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

项目摘要/摘要 撒哈拉以南非洲(SSA)每年有200多万5岁以下儿童死亡。最近出院的儿童 来自医院的儿童死亡风险特别高，这一时期没有针对任何干预措施。最近的临床试验 在SSA中发现，社区范围内单剂量阿奇霉素可使死亡率降低13%-49%； 人们对这种效应的机制知之甚少。Toto Bora试验(NIH/NICHD-HD079695)是双盲试验 安慰剂对照随机临床试验(RCT)测试阿奇霉素5天疗程的疗效 在出院时给予肯尼亚5岁以下儿童死亡率和再次住院治疗 随后6个月。利用这次审判的样本，我们有前所未有的机会来澄清 出院后发病率、死亡率和生长迟缓的机制以及确定的机制 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 从出院时和出院后3个月的儿童身上采集的大肠埃希菌 出院后6个月期间收集的再住院数据、生命状况和人体测量数据 句号。这项高效的嵌套研究的结果将为疫苗和病原体导向的靶标提供信息 可以降低出院后发病率和死亡率的药物。特定分子决定的病原体 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 经验型阿奇霉素降低儿童死亡率和识别特定人群的机制 可以用阿奇霉素治疗，以最大限度地提高效益，同时将耐药性降至最低。

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.