PDF(Pubmed)
Abstract：
BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting.
RESULTS: The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability.
CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored.
BACKGROUND: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.
RESULTS: The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability.
CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored.
BACKGROUND: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.
摘要：
背景：随机对照试验发现，每年两次的大量阿奇霉素给药（MDA）可降低儿童死亡率，大概是通过减少感染负担。世界卫生组织（WHO）发布了在撒哈拉以南非洲地区高死亡率环境中大量使用阿奇霉素的有条件指南，考虑到对抗生素耐药性的担忧。虽然在小型随机对照试验中，延长一年两次的MDA已被证明会增加抗生素耐药性，这项研究的目的是确定在更大的环境中，随着阿奇霉素MDA的持续时间，肠道中的大环内酯和非大环内酯耐药性是否增加。
结果：2014年12月至2020年6月在尼日尔进行了MacrolideOrauxpourRéduirelesDécèsavec和OeilsurlaRéresistance（MORDOR）研究。这是一项阿奇霉素（A）与安慰剂（P）的集群随机试验，旨在评估儿童死亡率。这是MORDOR试验中的一项子研究，旨在追踪阿奇霉素MDA延长后抗生素耐药性的变化。共有594个社区符合资格。在163个随机选择的社区中，1至59个月的儿童有资格接受治疗，并被纳入耐药性监测。参与者,工作人员,研究者对治疗分配蒙上了阴影.在MORDOR第一阶段结束时，通过设计,所有社区接受额外一年两次的阿奇霉素治疗(II期).因此，在第二阶段结束时，参与社区的治疗史(每6个月1个字母)为(PP-PP-AA)或(AA-AA-AA).在第三阶段，然后，参与社区被重新随机分配接受另外3轮阿奇霉素或安慰剂，从而导致4个治疗历史：第1组（AA-AA-AA-AA-A，N=51),第2组(PP-PP-AA-AA-A,N=40),组3(AA-AA-AA-PP-P,N=27),和第4组(PP-PP-AA-PP-P，N=32）。在最后一次治疗后6个月，从每个孩子（N=5,340）获得直肠拭子。每个孩子贡献1个直肠拭子，这些在社区一级汇集，处理DNA-seq，并分析了遗传抗性决定因素。主要的预设结果是肠道中的大环内酯抗性决定因素。次要结果是对β-内酰胺类和其他抗生素类的耐药性。最近随机分配给阿奇霉素的社区（第1组和第2组）的大环内酯耐药决定簇明显多于最近随机分配给安慰剂的社区（第3组和第4组）（倍数变化2.18，95％CI1.5至3.51，Punadj<0.001）。然而,与最近的2.5年（第2组）相比，治疗4.5年（第1组）的社区大环内酯耐药性没有显着增加（倍数变化0.80，95％CI0.50至1.00，Padj=0.010），或在过去治疗3年的社区(第3组)与过去仅1年的社区(第4组)之间(倍数变化1.00,95%CI0.78~2.35,Padj=0.52).我们还发现β-内酰胺或其他抗生素类别没有显着差异。我们研究的主要局限性是缺乏抗性的表型表征，没有完整的安慰剂组，在尼日尔以外没有监测，限制了普遍性。
结论：在这项研究中，我们观察到,尼日尔学龄前儿童中阿奇霉素在儿童死亡率中的大量分布增加了肠道中大环内酯类耐药决定因素,但在治疗2~3年后,耐药可能会趋于平稳.需要监控其他类的共同选择。
背景：NCT02047981https://classic。clinicaltrials.gov/ct2/show/NCT02047981.
结果：2014年12月至2020年6月在尼日尔进行了MacrolideOrauxpourRéduirelesDécèsavec和OeilsurlaRéresistance（MORDOR）研究。这是一项阿奇霉素（A）与安慰剂（P）的集群随机试验，旨在评估儿童死亡率。这是MORDOR试验中的一项子研究，旨在追踪阿奇霉素MDA延长后抗生素耐药性的变化。共有594个社区符合资格。在163个随机选择的社区中，1至59个月的儿童有资格接受治疗，并被纳入耐药性监测。参与者,工作人员,研究者对治疗分配蒙上了阴影.在MORDOR第一阶段结束时，通过设计,所有社区接受额外一年两次的阿奇霉素治疗(II期).因此，在第二阶段结束时，参与社区的治疗史(每6个月1个字母)为(PP-PP-AA)或(AA-AA-AA).在第三阶段，然后，参与社区被重新随机分配接受另外3轮阿奇霉素或安慰剂，从而导致4个治疗历史：第1组（AA-AA-AA-AA-A，N=51),第2组(PP-PP-AA-AA-A,N=40),组3(AA-AA-AA-PP-P,N=27),和第4组(PP-PP-AA-PP-P，N=32）。在最后一次治疗后6个月，从每个孩子（N=5,340）获得直肠拭子。每个孩子贡献1个直肠拭子，这些在社区一级汇集，处理DNA-seq，并分析了遗传抗性决定因素。主要的预设结果是肠道中的大环内酯抗性决定因素。次要结果是对β-内酰胺类和其他抗生素类的耐药性。最近随机分配给阿奇霉素的社区（第1组和第2组）的大环内酯耐药决定簇明显多于最近随机分配给安慰剂的社区（第3组和第4组）（倍数变化2.18，95％CI1.5至3.51，Punadj<0.001）。然而,与最近的2.5年（第2组）相比，治疗4.5年（第1组）的社区大环内酯耐药性没有显着增加（倍数变化0.80，95％CI0.50至1.00，Padj=0.010），或在过去治疗3年的社区(第3组)与过去仅1年的社区(第4组)之间(倍数变化1.00,95%CI0.78~2.35,Padj=0.52).我们还发现β-内酰胺或其他抗生素类别没有显着差异。我们研究的主要局限性是缺乏抗性的表型表征，没有完整的安慰剂组，在尼日尔以外没有监测，限制了普遍性。
结论：在这项研究中，我们观察到,尼日尔学龄前儿童中阿奇霉素在儿童死亡率中的大量分布增加了肠道中大环内酯类耐药决定因素,但在治疗2~3年后,耐药可能会趋于平稳.需要监控其他类的共同选择。
背景：NCT02047981https://classic。clinicaltrials.gov/ct2/show/NCT02047981.
