Frontiers in Microbiology (Jan 2020)

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

  • Yu-Feng Zhou,
  • Yu-Feng Zhou,
  • Liang Li,
  • Meng-Ting Tao,
  • Meng-Ting Tao,
  • Jian Sun,
  • Jian Sun,
  • Xiao-Ping Liao,
  • Xiao-Ping Liao,
  • Ya-Hong Liu,
  • Ya-Hong Liu,
  • Ya-Hong Liu,
  • Yan Q. Xiong,
  • Yan Q. Xiong

DOI
https://doi.org/10.3389/fmicb.2019.03080
Journal volume & issue
Vol. 10

Abstract

Read online

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.

Keywords