Four twice yearly distributions of azithromycin to infants and children in sub-Saharan African communities with varying rates of mortality went beyond the WHO recommended distribution to only infants in high-mortality settings, but was associated with reduction in all-cause mortality in children of up to 59 months of age.
Kieran O'Brien, PhD, MPH, Francis I. Proctor Foundation, University of California, San Francisco, CA, and colleagues explain that the more restricted distribution recommended by the WHO reflects concern with development of antimicrobial resistance (AMR), but suggest that the wider antibiotic use was shown in their trial to save children's lives, and that it can be provided while monitoring for AMR.1
"Given the immediate need to reduce mortality and the uncertain future effect of community-level resistance on morbidity and mortality, the WHO determined that azithromycin distribution is warranted in the populations that are most likely to benefit from it," O'Brien and colleagues noted."Our trial provides evidence that treating only infants may not be as effective as treating all children 1 to 59 months of age."
In an accompanying editorial that posed and answered the question of why this AVENIR "for life" trial was necessary, Kathryn Maitland, MD, PhD, Department of Infectious Disease and Institute of Global Health and Innovation, Division of Medicine, Imperial College, and Sarah Walker, PhD, Medical Research Council Clinical Trials Unit, University College London, both London, UK, trace this initiative to a reduction in all-cause mortality found after azithromyicin was distributed to children in trachoma-endemic regions.2
What You Need to Know
Administering azithromycin twice a year to children aged 1 to 59 months in sub-Saharan Africa significantly reduced all-cause mortality, surpassing the WHO recommendation to limit distribution to infants in high-mortality areas.
Although the broader use of azithromycin was shown to save lives, WHO's more restricted guidelines are based on concerns about antimicrobial resistance (AMR).
The AVENIR trial demonstrated that limiting azithromycin distribution to only infants is not as effective as including all children up to 59 months of age, challenging WHO's current mass distribution recommendations while highlighting the importance of balancing mortality reduction with AMR risks.
Maitland and Walker note, however, that the subsequent conditions recommended by the WHO, "set the bar very high for future implementation." Results from the trial by O'Brien and colleagues, they indicate, "challenge most of the current recommendations for mass distribution of azithromycin except for one—the specter of increased antimicrobial resistance."
In the double-blind, response-adaptive, cluster-randomized and placebo-controlled trial conducted with 382,586 children in 1273 communities in Niger with four mass distributions of antibiotic twice yearly, the investigators compared outcomes in four groups. Azithromcyin (single observed dose of 20mg/kg in an oral suspension) was provided to the child group (n=1229 communities in analysis) at ages 1 to 59 months, and to the Infant group age 1 to 11 months (n=751 communities). Placebo was provided to the child placebo group at 12 to 59 months of age, and to the Placebo group (n=929 communities) age 1 to 59 months.
O'Brien and colleagues reported observing a 14% lower mortality in the child group, age of 1 to 59 months than with placebo (11.0 deaths per 1000 person years [95% CI 11.3 to 12.6] vs 13.9 deaths [13.0-14.8]).The mortality among infants 1 to 11 months of age was not statistically significantly lower with azithromycin than placebo, however. While acknowledging that AMR must be monitored with such programs, the investigators nonetheless argue for its wider application.
"Overall the AVENIR trial showed that twice-yearly azithromycin distribution in children 1 to 59 months of age reduce morality, even in communities with lower mortality than were receiving seasonal malaria chemoprevention. The trial provides evidence that limiting distributions to infants 1 to 11 months of age is not as effective as including all children 1 to 59 months of age," O'Brien and colleagues declare.
References
1.O'Brien KS, Arzika AM, Amza A, et al. Azithromycin to reduce mortality—An adaptive cluster randomized trial. N Engl J Med 2024; 391:699-709.
2.Maitland K and Walker AS. Why was the azithromycin "for life" trial necessary? N Engl J Med 2024; 391:760-762.
