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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: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

OBJECTIVE: Most evidence supporting screening for undernutrition is for children aged 6-59 months. However, the highest risk of mortality and highest incidence of wasting occurs in the first 6 months of life. We evaluated relationships between neonatal anthropometric indicators, including birth weight, weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ) and mid-upper arm circumference (MUAC) and mortality and growth at 6 months of age among infants in Burkina Faso. DESIGN: Data arose from a randomised controlled trial evaluating neonatal azithromycin administration for the prevention of child mortality. We evaluated relationships between baseline anthropometric measures and mortality, wasting (WLZ < -2), stunting (LAZ < -2) and underweight (WAZ < -2) at 6 months of age were estimated using logistic regression models adjusted for the childs age and sex. SETTING: Five regions of Burkina Faso. PARTICIPANTS: Infants aged 8-27 d followed until 6 months of age. RESULTS: Of 21 832 infants enrolled in the trial, 7·9 % were low birth weight (

ImportanceRepeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions.ObjectiveTo evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention.Design, setting, and participantsThis cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities.InterventionsCommunities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023.Main outcomes and measuresThe primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census.ResultsA total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months.Conclusions and relevanceMortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference.Trial registrationClinicalTrials.gov Identifier: NCT03676764.

Mass antibiotic distribution to preschool children resulted in alterations of the gut microbiome months after distribution. This individually randomized, placebo-controlled trial evaluated changes in the gut microbiome and resistome in children aged 8 days to 59 months after one dose of oral azithromycin in Burkina Faso. A total of 450 children were randomized in a 1:1 ratio to either placebo or azithromycin. Rectal samples were collected at baseline, 2 weeks, and 6 months after randomization and subjected to DNA deep sequencing. Gut microbiome diversity and normalized antimicrobial resistance determinants for different antibiotic classes were evaluated. Azithromycin decreased gut bacterial diversity (Shannon P < 0.0001; inverse Simpson P < 0.001) 2 weeks after treatment relative to placebo. Concurrently, the normalized abundance of macrolide resistance genetic determinants was 243-fold higher (95% CI: 76-fold to 776-fold, P < 0.0001). These alterations did not persist at 6 months, suggesting that disruptions were transient. Furthermore, we were unable to detect resistance changes in other antibiotic classes, indicating that co-resistance with a single course of azithromycin when treated at the individual level was unlikely.

BACKGROUND: Antibiotic use during early infancy has been linked to childhood obesity in high-income countries. We evaluated whether a single oral dose of azithromycin administered during infant-well visits led to changes in infant growth outcomes at 6 months of age in a setting with a high prevalence of undernutrition in rural Burkina Faso. METHODS AND FINDINGS: Infants were enrolled from September 25, 2019, until October 22, 2022, in a randomized controlled trial designed to evaluate the efficacy of a single oral dose of azithromycin (20 mg/kg) compared to placebo when administered during well-child visits for prevention of infant mortality. The trial found no evidence of a difference in the primary endpoint. This paper presents prespecified secondary anthropometric endpoints including weight gain (g/day), height change (mm/day), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and mid-upper arm circumference (MUAC). Infants were eligible for the trial if they were between 5 and 12 weeks of age, able to orally feed, and their families were planning to remain in the study area for the duration of the study. Anthropometric measurements were collected at enrollment (5 to 12 weeks of age) and 6 months of age. Among 32,877 infants enrolled in the trial, 27,298 (83%) were followed and had valid anthropometric measurements at 6 months of age. We found no evidence of a difference in weight gain (mean difference 0.03 g/day, 95% confidence interval (CI) -0.12 to 0.18), height change (mean difference 0.004 mm/day, 95% CI -0.05 to 0.06), WAZ (mean difference -0.004 SD, 95% CI -0.03 to 0.02), WLZ (mean difference 0.001 SD, 95% CI -0.03 to 0.03), LAZ (mean difference -0.005 SD, 95% CI -0.03 to 0.02), or MUAC (mean difference 0.01 cm, 95% CI -0.01 to 0.04). The primary limitation of the trial was that measurements were only collected at enrollment and 6 months of age, precluding assessment of shorter-term or long-term changes in growth. CONCLUSIONS: Single-dose azithromycin does not appear to affect weight and height outcomes when administered during early infancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03676764.