Genomics of S. Aureus Colonization after Initial and Recurrent Skin Infections and the Impact of Antibiotics

初次和复发性皮肤感染后金黄色葡萄球菌定植的基因组学以及抗生素的影响

• 批准号: 9575851
• 负责人: Michael Zdenek David
• 金额: $ 77.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9575851
• 关键词: Accounting; Address; Affect; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacteremia; Bacteria; Bacterial Genes; Behavior; Behavioral; Characteristics; Chronically Ill; Clindamycin; Clinical; Clinical Treatment; Communities; Complex; Computer Simulation; Data; Development; Diagnostic; Environment; Epidemiology; Event; Evolution; Genes; Genetic; Genetic Variation; Genome; Genomics; Growth; Hospitals; Human; Human body; Individual; Infection; Infectious Skin Diseases; Intervention; Lead; Literature; Longitudinal Studies; Measures; Medical; Methods; Molecular Epidemiology; Mucous Membrane; Mutation; North America; Nose; Patient risk; Patients; Penicillins; Persons; Pilot Projects; Pneumonia; Population; Preventive Intervention; Preventive treatment; Prospective cohort study; Recording of previous events; Recurrence; Recurrent disease; Risk; Risk Factors; Sepsis; Site; Skin; Skin Tissue; Skin colonization; Soft Tissue Infections; Staphylococcus aureus; Staphylococcus aureus infection; Syndrome; Technology; Testing; Time; Toxic effect; Virulence; Virulent; Whole-Genome Shotgun Sequencing; antimicrobial; base; clinically relevant; clinically significant; data modeling; effective intervention; fitness; genetic makeup; genome analysis; genome sequencing; health care settings; high risk; human subject; methicillin resistant Staphylococcus aureus; mortality; new therapeutic target; predictive modeling; prevent; resistant strain; study characteristics; tool; whole genome

Project Summary Staphylococcus aureus is a bacterium that can live on the human body harmlessly (i.e., colonization), but it is also among the most common causes of skin and soft tissue infections (SSTIs), bloodstream infections, and pneumonia. Methicillin-resistant S. aureus (MRSA) strains that are resistant to nearly all antibiotics related to penicillin are particularly concerning, killing more than 11,000 people each year in the U.S. Furthermore, up to 50% of patients with an initial MRSA SSTI suffer from a recurrent SSTI within 12 months. It would be useful to know which patients are at high risk of recurrence so that they could be treated in the best way to prevent the recurrent infection. However, now we do not know who is at high risk of recurrence. The USA300 MRSA strain is the most common cause of MRSA infections in the U.S., especially SSTIs. New methods using whole genome sequencing (WGS) are available to track the evolutionary change in MRSA over time as it grows on the human body. Little is known about the communities of MRSA that develop over time, how diverse they are, how they are affected when a person takes an antibiotic, and what genetic changes in MRSA are associated with the onset of a recurrent infection or prolonged colonization. We propose a WGS study of 7,000 MRSA isolates obtained from 400 people with a MRSA SSTI collected over a one-year period. We will test the 400 subjects in the proposed study at 3 body sites quarterly over a year to address these unknowns for the first time, determining which bacterial genes change over time as USA300 and other MRSA strain types grow and evolve on the body. Colonizing bacteria are constantly interacting with their human hosts and the environment. We will therefore assess these gene changes in the colonizing bacteria over time as well as the demographic, behavioral, antibiotic exposure, and medical characteristics of studied human subjects to determine their relative impacts on the risk of a recurrent infection. Our central hypothesis is that USA300 and closely related (CC8) strains, independent of host characteristics: 1) colonize the skin for a longer period of time and cause recurrent infections; 2) more likely cause infections that require medical intervention; and 3) are more likely to survive as colonizers after antibiotic treatment than other strain types. We also hypothesize that a higher level of diversity among colonizing MRSA is a predictor of long-term colonization and ability to survive challenge with antibiotics. Our hypotheses will be assessed using a combination of analysis of genome data and computer modeling. We will also test the MRSA isolates that we collect to determine if specific genetic changes lead to changes in the fitness of MRSA, as measured by changes in their growth rate, relative to strains cultured earlier from the same subject. We aim to identify which clinical treatments lead to the most dramatic reduction in fitness of the surviving S. aureus population, and whether this is associated with lower likelihood of recurrent infections. We will apply the discoveries of the proposed study to identify MRSA patients at high risk of recurrent infections in order to give them the best preventive treatment.

项目概要 金黄色葡萄球菌是一种可以在人体上无害地生存（即定植）的细菌，但它 也是皮肤和软组织感染 (SSTI)、血液感染和 肺炎。耐甲氧西林金黄色葡萄球菌 (MRSA) 菌株对几乎所有与甲氧西林相关的抗生素具有耐药性 青霉素尤其令人担忧，在美国每年导致 11,000 多人死亡。此外，多达 50% 的初次 MRSA SSTI 患者会在 12 个月内复发 SSTI。这将是有用的 了解哪些患者复发风险较高，以便以最佳方式进行治疗，以预防复发 反复感染。然而，现在我们不知道谁是复发风险较高的人。 USA300 MRSA 菌株 是美国 MRSA 感染（尤其是 SSTI）的最常见原因。使用整体的新方法 基因组测序 (WGS) 可用于追踪 MRSA 随着时间的推移而发生的进化变化。 人体。人们对随着时间的推移而发展的 MRSA 群落以及它们的多样性知之甚少， 当一个人服用抗生素时，他们会受到怎样的影响，以及 MRSA 的哪些基因变化与之相关 随着反复感染或长期定植的发生。我们提议对 7,000 种 MRSA 进行全基因组测序 (WGS) 研究 一年内从 400 名 MRSA SSTI 感染者身上获得的分离株。我们将测试400 拟议研究中的受试者在一年内每季度对 3 个身体部位进行研究，以首次解决这些未知问题 确定哪些细菌基因随着 USA300 和其他 MRSA 菌株类型的生长而变化 在身体上进化。定殖细菌不断与其人类宿主和环境相互作用。 因此，我们将评估定植细菌随时间以及人口统计的这些基因变化， 研究人类受试者的行为、抗生素暴露和医学特征，以确定他们的 对复发感染风险的相对影响。我们的中心假设是 USA300 与 (CC8) 菌株，与宿主特征无关：1) 在皮肤上定植较长时间并引起 反复感染； 2）更有可能引起需要医疗干预的感染； 3）更有可能 在抗生素治疗后比其他菌株类型更能作为定植者存活。我们还假设更高水平 定植 MRSA 的多样性是长期定植和生存挑战能力的预测指标 与抗生素。我们的假设将通过基因组数据分析和 计算机建模。我们还将测试我们收集的 MRSA 分离株，以确定特定基因是否 变化会导致 MRSA 的适应度发生变化（通过其相对于 MRSA 的生长速度的变化来衡量） 早期从同一受试者培养的菌株。我们的目标是确定哪些临床治疗最能带来 幸存的金黄色葡萄球菌种群的适应性急剧下降，以及这是否与较低的 反复感染的可能性。我们将应用拟议研究的发现来识别 MRSA 患者 反复感染的高风险人群，以便为他们提供最好的预防性治疗。