Microbial Community Disruption Following Topical Antimicrobial Application in Staphylococcus aureus-Affected Households

项目总结 国家抗击耐药细菌行动计划确定了关键的研究需求 面对日益严重的抗菌素耐药性威胁。这些包括了解微生物的本质 确定抗生素对这些社区的影响，并利用这些社区 制定疾病预防战略。金黄色葡萄球菌在中国引起显著的发病率和死亡率 医疗保健和社区环境。携带金黄色葡萄球菌会增加内源性感染的风险。以前的研究 调查与金黄色葡萄球菌定植和感染有关的临床和流行病学因素，尽管 皮肤和鼻腔微生物区系对金黄色葡萄球菌感染的影响尚不清楚。我们假设这些特征 共生微生物群的存在可能使金黄色葡萄球菌对金黄色葡萄球菌的获取具有敏感性或提供保护。 以及后续感染的发展。此外，为了防止金黄色葡萄球菌的获得和感染， 在医疗保健和社区环境中经常使用局部使用抗菌剂的非殖民化。然而， 广谱局部应用抗菌剂可能会破坏共生微生物区系，从而促进 获取或浓缩具有多药耐药性和/或潜在致病微生物。这件事的影响 潜在的不良影响仍未得到充分研究。 在这个拟议的项目中，我们将分析一个巨大的、无与伦比的生物信息库，其中包括13,000个皮肤和鼻拭子 样本是从476名参与者的队列中纵向收集的，历时24个月， 包括99名患有耐甲氧西林金黄色葡萄球菌皮肤感染的儿童患者及其家庭接触者， 所有这些人都有感染金黄色葡萄球菌的高风险。这些样本是在12个月内收集的 进行纵向采样(自然历史阶段)，然后进行为期5天的随机非殖民化干预 局部应用抗菌药物，随后进行为期12个月的纵向采样(非殖民化后 阶段)。我们将执行元基因组鸟枪式测序(实现物种和菌株的分类 水平)，以纵向描述金黄色葡萄球菌背景下的皮肤和鼻部微生物群落 殖民和疾病。我们将比较微生物群落特征与易感性或 具有不同表型结果的家庭接触者之间对金黄色葡萄球菌获取的抵抗力(例如， 殖民和感染)，并将这些数据与详细的流行病学数据相结合，以预测 感染金黄色葡萄球菌和/或出现症状感染的风险。我们将量化这些变化 局部应用抗菌药物后的微生物群落结构，并将这种干扰与 金黄色葡萄球菌和其他病原体随后的获得性和持久性。最后，我们将采用创新的 靶向序列捕获以量化抗菌素耐药性(耐药组)的遗传决定因素 非殖民化前后采集的样本。这项研究产生的基本知识将优化 金黄色葡萄球菌定植和感染的预防战略及其针对易感人群。

PROJECT SUMMARY The National Action Plan for Combating Antibiotic-Resistant Bacteria identified critical research needs to confront the advancing threat of antimicrobial resistance. These include understanding the nature of microbial communities, determining the effects of antibiotics on these communities, and harnessing these communities to develop strategies for disease prevention. Staphylococcus aureus causes significant morbidity and mortality in healthcare and community settings. S. aureus carriage confers risk for endogenous infection. Previous studies investigated clinical and epidemiological factors associated with S. aureus colonization and infection, although the influence of the skin and nasal microbiota on S. aureus acquisition is unclear. We hypothesize that features of the commensal microbiota may confer susceptibility to, or provide protection against, S. aureus acquisition and development of subsequent infection. Further, in an effort to prevent S. aureus acquisition and infection, decolonization with topical antimicrobials is frequently employed in healthcare and community settings. However, broad-spectrum topical antimicrobial application may disrupt commensal microbiota, thereby promoting the acquisition or enrichment of multidrug-resistant and/or potentially pathogenic microorganisms. The impact of this potential adverse effect remains understudied. In this proposed project, we will analyze a vast and unmatched biorepository of >13,000 skin and nasal swab samples that were longitudinally collected over 24 months from a well-characterized cohort of 476 participants, including 99 pediatric patients with methicillin-resistant S. aureus skin infections and their household contacts, all of whom are at high risk for S. aureus acquisition and infection. The samples were collected during 12 months of longitudinal samplings (the natural history phase) followed by a randomized, 5-day decolonization intervention with topical antimicrobial application, and subsequent longitudinal sampling for 12 months (post-decolonization phase). We will perform metagenomic shotgun sequencing (enabling classification at the species and strain levels), to longitudinally characterize skin and nasal microbial communities in the context of S. aureus colonization and disease. We will compare microbial community features associated with susceptibility or resistance to S. aureus acquisition between household contacts with different phenotypic outcomes (e.g., colonization and infection), and integrate these data with detailed epidemiological data to predict individuals at risk for acquiring S. aureus colonization and/or developing symptomatic infection. We will quantify changes in microbial community structures following topical antimicrobial application, and correlate this disruption with subsequent acquisition and persistence of S. aureus and other pathogens. Finally, we will employ innovative targeted sequence capture to quantify genetic determinants of antimicrobial resistance (the “resistome”) in samples collected before and after decolonization. The essential knowledge generated by this study will optimize preventive strategies for S. aureus colonization and infection and their targeting to susceptible individuals.