The role of enteric pathogens and antimicrobial resistance in driving clinical and nutritional deterioration, and azithromycin's potential effect, among children discharged from hospital in Kenya

肠道病原体和抗菌药物耐药性在导致肯尼亚出院儿童临床和营养恶化中的作用以及阿奇霉素的潜在影响

• 批准号: 10341184
• 负责人: Patricia Pavlinac
• 金额: $ 67.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10341184
• 关键词: Affect; Africa South of the Sahara; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Automobile Driving; Azithromycin; Bacteria; Campylobacter; Cessation of life; Child; Child Mortality; Childhood; Clinical; Clinical Trials; Communities; Cotrimoxazole; Data; Detection; Deterioration; Development; Disease; Dose; Double-Blind Method; Enteral; Enterobacteriaceae; Environment; Escherichia coli; Exposure to; Failure; Functional disorder; Genes; Genotype; Growth; HIV; Hospitalization; Hospitals; Intervention; Kenya; Lead; Link; Macrolide-resistance; Macrolides; Mediating; Molecular; Morbidity - disease rate; National Institute of Child Health and Human Development; Nosocomial Infections; Nutritional; Outcome; Pathogen detection; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Prevalence; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Recovery; Reporting; Resistance; Resource-limited setting; Risk; Role; Sampling; Shigella; Testing; United States National Institutes of Health; Vaccines; Vital Status; antimicrobial; azithromycin resistance; beta-Lactam Resistance; clinical efficacy; clinically relevant; cohort; diagnostic tool; enteric pathogen; enterotoxigenic Escherichia coli; high risk; hospital readmission; improved; microbial; molecular diagnostics; mortality; mortality risk; pathogen; pathogenic bacteria; predictive marker; prevent; randomized placebo-controlled clinical trial; recurrent infection; repository; resistance gene

PROJECT SUMMARY/ABSTRACT More than 2 million children under 5 die each year in sub-Saharan Africa (SSA). Children recently discharged from hospital suffer a particularly high risk of death and no interventions target this period. Recent clinical trials found 13%-49% mortality reductions associated with community-wide singe-dose azithromycin in SSA, and mechanisms of this effect are poorly understood. The Toto Bora trial (NIH/NICHD-HD079695) is a double-blind placebo-controlled randomized clinical trial (RCT) testing the effect of a 5-day course of azithromycin administered at hospital discharge to Kenyan children under 5 years on mortality and re-hospitalization in the subsequent 6-months. Utilizing samples from this trial, we have the unprecedented opportunity to elucidate mechanisms of post-discharge morbidity, mortality, and growth faltering AND determine mechanisms of azithromycin’s effect. We will test for enteropathogens and resistance genes in fecal samples and Escherichia coli collected from children at hospital discharge and 3-months thereafter using qPCR and link this molecular data to re-hospitalization, vital status, and anthropometric data collected throughout the 6-month post-discharge period. Results from this highly efficient nested study will inform targets for vaccines and pathogen-directed medications that could reduce post-discharge morbidity and mortality. Specific molecularly-determined pathogen or resistance markers that predict azithromycin’s effects on mortality, morbidity, and growth will elucidate mechanisms by which empiric azithromycin reduces child mortality and may identify specific populations who can be treated with azithromycin to maximize benefit while minimizing resistance.

项目摘要/摘要 在撒哈拉以南非洲（SSA），每年有超过200万儿童死亡。儿童最近出院 医院的死亡风险特别高，没有干预措施针对这一时期。最近的临床试验 发现与SSA中的社区全剂量阿奇霉素有关的13％-49％的死亡率降低，以及 这种作用的机制知之甚少。 Toto Bora试验（NIH/NICHD-HD079695）是双盲 安慰剂对照的随机临床试验（RCT）测试了阿奇霉素5天的效果 在肯尼亚儿童出院时，在5岁以下的肯尼亚儿童死亡率和重新住院时管理 随后的6个月。利用该试验中的样本，我们有前所未有的机会来阐明 放电后发病率，死亡率和生长伪造的机制，并确定机制 阿奇霉素的作用。我们将测试粪便样品和大肠疾病中的肠病原体和抗性基因 从医院出院的儿童收集的大肠杆菌，此后3个月使用qPCR并将此分子联系起来 在整个6个月后收集的数据中，数据重新占地，生命状态和人体测量数据 时期。这项高效嵌套研究的结果将为疫苗和病原体定向的靶标提供信息 可以降低病后发病率和死亡率的药物。特定的分子确定病原体 或预测阿奇霉素对死亡率，发病率和生长的影响的电阻标记将阐明 经验性阿奇霉素降低儿童死亡率并可能确定特定人群的机制 可以用阿奇霉素治疗，以最大程度地提高益处，同时最大程度地减少耐药性。