Treatment of bacterial pneumonia after influenza

流感后细菌性肺炎的治疗

基本信息

批准号：
7880623
负责人：
JONATHAN A MCCULLERS
金额：
$ 19.98万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7880623
关键词：
A Mouse Accounting Address Animals Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Asia Bacteremia Bacteria Bacterial DNA Bacterial Infections Bacterial Pneumonia Biological Bioterrorism Birds Blood Circulation Case Fatality Rates Cell Wall Cellular Infiltration Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Complement component C1s Complex Cytolysis Data Europe Event Excess Mortality Failure Frail Elderly Generations Generic Drugs Goals Health Human In Vitro Incidence Infection Inflammation Inflammatory Inflammatory Response Influenza Influenza A Virus, H5N1 Subtype Laboratories Lead Link Lobar Lung Lytic Modeling Molecular Mus Organism Outcome Pathogenesis Pathway interactions Pattern Pattern Recognition Pattern recognition receptor Persons Pneumococcal Pneumonia Population Pre-Clinical Model Publications Severity of illness Source Staging Staphylococcal Pneumonia Staphylococcus aureus Streptococcus pneumoniae Streptococcus pneumoniae plY protein System Testing Toll-Like Receptor 2 Treatment Failure Treatment Protocols Virulence Factors Virulent Virus Work alternative treatment antimicrobial drug base clinical practice cytokine effective therapy in vivo influenza epidemic influenzavirus interest macrophage mortality mouse model pandemic disease pandemic influenza pathogen preclinical study public health relevance treatment strategy

项目摘要

DESCRIPTION (provided by applicant): A synergistic interaction between influenza virus and bacteria contributes to excess mortality during influenza epidemics. Bacterial pneumonia after influenza infection typically presents at a more advanced stage, has complex features including multi-lobar involvement and bacteremia, and targets the frail and the elderly. For these reasons and because of the contribution of the virus itself to the pathogenesis, secondary bacterial pneumonia is more difficult to treat and the case fatality rate is higher. In addition, pre-clinical studies suggest that an over-exuberant host inflammatory response contributes to the severity of the illness and to treatment failures. The use of cell wall active antibiotics may be a contributing factor to these poor outcomes. The antibiotics most commonly used in clinical practice rapidly lyse organisms like Streptococcus pneumoniae and Staphylococcus aureus causing release of pathogen associated molecular patterns that act as triggers for inflammatory pathways, This problem may be exacerbated by the propensity of highly pathogenic influenza viruses such as the 1918 strain or the H5N1 strains currently infecting people in Asia and Europe to cause massive cytokine release. Since secondary bacterial infections account for a significant proportion of the deaths that occur during circulation of virulent strains, it is critical that we develop more effective treatment regimens before the next highly pathogenic influenza virus enters the population from avian sources or as a result of bioterrorism. We hypothesize that alternative treatment regimens, that do not lead to a robust host inflammatory response, will be more effective in the therapy of post-influenzal secondary bacterial pneumonia. This hypothesis will be tested in well described models of secondary pneumococcal and staphylococcal pneumonia. The goal of the proposed studies is to develop an effective treatment strategy for secondary bacterial pneumonia following influenza. The data generated by this work will provide a basis for educated treatment decisions in humans. PUBLIC HEALTH RELEVANCE: Secondary bacterial infections are a common cause of mortality during influenza epidemics, and are expected to be even more important during circulation of highly pathogenic influenza viruses such as pandemic strains or those released for the purposes of bioterrorism. Treatment of these infections is difficult and clinical failures are common for reasons that are at present unclear. The goal of the Proposed Studies is to generate information in a relevant pre-clinical model that will be immediately useful in planning for an influenza pandemic or bioterrorist event, as well as for annual influenza epidemics.

描述（由申请人提供）：流感病毒和细菌之间的协同相互作用导致流感流行期间死亡率过高。流感感染后的细菌性肺炎通常出现在较晚期，具有复杂的特征，包括多肺叶受累和菌血症，并且针对体弱和老年人。由于这些原因以及病毒本身对发病机制的贡献，继发性细菌性肺炎更加难以治疗，病死率也更高。此外，临床前研究表明，过度旺盛的宿主炎症反应会导致疾病的严重程度和治疗失败。使用细胞壁活性抗生素可能是导致这些不良结果的一个因素。临床实践中最常用的抗生素会快速裂解肺炎链球菌和金黄色葡萄球菌等微生物，导致释放病原体相关分子模式，从而触发炎症途径。高致病性流感病毒（例如 1918 株）的倾向可能会加剧这一问题。或目前感染亚洲和欧洲人群并导致大量细胞因子释放的 H5N1 病毒株。由于继发细菌感染在强毒株传播过程中发生的死亡中占很大比例，因此在下一种高致病性流感病毒从禽类来源或生物恐怖主义进入人群之前，我们必须制定更有效的治疗方案，这一点至关重要。我们假设，不会导致强烈宿主炎症反应的替代治疗方案将更有效地治疗流感后继发性细菌性肺炎。这一假设将在已详细描述的继发性肺炎球菌和葡萄球菌肺炎模型中得到检验。拟议研究的目标是制定流感后继发细菌性肺炎的有效治疗策略。这项工作产生的数据将为人类的有根据的治疗决策提供基础。公共卫生相关性：继发细菌感染是流感流行期间死亡的常见原因，预计在高致病性流感病毒（例如大流行毒株或出于生物恐怖主义目的而释放的毒株）传播期间更为重要。这些感染的治疗很困难，临床失败也很常见，原因目前尚不清楚。拟议研究的目标是在相关的临床前模型中生成信息，这些信息将立即用于规划流感大流行或生物恐怖事件以及年度流感流行。