Antibiotic Combined with Epitope-Specific Monoclonal Antibody Cocktail Protects Mice Against Bacteremia and Acute Pneumonia from Methicillin-Resistant Staphylococcus aureus Infection.
Antibiotic Combined with Epitope-Specific Monoclonal Antibody Cocktail Protects Mice Against Bacteremia and Acute Pneumonia from Methicillin-Resistant Staphylococcus aureus Infection.
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DOI：
10.2147/jir.s325286
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发表时间：
2021
影响因子：
4.5
通讯作者：
Zhao Z
中科院分区：
文献类型：
--
作者：
Duan L;Zhang J;Chen Z;Gou Q;Xiong Q;Yuan Y;Jing H;Zhu J;Ni L;Zheng Y;Liu Z;Zhang X;Zeng H;Zou Q;Zhao Z
我们之前曾报道，单抗(MAb)鸡尾酒可提高金黄色葡萄球菌感染的存活率。本研究采用急性肺炎模型和致死性脓毒症模型，探讨抗生素联合表位特异性单抗鸡尾酒治疗MRSA252感染的疗效。通过尾静脉注射或气管插管激发MRSA252建立脓毒症模型或肺炎模型。感染后1小时，单次静脉注射生理盐水、万古霉素、万古霉素联合单抗、利奈唑胺或利奈唑胺联合单抗。每日记录小鼠存活率(共7天)、细菌载量、组织学、血清和肺泡灌洗液细胞因子分析，以及体外抗SEB毒素和人类白细胞抗原毒素抗体中和能力的测定，解释了抗体作用的机制。在急性肺炎模型(70%、80%)和致死性脓毒症模型(80%、80%)中，mAb鸡尾酒联合低剂量万古霉素或利奈唑胺可提高存活率。在体外，表位特异性的单抗可减少细菌在小鼠肾脏和肺部的定植，并抑制毒素H1a和SEB的生物学功能。联合用药组IL-1α、IL-1β、干扰素-γ水平较单用抗生素组高，而IL-6、IL-10、肿瘤坏死因子-α水平低于单用抗生素组和PBS组。此外，在致死性脓毒症模型中，抗生素和单抗的组合提高了对临床MRSA分离株的感染存活率。这项研究展示了一种治疗抗药性金黄色葡萄球菌感染免疫力低下的人的新方法。
We previously reported that monoclonal antibody (mAb) cocktail improves survival in Staphylococcus aureus infection. In this study, we used acute pneumonia model and lethal sepsis model to investigate the efficacy of antibiotic combined with epitope-specific mAb cocktail in treating MRSA252 infection. MRSA252 was challenged by tail vein injection or tracheal intubation to establish sepsis model or pneumonia model. One hour after infection, the mice received a single intravenous injection of normal saline, vancomycin, and vancomycin combined monoclonal antibody, linezolid alone or linezolid combined monoclonal antibody. Daily record survival rate (total 7 days), bacterial load, histology, cytokine analysis of serum and alveolar lavage fluid, and in vitro determination of the neutralizing ability of antibodies to SEB toxin and Hla toxin explained the mechanism of antibody action. The mAb cocktail combined with low doses of vancomycin or linezolid improved survival rates in acute pneumonia model (70%, 80%) and lethal sepsis model (80%, 80%). Epitope-specific monoclonal antibodies reduced bacterial colonization in the kidneys and lungs of mice and inhibited the biological functions of the toxins Hla and SEB in vitro. Compared to the antibiotic alone or PBS groups, the combination group had higher levels of IL-1α, IL-1β and IFN-γ and lower levels of IL-6, IL-10, TNF-α. Further, the combination of antibiotic and mAb cocktail improved infection survival against the clinical MRSA isolates in a lethal sepsis model. This study demonstrates a novel method to treat people with low immunity against drug-resistant S. aureus infections.