From the Francis I. Proctor Foundation (J.D.K., K.J.R., C.C., E.L., K.S.O., T.C.P., T.M.L.), the Departments of Ophthalmology (J.D.K., T.C.P., T.M.L.) and Epidemiology and Biostatistics (T.C.P., T.M.L.), and the Institute for Global Health Sciences (T.C.P., T.M.L.), University of California, San Francisco, San Francisco; London School of Hygiene and Tropical Medicine, London (R.L.B., J.H.); the Dana Center, Johns Hopkins University School of Medicine, Baltimore (S.K.W., J.W.); the Carter Center, Niamey, Niger (A.M.A.); Blantyre Institute for Community Outreach and the College of Medicine, University of Malawi, Blantyre (K.K.); National Institute for Medical Research, Dar es Salaam, Tanzania (Z.M.); and the International Trachoma Initiative, Decatur (P.M.E.), and Emory University, Atlanta (P.M.E.) - both in Georgia.
N Engl J Med. 2018 Apr 26;378(17):1583-1592. doi: 10.1056/NEJMoa1715474.
We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations.
In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses.
A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing.
Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).
我们假设在撒哈拉以南非洲地区，为学龄前儿童广泛分布广谱抗生素会降低死亡率，这些地区目前远未达到联合国可持续发展目标的要求。
在这项整群随机试验中，我们将马拉维、尼日尔和坦桑尼亚的社区分配到每年两次的口服阿奇霉素（约 20 毫克/千克体重）或安慰剂的大规模分布中。每年两次的人口普查确定了 1 至 59 个月大的儿童，并邀请他们参加试验。随后的人口普查确定了生存状况。主要结局是总死亡率；在预先指定的亚组分析中评估了国家特定的死亡率。
共有 1533 个社区接受了随机分组，基线时在人口普查中确定了 190238 名儿童，监测了 323302 人年。四次双年度分布中，阿奇霉素和安慰剂的平均（±SD）覆盖率分别为 90.4±10.4%。接受阿奇霉素治疗的社区的年死亡率为每 1000 人年 14.6 例（马拉维 9.1 例，尼日尔 22.5 例，坦桑尼亚 5.4 例），接受安慰剂治疗的社区的年死亡率为每 1000 人年 16.5 例（马拉维 9.6 例，尼日尔 27.5 例，坦桑尼亚 5.5 例）。接受阿奇霉素治疗的社区死亡率总体下降 13.5%（95%置信区间，6.7 至 19.8），低于接受安慰剂治疗的社区（P<0.001）；在马拉维，死亡率下降 5.7%（95%置信区间，-9.7 至 18.9），在尼日尔下降 18.1%（95%置信区间，10.0 至 25.5），在坦桑尼亚下降 3.4%（95%置信区间，-21.2 至 23.0）。1 至 5 个月大的儿童从阿奇霉素中获益最大（死亡率比安慰剂组低 24.9%；95%置信区间，10.6 至 37.0）。在接受试验药物或安慰剂治疗后一周内发生的严重不良事件并不常见，且两组之间的发生率无显著差异。正在对选择抗生素耐药性进行评估。
在撒哈拉以南非洲的新生儿后、学龄前儿童中，随机分配接受阿奇霉素大规模分布的社区儿童死亡率低于随机分配接受安慰剂的社区，尼日尔的效果最大。任何实施大规模分发政策的举措都需要强烈考虑这一策略对抗生素耐药性的潜在影响。（由比尔和梅林达盖茨基金会资助；MORDOR 临床试验.gov 编号，NCT02047981 ）。
