Mass Azithromycin Distribution and Community Microbiome: A Cluster-Randomized Trial

Abstract

Background: Mass distributions of oral azithromycin have long been used to eliminate trachoma, and they are now being proposed to reduce childhood mortality. The observed benefit appears to be augmented with each additional treatment, suggesting a possible community-level effect. Here, we assess whether 2 biannual mass treatments of preschool children affect the community's gut microbiome at 6 months after the last distribution.

Methods: In this cluster-randomized controlled trial, children aged 1-60 months in the Dossa region of Niger were randomized at the village level to receive a single dose of azithromycin or placebo every 6 months. Fecal samples were collected 6 months after the second treatment for metagenomic deep sequencing. The prespecified primary outcome was the Euclidean PERMANOVA of the gut microbiome, or effectively the distance between the genus-level centroid at the community level, with the secondary outcome being the Simpson's α diversity.

Results: In the azithromycin arm, the gut microbial structures were significantly different than in the placebo arm (Euclidean PERMANOVA, P < .001). Further, the diversity of the gut microbiome in the azithromycin arm was significantly lower than in the placebo arm (inverse Simpson's index, P = .005).

Conclusions: Two mass azithromycin administrations, 6 months apart, in preschool children led to long-term alterations of the gut microbiome structure and community diversity. Here, long-term microbial alterations in the community did not imply disease but were associated with an improvement in childhood mortality.

Clinical trials registration: NCT02048007.

Keywords: antibiotics; azithromycin; children; gut microbiome; randomized controlled trial.

Figure 1.

Trial profile. Children aged 1–60 months, from 30 villages, were randomly assigned to either the placebo or azithromycin-treated groups. Rectal samples from 10 children in each village were pooled and subjected to metagenomic RNA sequencing and analysis.

Figure 2.

Two biannual treatments of azithromycin cause long-term alterations of the gut microbial communities of children. A, Principal coordinate analyses of the Euclidean distances for the placebo (gray) and the azithromycin-treated (orange) villages. Beta-dispersions were similar (P = .20) between treatment groups. B, Stacked bar graph of the abundance of the different taxonomic groups. Distributions of the inverse Simpson’s diversity index (C) and Shannon’s diversity index (D) for the placebo and azithromycin-treated villages. Abbreviation: PCoA, principal coordinate.