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

项目摘要 《抗击抗生素耐药性细菌国家行动计划》确定了关键的研究需求， 对抗日益严重的抗菌素耐药性威胁。其中包括了解微生物的性质 社区，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。金黄色葡萄球菌引起显著的发病率和死亡率， 医疗保健和社区环境。S.金黄色葡萄球菌携带赋予内源性感染的风险。以前的研究 调查了与S.金黄色葡萄球菌定植和感染，虽然 皮肤和鼻腔微生物群对S. Aureus收购尚不清楚。我们假设这些特征 可能赋予对S的易感性或提供针对S的保护。金黄色采集 以及后续感染的发展。此外，为了防止S.金黄色葡萄球菌获得和感染， 在保健和社区环境中经常采用局部抗菌剂的去殖民化。然而，在这方面， 广谱局部抗菌剂应用可能破坏肠道微生物群，从而促进 获得或富集多重耐药和/或潜在致病微生物。这样做的影响 潜在的不利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和无与伦比的生物储存库，超过13，000个皮肤和鼻拭子 在24个月内从476名参与者的良好表征的队列中纵向收集的样本， 包括99名患有耐甲氧西林S.金黄色葡萄球菌皮肤感染及其家庭接触， 他们都有患S的高风险金黄色葡萄球菌获得和感染。在12个月期间收集样品 纵向采样（自然历史阶段），随后进行随机化、为期5天的非殖民化干预 局部应用抗菌剂，随后纵向取样12个月（去殖民化后 阶段）。我们将进行宏基因组鸟枪测序（使物种和菌株分类 水平），纵向表征皮肤和鼻腔微生物群落的背景下，S。金黄色 殖民和疾病。我们将比较与易感性或 对S.具有不同表型结果的家庭接触者之间的金黄色葡萄球菌获得（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，以预测个体在 获取S的风险。金黄色葡萄球菌定植和/或发展为有症状的感染。我们将量化 局部应用抗菌剂后的微生物群落结构，并将这种破坏与 S.金黄色葡萄球菌和其他病原体。最后，我们将创新 靶向序列捕获，以量化抗微生物剂抗性的遗传决定因素（“抗性基因组”）， 在非殖民化前后采集的样本。这项研究所产生的基本知识将优化 S.金黄色葡萄球菌定殖和感染以及它们对易感个体的靶向。

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.