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


ABSTRACT: 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.

SUBMITTER: Zhou YF 

PROVIDER: S-EPMC6971047 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Zhou Yu-Feng YF   Li Liang L   Tao Meng-Ting MT   Sun Jian J   Liao Xiao-Ping XP   Liu Ya-Hong YH   Xiong Yan Q YQ  

Frontiers in microbiology 20200114


Linezolid resistance mediated by the <i>cfr</i> gene in MRSA represents a global concern. We investigated relevant phenotype differences between <i>cfr</i>-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, <i>cfr</i>-positive MRSA exhibited significantly reduced susceptibilities to the host defense peptides tPMPs, human neutrophil peptide-1  ...[more]

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