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Antimicrob. Agents Chemother. doi:10.1128/AAC.00342-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Rifampin and Rifaximin Resistance in Clinical Isolates of Clostridium difficile

Hines Veterans Affairs Hospital, Hines, Illinois; Loyola University Medical Center and Loyola University Stritch School of Medicine, Maywood, Illinois

^* To whom correspondence should be addressed. Email: sjohnson{at}lumc.edu.

	Abstract

Rifaximin, a poorly absorbed rifamycin derivative, is a promising alternative for the treatment of Clostridium difficile infections. Resistance to this agent has been reported, but no commercial test for rifaximin resistance exists and the molecular basis of this resistance has not been previously studied in C. difficile. To evaluate whether the rifampin E-test would be a suitable substitute for rifaximin susceptibility testing in the clinical setting, we analyzed the in vitro rifaximin susceptibility of 80 clinical isolates from our collection by agar dilution and compared these results to rifampin susceptibility by agar dilution and E-test. We found rifaximin susceptibility data to agree with rifampin susceptibility: all isolates had either very low or very high MICs for both antimicrobials. Fourteen rifaximin-resistant (MIC32µg/ml) unique patient isolates from diverse locations in three countries were identified. Molecular typing analysis showed that nine of these isolates (64%) belonged to the epidemic BI/NAP1/027 group that is responsible for multiple outbreaks and increased disease severity in the United Kingdom, Europe and North America. The molecular basis of rifaximin and rifampin resistance in these isolates was investigated by sequence analysis of rpoB, which encodes the -subunit of RNA polymerase, the target of rifamycins. Resistance-associated rpoB sequence differences that resulted in specific amino acid substitutions in an otherwise conserved region of RpoB were found in all resistant isolates. Seven different RpoB amino acid substitutions were identified in the resistant isolates, which were divided into five distinct groups by restriction endonuclease analysis (REA) typing. These results suggest that the amino acid substitutions associated with rifamycin resistance were independently derived rather than disseminated from specific rifamycin-resistant clones. We propose that rifaximin resistance in C. difficile results from mutations in RpoB and that rifampin resistance predicts rifaximin resistance for this organism.