Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early Defervescence
Virulence-Suppressing Effects of Linezolid on Methicillin-Resistant Staphylococcus aureus: Possible Contribution to Early Defervescence
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DOI：
10.1128/aac.05430-11
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发表时间：
2012-01
影响因子：
4.9
通讯作者：
S. Yoshizawa;K. Tateda;T. Saga;Y. Ishii;K. Yamaguchi
中科院分区：
文献类型：
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作者：
S. Yoshizawa;K. Tateda;T. Saga;Y. Ishii;K. Yamaguchi
摘要本研究评价了利奈唑胺（LZD）对耐甲氧西林金黄色葡萄球菌（MRSA）感染的免疫调节作用。我们回顾性分析了LZD治疗52例严重MRSA感染患者的疗效。64%的发热患者在3天内表现出明显的退热，尽管存在阳性培养结果。我们推测这一发现可能是由于LZD的早期抗炎作用，为了进一步研究这一点，我们使用小鼠MRSA肺炎模型开始了体内实验。在MRSA鼻内给药后立即用LZD或万古霉素（VCM）处理小鼠。测定肺部细菌数量和炎性细胞因子水平。两组肺内细菌负荷无明显差异，但LZD组能显著降低肺内炎性细胞因子的产生（P < 0.05），而VCM组无显著差异。为了评估这种抗炎反应是否是由于毒力因子表达的抑制，将MRSA的过滤灭菌上清液与LZD的亚MIC一起在肉汤中孵育过夜，皮下给予小鼠。为了阐明LZD是否具有直接的宿主调节活性，在用LZD预处理的小鼠中检查了对上清液的细胞因子应答。有趣的是，在LZD的亚MIC存在下制备的MRSA溶液显示以剂量依赖性方式显著抑制白细胞介素6（IL-6）（P < 0.05），但用LZD预处理小鼠未显示细胞因子的变化。这些结果表明，LZD的亚MIC可能抑制MRSA的毒力因子，这可能与内源性热原的减少有关。这些数据至少可以部分解释LZD治疗个体中观察到的早期退热。
ABSTRACT In the present study, immunomodulatory effects of linezolid (LZD) on methicillin-resistance Staphylococcus aureus (MRSA) infections were evaluated. We have retrospectively reviewed treatment effects of LZD on 52 patients with severe MRSA infections. Sixty-four percent of the febrile patients demonstrated significant defervescence within 3 days, despite the presence of positive culture results. We speculated that this finding might be due to early anti-inflammatory effects of LZD, and to investigate this further we initiated in vivo experiments using mice MRSA pneumonia models. Mice were treated with either LZD or vancomycin (VCM) immediately after intranasal administration of MRSA. Bacterial numbers and levels of inflammatory cytokines in the lungs were determined. Although the bacterial burden in the lungs was not apparently different between the two groups, LZD but not VCM treatment significantly reduced induction of inflammatory cytokines in the lungs (P < 0.05). To evaluate whether this anti-inflammatory response was due to suppression of virulence factor expression, filter-sterilized supernatants of MRSA incubated in broth overnight with sub-MICs of LZD were subcutaneously administered to mice. To clarify whether LZD possesses direct host-modulating activity, cytokine responses to the supernatants were examined in mice pretreated with LZD. Interestingly, MRSA solutions prepared in the presence of sub-MICs of LZD revealed significant suppression of interleukin 6 (IL-6) in a dose-dependent manner (P < 0.05), but pretreatment of mice with LZD revealed no changes in cytokines. These findings suggest that sub-MICs of LZD might suppress virulence factors of MRSA, which may be associated with a reduction in endogenous pyrogens. These data may explain at least in part early defervescence observed in LZD-treated individuals.