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Linezolid resistance mediated by the  cfr  gene in MRSA represents a global concern. We investigated relevant phenotype differences between  cfr -positive and -negative MRSA that contribute to pathogenesis, and the efficacy of linezolid-based combination therapies in murine models of bacteremia and skin and skin structure infection (SSSI). As a group,  cfr -positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 ( P  < 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in  cfr -positive vs. -negative MRSA.  In vitro  phenotypes of  cfr -positive MRSA translated into poor outcomes of linezolid monotherapy  in vivo  in murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the EC 50  of linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against  cfr -positive MRSA at clinically relevant doses. Altogether, these data suggest that the use of linezolid in combination with rifampicin poses a viable therapeutic alternative for bacteremia and SSSI caused by  cfr -positive multidrug resistant MRSA.

frontiers in microbiology

Linezolid and Rifampicin Combination to Combat cfr-Positive Multidrug-Resistant MRSA in Murine Models of Bacteremia and Skin and Skin Structure Infection