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JAC Advance Access published online on March 16, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm045
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Daptomycin-reversible rifampicin resistance in vancomycin-resistant Enterococcus faecium

Kenneth H. Rand1,*, Herbert J. Houck1 and Jared A. Silverman2

1 Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA 2 Cubist Pharmaceuticals, Lexington, MA 02421, USA

Received 20 October 2006; returned 20 November 2006; revised 12 January 2007; accepted 22 January 2007

* Corresponding author. Tel: +1-352-392-5621; Fax: +1-352-392-4693; E-mail: rand{at}pathology.ufl.edu

Objectives: In a previous study, we observed marked synergy between daptomycin and rifampicin against 73% of rifampicin-resistant, vancomycin-resistant Enterococcus faecium (VRE), with approximately 100-fold reductions in rifampicin MICs observed at one-eighth to one-fourth daptomycin MIC. The purpose of this study was to determine whether the synergy between daptomycin and rifampicin could be explained by enhanced entry of rifampicin into the cell or was related to amino acid substitutions in the rifampicin-binding site in the ß subunit (rpoß) of the RNA polymerase.

Methods: We developed a bioassay for rifampicin to measure cell-bound rifampicin levels as well as metabolic inactivation of rifampicin. In addition, we sequenced the rifampicin-binding site in the rpoß of VRE strains with and without synergy between daptomycin and rifampicin.

Results: Cell-bound rifampicin levels were the same in rifampicin-susceptible VRE as in rifampicin-resistant VRE showing daptomycin synergy and were not affected by the presence of daptomycin. In contrast, rifampicin-resistant VRE without daptomycin synergy had undetectable cell-bound rifampicin. Sequencing the rpoß rifampicin-binding site revealed that the synergistic strains had the same sequence as rifampicin-susceptible wild-type E. faecium. The daptomycin synergy-resistant strains all had mutations in known rifampicin-binding sites.

Conclusions: Daptomycin is able to reverse rifampicin resistance in some strains of VRE, but the mechanism could not be explained by an effect of daptomycin on entry of rifampicin into or transport out of the cell, by inactivation of rifampicin or by mutation involving the rifampicin-binding site.

Key Words: rpoß , rifampicin-binding site , E. faecium , VRE


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Effects of daptomycin in combination with other antimicrobial agents: a review of in vitro and animal model studies
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