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,Meng-Ting Tao,Yan Q Xiong,Ya-Hong Liu,Xiao-Ping Liao,Liang Li,Jian Sun

doi:10.3389/fmicb.2019.03080

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.

Highlights

MRSA is challenging due to its inherent pathogenicity and multidrug resistant phenotypes contributing to a variety of infectious diseases, ranging from skin and skin structure infection (SSSI) to bacteremia (Tong et al, 2015; Wang et al, 2019)
In the presence of linezolid, rifampicin achieved the highest therapeutic potential as a combinatorial partner with a greater than 8-fold reduction in MIC against 8/10 MRSA isolates, and this was independent of cfr expression (Figure 1A)
The combination of linezolid and rifampicin resulted in synergistic activity against 5/6 cfr-positive MRSA isolates and 2/4 cfrnegative MRSA isolates, with fractional inhibitory concentration index (FICI) ranging from 0.375 to 0.5 (Table 1)

Summary

Introduction

MRSA is challenging due to its inherent pathogenicity and multidrug resistant phenotypes contributing to a variety of infectious diseases, ranging from skin and skin structure infection (SSSI) to bacteremia (Tong et al, 2015; Wang et al, 2019). The cfr gene encodes a 23S rRNA methyltransferase that confers combined resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A (PhLOPSA phenotype) (Long et al, 2006; Witte and Cuny, 2011). Infections due to cfr-positive MRSA are increasing and pose a serious threat to the clinical success of oxazolidinone antibiotics (Witte and Cuny, 2011). Linezolidresistant MRSA strains carrying cfr were associated with prolonged use of linezolid in patients (Endimiani et al, 2011). These data suggest that in addition to the cfr-mediated linezolid resistance, cfr-positive MRSA may possess phenotypes associated with pathogenesis that contribute to poor in vivo treatment outcomes

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Conclusion