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Antimicrobial Agents and Chemotherapy, August 2008, p. 2813-2817, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00342-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Rifampin and Rifaximin Resistance in Clinical Isolates of Clostridium difficile{triangledown} ,{dagger}

Jennifer R. O'Connor,1 Minerva A. Galang,2,{ddagger} Susan P. Sambol,1 David W. Hecht,1,2 Gayatri Vedantam,1,2 Dale N. Gerding,1,2 and Stuart Johnson1,2*

Hines Veterans Affairs Hospital, Hines, Illinois,1 Loyola University Medical Center and Loyola University Stritch School of Medicine, Maywood, Illinois2

Received 11 March 2008/ Returned for modification 22 April 2008/ Accepted 5 June 2008

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 Etest would be a suitable substitute for rifaximin susceptibility testing in the clinical setting, we analyzed the in vitro rifaximin susceptibilities of 80 clinical isolates from our collection by agar dilution and compared these results to rifampin susceptibility results obtained by agar dilution and Etest. We found rifaximin susceptibility data to agree with rifampin susceptibility; the MICs of both antimicrobials for all isolates were either very low or very high. Fourteen rifaximin-resistant (MIC, ≥32 µg/ml) unique isolates from patients at diverse locations in three countries were identified. Molecular typing analysis showed that nine (64%) of these isolates 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 β 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 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.

* Corresponding author. Mailing address: Research (151), Hines VA Hospital, 5000 South 5th Ave., Hines, IL 60141-3030. Phone: (708) 216-3232. Fax: (708) 216-8198. E-mail: sjohnson{at}lumc.edu

{triangledown} Published ahead of print on 16 June 2008.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

{ddagger} Present address: Saint Mary's Health Care and McAuley Health Center, Grand Rapids, MI.

Antimicrobial Agents and Chemotherapy, August 2008, p. 2813-2817, Vol. 52, No. 8
0066-4804/08/$08.00+0     doi:10.1128/AAC.00342-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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