suggested reasons for the low risk of development of clinically relevant microbial resistance to rifaximin-α^a

Mechanism	Comment
Rifaximin-α is essentially non-absorbed. Rifaximin-α shows low water solubility (10), minimizing drug concentrations in the aqueous colon.	Systemic resistance, outside the gut, is unlikely to occur. Bacterial responses to antimicrobial agents are concentration dependent (46). Sub-inhibitory concentrations of rifaximin alter organisms’ virulence while preventing widespread major changes in the microbiome and persistence of resistant strains.
One-step chromosomal resistance to rifamycins involving rpoB gene is not associated with mobilization to other strains (31, 34).	Acquisition of rifaximin-α resistance is transient, disappearing when the drug is stopped, and resistance is not mediated by plasmid/transposon factors, which prevents spread in the gut to other bacterial strains.
Metabolic modifications of antibiotic-resistant mutants minimize persistence.	Resistant mutants with their membrane saturated fatty acids (47) lack “fitness” and are not given selective advantage in the face of continued rifaximin-α therapy.
Mycobacterium tuberculosis shows low potential for development of resistance to rifaximin-α (48).	Rifaximin does not select for resistant strains of M. tuberculosis in artificial media (48) or in experimental animals (49). The non-systemic nature of the drug is a deterrent to emergence of resistance for this pathogen.

^a rpoB, bacterial DNA-dependent RNA polymerase.