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We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs.Clinical trials registrationNCT02047981.

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. Methods and findings: 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. Trial registration: NCT02047981https://classic.clinicaltrials.gov/ct2/show/NCT02047981. Thuy Doan and co-workers explore the impact of mass azithromycin distribution on the antibiotic resistance in the gut of Nigerien pre-school children. Author summary: Why was this study done?: Mass azithromycin distributions to children aged 1 to 59 months in sub-Saharan countries improve childhood mortality. Prolonged mass azithromycin distributions may be necessary until a definitive solution is found for child mortality. However, mass azithromycin distributions also select for antibiotic resistance. Here, we compare communities randomized to different treatment histories to assess how antibiotic resistance changes over several years. What did the researchers do and find?: MORDOR was a cluster-randomized trial of azithromycin versus placebo aimed at evaluating childhood mortality. Randomization was performed at the village level. We conducted a sub-study of the MORDOR trial to track changes to antibiotic resistance in the gut, and 5,340 children from 150 villages were included. Rectal swabs were obtained, pooled, and sequenced for antibiotic resistance. We found that macrolide resistance determinants were increased in the gut of children whose villages were treated with twice-yearly azithromycin administration within the past 2 years compared to those who were treated with placebo. Longer periods of treatment with azithromycin were not associated with increased macrolide resistance and no changes to non-macrolide resistance determinants were detected. The main limitations of this study include the lack of phenotypic resistance assessment, the absence of a treatment arm where communities received a placebo for all 5 years, and that interpretations are limited to the community level in the Dosso region of Niger. What do these findings mean?: These findings are consistent with prior smaller studies showing that twice-yearly azithromycin treatment, at the dose recommended to improve childhood mortality, selects for macrolide resistance. However, resistance may plateau after several years, rather than continuing to increase. Non-macrolide resistance determinants were not significantly different between treatment arms, although p-values and confidence intervals need to be interpreted with caution. These findings suggest that careful surveillance for antibiotic resistance should be continued for mass drug distribution for childhood mortality. [ABSTRACT FROM AUTHOR]