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: 10569512
• 负责人: Patricia Pavlinac
• 金额: $ 67.6万
• 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/10569512
• 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; 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; Predisposition; Prevalence; Randomized; Randomized, Controlled Trials; Recommendation; Recovery; Reporting; Resistance; Resource-limited setting; Risk; Risk Reduction; 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; randomized, clinical trials; 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.

项目总结/摘要 在撒哈拉以南非洲，每年有200多万5岁以下儿童死亡。最近出院的儿童 住院后死亡的风险特别高，没有针对这一时期的干预措施。最近的临床试验 发现SSA患者在社区范围内单剂量阿奇霉素可降低13%-49%的死亡率， 这种效应的机制知之甚少。Toto Bora试验（NIH/NICHD-HD 079695）是一项双盲试验， 一项安慰剂对照随机临床试验（RCT），检测阿奇霉素5天疗程的疗效 在出院时对肯尼亚5岁以下儿童进行的死亡率和再住院治疗， 随后的6个月。利用这次试验的样本，我们有前所未有的机会来阐明 出院后发病率、死亡率和生长迟缓的机制，并确定 阿奇霉素的作用。我们将检测粪便样本和大肠杆菌中的肠道病原体和耐药基因， 使用qPCR从出院时和出院后3个月的儿童中收集大肠杆菌，并将该分子 出院后6个月内收集的再住院数据、生命状态和人体测量数据 期这项高效巢式研究的结果将为疫苗和病原体导向的靶点提供信息。 可以降低出院后发病率和死亡率的药物。特异性分子决定病原体 或预测阿奇霉素对死亡率、发病率和生长的影响的耐药标志物将阐明 经验性阿奇霉素降低儿童死亡率的机制， 可以用阿奇霉素治疗，以最大限度地提高疗效，同时最大限度地减少耐药性。