Rifaximin prophylaxis causes resistance to the last-resort antibiotic daptomycin

Area of Science:

• Microbiology
• Molecular Biology
• Infectious Diseases

Background:

• Multidrug-resistant pathogens like vancomycin-resistant Enterococcus faecium (VREfm) pose a significant global health threat.
• Daptomycin is a crucial last-resort antibiotic for VREfm infections, but unexplained resistance is emerging.

Purpose of the Study:

• To investigate the mechanism of unexplained daptomycin resistance in VREfm.
• To determine if rifaximin, an unrelated antibiotic, contributes to daptomycin resistance.

Main Methods:

• Investigated amino acid changes in bacterial RNA polymerase following rifaximin exposure.
• Analyzed the upregulation of a novel operon (prdRAB) and its effect on cell membrane remodeling.
• Assessed the impact of these mutations on daptomycin binding and resistance.

Main Results:

• Rifaximin exposure induces mutations in bacterial RNA polymerase, leading to the upregulation of the prdRAB operon.
• This operon causes cell membrane remodeling, reducing daptomycin binding and conferring cross-resistance.
• Mutations conferring this resistance are globally prevalent in VREfm strains.

Conclusions:

• Widespread rifaximin use, previously considered low-risk for resistance, can compromise daptomycin's clinical effectiveness.
• This unanticipated cross-resistance mechanism highlights a flaw in current antibiotic stewardship assumptions.
• Urgent reassessment of rifaximin use, especially in liver disease patients, is needed to preserve last-resort antibiotics.