Rifamycin use and gut microbial antibiotic resistance genes in cirrhosis: Results from a double-blind, placebo-controlled clinical trial.

Rifamycin SV MMX (RiVM) induced minimal perturbation of the gut resistome in patients with compensated cirrhosis.

• The RIVET trial was randomized, double-blind and placebo-controlled, with 15 RiVM and 15 placebo participants.
• Shotgun metagenomic sequencing was performed before and after 30 days of therapy.
• ARGs were annotated using the Comprehensive Antibiotic Resistance Database (CARD).
• No significant change in ARGs was found after FDR adjustment.

Both univariable and multivariable analyses showed a trend toward lower vancomycin resistance ARGs after RiVM exposure.

• The reduced genes included vanW and vanT operon-associated genes.
• Methods used were LEfSe, paired-Wilcoxon testing and MaAsLin3.
• The abstract describes this as a trend, not a result that was significant after FDR.

Several Enterobacteriaceae-associated multidrug efflux regulators showed nominal increases after rifamycin that did not survive FDR correction.

• The genes named were evgS, emrK and mdtA.
• The increases were nominal only and did not withstand FDR adjustment.

Group-level machine learning discriminated poorly between RiVM and placebo, whereas within-subject longitudinal models classified better.

• ML was applied to determine ARG changes at both subject and group levels.
• Group-level models gave limited discrimination between the treatment groups.
• Within-subject longitudinal models achieved improved classification performance.

No increase in infections or treatment-related safety concerns was observed with RiVM.

• The trial lasted 30 days in compensated cirrhosis patients.
• RiVM was not associated with infections compared with placebo.

Rifamycin MMX did not enrich antimicrobial resistance genes relative to placebo in this small trial.

• The authors note a tendency toward reduced vancomycin resistance and ARG reduction after rifamycin exposure.
• The study was small (30 participants) and short (30 days).

The study was motivated by the link between ARG carriage and poor outcomes in cirrhosis, and by preclinical data linking rifaximin to ARG expansion.

• ARG carriage is associated with poor outcomes in cirrhosis and is worsened by repeated antibiotic exposure and hospitalization.
• The effects of RiVM on the gut resistome were previously unknown.