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 EC50 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.