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.

项目概要/摘要 最近出院的撒哈拉以南非洲儿童 (SSA) 每年有超过 200 万 5 岁以下儿童死亡。 从医院出来的患者死亡风险特别高，并且最近没有针对这一时期的临床试验。 发现 SSA 社区范围内单剂量阿奇霉素可降低 13%-49% 的死亡率，并且 对这种效应的机制知之甚少。Toto Bora 试验（NIH/NICHD-HD079695）是一项双盲试验。 安慰剂对照随机临床试验 (RCT)，测试阿奇霉素 5 天疗程的效果 在肯尼亚 5 岁以下儿童出院时对死亡率和再住院情况进行管理 在接下来的 6 个月里，我们获得了前所未有的机会来阐明这一点。 出院后发病、死亡和生长迟缓的机制并确定 我们将测试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 个月的儿童身上采集大肠杆菌，并将该分子连接起来 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 这项高效嵌套研究的结果将为疫苗和病原体导向的目标提供信息。 可以降低出院后发病率和死亡率的药物。 或预测阿奇霉素对死亡率、发病率和生长影响的耐药标记将阐明 经验性阿奇霉素降低儿童死亡率的机制，并可确定特定人群 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。