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: 10224029
• 负责人: Michael Zdenek David
• 金额: $ 76.06万
• 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/10224029
• 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 Models; 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; Patients; Penicillins; Persons; Pilot Projects; Pneumonia; Population; 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; antibiotic resistant infections; antimicrobial; base; clinically relevant; clinically significant; data modeling; effective intervention; fitness; genetic makeup; genome analysis; genome sequencing; health care settings; high risk; human subject; infection risk; methicillin resistant Staphylococcus aureus; mortality; new therapeutic target; predictive modeling; prevent; preventive intervention; recurrent infection; 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.

项目摘要 金黄色葡萄球菌是一种可以无害地生活在人体上的细菌（即殖民化），但它是 同样是皮肤和软组织感染（SSTI），血液感染以及 肺炎。耐甲氧西林的金黄色葡萄球菌（MRSA）菌株几乎对所有与 青霉素特别关注，每年在美国杀死11,000多人 最初的MRSA SSTI患者中有50％在12个月内患有复发性SSTI。这很有用 知道哪些患者患有高风险复发，因此可以以最佳方式对待他们 复发感染。但是，现在我们不知道谁有重复的高风险。 USA300 MRSA菌株 是美国MRSA感染的最常见原因，尤其是SSTI。使用整体的新方法 随着时间的流逝，基因组测序（WGS）可用于跟踪MRSA的进化变化 人体。关于随着时间的流逝，它们的多样化的MRSA社区知之甚少， 当一个人服用抗生素时，它们如何受到影响，而MRSA中有哪些遗传变化 随着复发感染或长期定殖的开始。我们建议对7,000 MRSA的WGS研究 从400人获得MRSA SSTI的人中获得的分离株在一年内收集。我们将测试400 拟议研究的受试者每季度每季度在3个身体部位的研究中，以解决这些未知数 时间，确定随着USA300和其他MRSA菌株类型的增长和 在身体上进化。殖民细菌不断与人类宿主和环境互动。 因此，我们将随着时间的流逝以及人群的殖民细菌评估这些基因的变化， 所研究受试者的行为，抗生素暴露和医学特征以确定其 相对影响反复感染的风险。我们的中心假设是USA300并密切相关 （CC8）菌株，独立于宿主特征：1）在更长的时间内定居于皮肤，并导致 复发感染； 2）更可能引起需要医疗干预的感染； 3）更有可能 抗生素治疗后比其他菌株类型生存。我们还假设更高的水平 殖民MRSA的多样性是长期定植和生存能力挑战的预测指标 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，以确定特定的遗传 变化导致MRSA适应性的变化，这是通过其增长率的变化来衡量的 较早从同一主题培养的菌株。我们旨在确定哪种临床治疗最大 存活的金黄色葡萄球菌种群的适应性显着降低，以及这是否与较低有关 复发感染的可能性。我们将应用拟议研究的发现来识别MRSA患者 以重复感染的高风险，以便给予他们最佳的预防治疗。