title: Rifaximin resistance in Escherichia coli associated with inflammatory bowel disease correlates with prior rifaximin use, mutations in rpoB, and activity of Phe-Arg-β-naphthylamide-inhibitable efflux pumps.
abstract: Escherichia coli is implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a nonabsorbable derivative of rifampin effective against E. coli, improves symptoms in mild-to-moderate IBD. However, rifaximin resistance can develop in a single step in vitro. We examined the prevalence and mechanisms of rifaximin resistance in 62 strains of E. coli isolated from the ileal mucosa of 50 patients (19 with ileal Crohn's disease [L1+L3], 6 with colonic Crohn's disease [L2], 13 with ulcerative colitis [UC], 4 with symptomatic non-IBD diagnoses [NI], and 8 healthy [H]). Resistance (MIC > 1,024 mg/liter) was present in 12/48 IBD-associated ileal E. coli strains. Resistance correlated with prior rifaximin treatment (P < 0.00000001) but not with the presence of ileal inflammation (P = 0.73) or E. coli phylogroup. Mutations in a 1,057-bp region of rpoB, which encodes the bacterial target of rifaximin, were identified in 10/12 resistant strains versus 0/50 sensitive strains (P < 0.000000001) and consisted of seven amino acid substitutions. The efflux pump inhibitor Phe-Arg-β-naphthylamide (PAβN) lowered the MIC of 9/12 resistant strains 8- to 128-fold. Resistance was stable in the absence of rifaximin in 10/12 resistant strains after 30 passages. We conclude that IBD-associated ileal E. coli frequently manifest resistance to rifaximin that correlates with prior rifaximin use, amino acid substitutions in rpoB, and activity of PAβN-inhibitable efflux pumps, but not with the presence of ileal inflammation or E. coli phylogroup. These findings have significant implications for treatment trials targeting IBD-associated E. coli.
authors.affiliation: College of Agriculture and Life Sciences, Cornell University, Ithaca, New York, USA.
authors.forename: Vishesh
authors.initials: V
authors.lastname: Kothary
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Scherl
authors.forename: Brian
authors.initials: B
authors.lastname: Bosworth
authors.forename: Zhi-Dong
authors.initials: ZD
authors.lastname: Jiang
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Dupont
authors.forename: Josee
authors.initials: J
authors.lastname: Harel
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Simpson
authors.forename: Belgin
authors.initials: B
authors.lastname: Dogan
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000382:microbiology; D003424:Crohn Disease / Q000382:microbiology; D012321:DNA-Directed RNA Polymerases; D004151:Dipeptides / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D029968:Escherichia coli Proteins / Q000235:genetics*; D006801:Humans; D007082:Ileum / Q000382:microbiology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D009154:Mutation; D012293:Rifampin / Q000494:pharmacology; D012294:Rifamycins / Q000494:pharmacology*; D000078262:Rifaximin
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D004151:Dipeptides; D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; D012294:Rifamycins; C474925:phenylalanylarginine-naphthylamide; C540081:rpoB protein, E coli; D012321:DNA-Directed RNA Polymerases; D000078262:Rifaximin; D012293:Rifampin