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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.

TitleRifaximin 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.
Publication TypeJournal Article
Year of Publication2013
AuthorsKothary V, Scherl EJ, Bosworth B, Jiang Z-D, Dupont HL, Harel J, Simpson KW, Dogan B
JournalAntimicrob Agents Chemother
Volume57
Issue2
Pagination811-7
Date Published2013 Feb
ISSN1098-6596
KeywordsAmino Acid Substitution, Anti-Bacterial Agents, Anti-Infective Agents, Colitis, Ulcerative, Crohn Disease, Dipeptides, Drug Resistance, Bacterial, Escherichia coli, Escherichia coli Proteins, Humans, Ileum, Intestinal Mucosa, Membrane Transport Proteins, Microbial Sensitivity Tests, Mutation, Rifampin, Rifamycins
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.

DOI10.1128/AAC.02163-12
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID23183443
PubMed Central IDPMC3553721