Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution
Macrolide and Nonmacrolide Resistance with Mass Azithromycin Distribution
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DOI：
10.1056/nejmoa2002606
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发表时间：
2020-11-12
影响因子：
158.5
通讯作者：
Lietman, Thomas M.
中科院分区：
文献类型：
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作者：
Thuy Doan;Worden, Lee;Lietman, Thomas M.
背景：在撒哈拉以南非洲地区，每年两次、持续两年的学龄前儿童大量使用阿奇霉素可降低儿童死亡率，但代价是增加大环内酯类药物耐药性。每年两次长期服用阿奇霉素对肠道抵抗组（体内抗菌素耐药基因的储存库）的影响尚不清楚。方法对每年两次使用阿奇霉素的儿童进行为期4年的肠道抵抗组调查。在MORDOR试验的尼日尔站点，我们在一项同步试验中招募了30个村庄，随机分配他们接受阿奇霉素或安慰剂的大规模分发，每6个月向所有1至59个月大的儿童提供4年。在基线、36个月和48个月时收集直肠拭子，用于分析参与者的肠道抵抗组。主要结局是48个月时阿奇霉素组与安慰剂组大环内酯耐药决定因素的比率。结果在整个48个月期间，安慰剂组的平均（+/- SD）覆盖率为86.6 +/- 12%，阿奇霉素组的平均（+/- SD）覆盖率为83.2 +/- 16.4%。整个试验期间共采集样本3232份；在48个月的监测访问中获得的样本中，分析了来自15个接受安慰剂的村庄的546个样本和来自14个接受阿奇霉素的村庄的504个样本。阿奇霉素组大环内酯类药物耐药的决定因素高于安慰剂组：36个月时高7.4倍（95%可信区间[CI]， 4.0至16.7），48个月时高7.5倍（95% CI， 3.8至23.1）。阿奇霉素的持续大规模分布也被认为是非大环内酯类药物耐药性的决定因素，包括对-内酰胺类抗生素的耐药性，这是非洲该区域经常开处方的一类抗生素。结论在连续4年每年2次大规模分配阿奇霉素或安慰剂的村庄中，阿奇霉素组的耐药发生率高于安慰剂组。该试验表明，大量分布的阿奇霉素可能传播抗生素耐药性。
BACKGROUNDMass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear.METHODSWe investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months.RESULTSOver the entire 48-month period, the mean (+/- SD) coverage was 86.6 +/- 12% in the villages that received placebo and 83.2 +/- 16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of non-macrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa.CONCLUSIONSAmong villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance.