University of Southern California, School of Pharmacy, 1985 Zonal Avenue, Los Angeles, CA, 90089, USA.
Ann Clin Microbiol Antimicrob. 2020 Nov 3;19(1):50. doi: 10.1186/s12941-020-00392-w.
Persistent bacteremia occurs in at least 30% of patients with Staphylococcus aureus bloodstream infection (SAB) and may be attributable to a dysregulated host immune response. Neutrophils interact with a variety of S. aureus microbial factors, including lipoteichoic acid (LTA), to activate phagocytic function in a concentration-dependent manner. Antibiotics have been shown to exert both direct antimicrobial action as well as immunomodulatory effects. In this study, we compared the effects of different anti-staphylococcal antibiotics on LTA-mediated immune activation of neutrophils.
Neutrophils obtained from healthy volunteers were exposed to two levels of LTA (1 and 10 μg/ml) with or without addition of antibiotics from different pharmacologic classes (vancomycin, daptomycin, ceftaroline). Neutrophil function was assessed by examining phagocytic response, activation (CD11b, CD62L expression), Toll-like receptor-2 expression, cell survival and apoptosis, and CXCL8 release.
Differential LTA-mediated antibiotic effects on neutrophil function were observed primarily at the high LTA exposure level. Ceftaroline in the presence of 10 μg/ml LTA had the most prominent effects on phagocytosis and CD11b and CD62L expression, with trends towards increased neutrophil survival and preservation of CXCL8 release when compared to daptomycin and vancomycin with the latter significantly dampening PMN CXCL8 release.
Select antimicrobial agents, such as ceftaroline, exert immunostimulatory effects on neutrophils exposed to S. aureus LTA, which when confirmed in vivo, could be leveraged for its dual immunomodulatory and antibacterial actions for the treatment of persistent SAB mediated by a dysregulated host response.
金黄色葡萄球菌血流感染（SAB）患者中至少有 30%存在持续性菌血症，这可能归因于宿主免疫反应失调。中性粒细胞与多种金黄色葡萄球菌微生物因子相互作用，包括脂磷壁酸（LTA），以浓度依赖的方式激活吞噬功能。抗生素已被证明具有直接的抗菌作用和免疫调节作用。在这项研究中，我们比较了不同抗葡萄球菌抗生素对 LTA 介导的中性粒细胞免疫激活的影响。
从健康志愿者中获得中性粒细胞，用或不用来自不同药理类别的抗生素（万古霉素、达托霉素、头孢洛林）暴露于两个 LTA 水平（1 和 10μg/ml）。通过检查吞噬反应、中性粒细胞的活化（CD11b、CD62L 表达）、Toll 样受体-2 表达、细胞存活和凋亡以及 CXCL8 释放来评估中性粒细胞功能。
在高浓度 LTA 暴露水平下，观察到 LTA 介导的抗生素对中性粒细胞功能的差异作用。与达托霉素和万古霉素相比，头孢洛林在 10μg/ml LTA 存在时对吞噬作用和 CD11b 和 CD62L 表达具有最显著的影响，并且具有增加中性粒细胞存活和保持 CXCL8 释放的趋势，而后者显著抑制 PMN CXCL8 释放。
某些抗菌药物，如头孢洛林，对暴露于金黄色葡萄球菌 LTA 的中性粒细胞具有免疫刺激作用，如果在体内得到证实，可利用其双重免疫调节和抗菌作用来治疗由宿主反应失调介导的持续性 SAB。
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