Mass azithromycin distribution and antibiotic resistance in the gut and nasopharynx: a cluster-randomized trial.

Child-azithromycin MDA significantly increased gut macrolide AMR burden compared to placebo.

• Gut macrolide AMR burden fold change for child-azithromycin compared with placebo was 1.16 (95% CI: 1.06–1.28; P < 0.01).
• The trial met its primary AMR endpoint for the gut.
• The study used a double-blind, cluster-randomized, placebo-controlled design with 3,000 communities randomized in a 1:1:1 allocation.
• 4,382 rectal samples were included in the analysis.
• 150 communities (50 per arm) were selected for this resistance analysis.

Child-azithromycin MDA significantly increased gut macrolide AMR burden compared to infant-azithromycin MDA.

• Gut macrolide AMR burden fold change for child-azithromycin compared with infant-azithromycin was 1.13 (95% CI: 1.02–1.23; P = 0.01).
• Child-azithromycin arm targeted children aged 1–59 months with semiannual azithromycin MDA.
• Infant-azithromycin arm targeted only 1–11-month-olds with azithromycin, while 12–59-month-olds received placebo.
• MDA was administered semiannually over 2 years.

Infant-azithromycin MDA did not significantly increase gut macrolide AMR burden compared to placebo.

• Gut macrolide AMR burden fold change for infant-azithromycin compared with placebo was 1.04× (95% CI: 0.94–1.15×; P = 0.66).
• This comparison was not statistically significant.
• The infant-azithromycin arm restricted treatment to children aged 1–11 months only.

There were no statistically significant differences in nasopharyngeal macrolide AMR between any of the three trial arms.

• Nasopharyngeal macrolide AMR fold change for child-azithromycin versus placebo was 2.14 (95% CI: 0.93–4.99).
• Nasopharyngeal macrolide AMR fold change for infant-azithromycin versus placebo was 2.08 (95% CI: 0.93–4.69).
• Nasopharyngeal macrolide AMR fold change for child-azithromycin versus infant-azithromycin was 1.03 (95% CI: 0.46–2.30).
• The trial did not meet its primary AMR endpoint for the nasopharynx.
• 4,402 nasopharyngeal samples were included in the analysis.

The AVENIR trial was a large cluster-randomized trial in Niger evaluating azithromycin MDA targeting different age groups on both mortality and antimicrobial resistance.

• 3,000 communities were randomized in a 1:1:1 allocation to three arms: child-azithromycin, infant-azithromycin, and placebo.
• The co-primary endpoints were mortality (previously published) and resistance (reported in this paper).
• MDA consisted of semiannual treatment over 2 years.
• The trial was double-blind and placebo-controlled (ClinicalTrials.gov: NCT04224987).
• The study was conducted in sub-Saharan Africa, where azithromycin MDA programs are being implemented to reduce childhood mortality.

Close monitoring of antimicrobial resistance is recommended as an essential component of MDA programs for childhood mortality.

• Repeated semiannual azithromycin MDA to children has been shown to reduce all-cause childhood mortality.
• Antibiotic resistance is described as a major public health concern as the program is being implemented in sub-Saharan Africa.
• The findings suggest that restricting azithromycin MDA to infants (1–11 months) may reduce AMR selection pressure in the gut compared to treating all children 1–59 months.