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

Linezolid resistance mediated by thegene in MRSA represents a global concern. We investigated relevant phenotype differences between-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,-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1 (hNP-1), and cathelicidin LL-37 (< 0.01). In addition, increased binding to fibronectin (FN) and endothelial cells paralleled robust biofilm formation in-positive vs. -negative MRSA.phenotypes of-positive MRSA translated into poor outcomes of linezolid monotherapyin murine bacteremia and SSSI models. Importantly, rifampicin showed synergistic activity as a combinatorial partner with linezolid, and the ECof linezolid decreased 6-fold in the presence of rifampicin. Furthermore, this combination therapy displayed efficacy against-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-positive multidrug resistant MRSA.