The NICU Antibiotics and Outcomes (NANO) Trial

摘要 NANO（NICU抗生素和结局）试验的目标是研究长期的临床实践， 经验性地对极低出生体重（ELBW）新生儿静脉内施用抗生素。ELBW 婴儿通常在出生后立即接受抗生素治疗，然后在随后的2-3天内接受抗生素治疗，而临床医生则 等待微生物培养结果。通常，这些培养结果用于指导继续或 根据血流感染的存在与否停用抗生素。的基本假设 这种做法是，早期抗生素管理将改善婴儿的结果， 早发型脓毒症（EOS）。然而，没有数据支持或反驳这一假设， 研究表明，>98%的接受经验性抗生素（EA）的ELBW婴儿没有EOS。最近 微生物组研究表明，广谱抗生素暴露与不良反应有关。 儿童期结果，这可能在早期细菌定植的关键窗口期特别相关 在新生儿中。我们只是不知道是否早期EA ELBW婴儿改善健康结果， 结果，或不影响结果。我们小组和其他人的数据记录了抗生素对 微生物组的发展，并证明抗生素天数与 ELBW婴儿迟发性脓毒症（LOS）、坏死性小肠结肠炎（NEC）或死亡的复合结局。 正式研究在第一周接受EA的婴儿中不良结局的发生率是否更高 与接受安慰剂的婴儿相比，我们提出了NANO试验，一项802名受试者的安慰剂对照试验。 多中心随机临床试验。我们的目标人群是婴儿，临床决定使用或 不使用EA是2018年最具挑战性的。我们将入组临床稳定的胎龄≤28岁的ELBW婴儿 周，不包括EOS高风险（例如疑似暴露于羊膜内感染）和 EOS风险低（例如，通过无并发症的剖腹产分娩，用于母体适应症）。的目标 本研究的目的是（1）检验以下假设： EA与接受安慰剂的婴儿的发病率显著不同，（2）为了检验以下假设， 接受EA的婴儿出生后第一个月的粪便样本将含有较低的多样性和较高的丰度 与接受安慰剂的婴儿的粪便样品相比， 体重和身长z评分）。结果 本研究的结果可能验证当前关于抗生素给药的临床实践模式，或者他们可能 为进一步减少NICU中抗生素的使用提供了重要的理论依据。除了改善结果外， 通过减少抗生素暴露，这种改变可以减轻全球范围内日益增长的负担， 抗生素耐药性和医院感染的风险。

ABSTRACT The goal of the NANO (NICU Antibiotics and Outcomes) Trial is to study the longstanding clinical practice of empirically administering intravenous antibiotics to newborn extremely low birthweight (ELBW) infants. ELBW infants commonly receive antibiotics immediately after birth and then for 2-3 subsequent days while clinicians await microbiology culture results. Typically, these culture results are used to guide a decision to continue or discontinue antibiotics based on the presence or absence of a bloodstream infection. The assumption underlying this practice is that early antibiotic administration will improve outcomes in infants undergoing evaluation for early onset sepsis (EOS). However, there are no data to support or refute this assumption, and numerous studies have shown that >98% of ELBW infants receiving empiric antibiotics (EA) do not have EOS. Recent microbiome research has demonstrated that broad-spectrum antibiotic exposure is associated with adverse childhood outcomes, and this may be particularly relevant during a critical window of early bacterial colonization in newborns. We simply do not know whether early EA for ELBW infants improves health outcomes, worsens outcomes, or does not affect outcomes. Data from our group and others document the impact of antibiotics on microbiome development and demonstrate a dose-dependent association between antibiotic days and a composite outcome of late onset sepsis (LOS), necrotizing enterocolitis (NEC), or death in ELBW infants. To formally study whether the incidence of adverse outcomes is higher in infants receiving EA in the first week of life compared to babies receiving placebo, we propose the NANO Trial, an 802-subject placebo-controlled multicenter randomized clinical trial. We target a population of infants for whom the clinical decision to use or not use EA is most challenging in 2018. We will enroll clinically stable ELBW infants with gestational age ≤28 weeks, excluding those at high risk for EOS (e.g. suspected exposure to intraamniotic infection) and those at low risk for EOS (e.g. delivery via uncomplicated caesarean section for maternal indications). The aims of the study are (1) To test the hypothesis that the composite incidence of LOS, NEC, or death in infants that receive EA is significantly different than the incidence among infants that receive placebo, (2) To test the hypothesis that fecal samples in the first month of life from infants receiving EA will contain lower diversity and higher abundance of pathogens than fecal samples from infants receiving placebo, and (3) To compare somatic growth (weekly weight and length z-scores) in infants receiving EA and infants receiving placebo (exploratory aim). The results from this study may validate current clinical practice patterns regarding antibiotic administration, or they may provide a critical rationale for further reducing antibiotic usage in the NICU. In addition to improving outcomes for individual babies by reducing antibiotic exposure, such a change could mitigate the growing worldwide burden of antibiotic resistance and nosocomial infections.