In the latest in a series of studies investigating the effect of mass azithromycin distribution on childhood mortality in sub-Saharan Africa, researchers have found that giving the antibiotic to all children up to 5 years old has a bigger impact than limiting it to younger children.
The study, published yesterday in the New England Journal of Medicine, found that twice-yearly distribution of azithromycin to children ages 1 to 59 months in rural communities in Niger reduced childhood mortality by 14% when compared with children who received a placebo.
The findings are significant, because in 2020 the World Health Organization (WHO) recommended the intervention be considered in settings with high childhood mortality in sub-Saharan Africa, but only for children ages 1 to 11 months. The recommendation was based on a 2018 study that found mass azithromycin distribution—an intervention initially implemented in parts of Africa to eliminate trachoma—significantly reduced childhood mortality in rural communities in Niger, Malawi, and Tanzania.
The WHO wanted to limit treatment to that younger age-group, because that's where the biggest impact on mortality had been seen and because of concerns that wider azithromycin distribution might promote antibiotic resistance.
But the new study found that targeting only children ages 1 to 11 months did not lead to a significant reduction in childhood mortality compared with the placebo group. Furthermore, the reduction in mortality was even greater in those younger infants when older children also received azithromycin.
"This suggests we need this community-level effect in order to see those large mortality reductions in children in that younger age-group," the study's first author, Kieran O'Brien, PhD, MPH, an epidemiologist and assistant professor with the University of California-San Francisco (UCSF) Francis I. Proctor Foundation, told CIDRAP News.
Looking for the biggest mortality benefit
In the AVENIR (Azithromycine pour la Vie des Enfants au Niger: Implementation et Recherche) trial, researchers from UCSF, the Niger Ministry of Health, and Centre de Recherche et Interventions en Sante Publique in Niger conducted a cluster-randomized trial, assigning rural communities in Niger to three different treatment groups from November 2020 through July 2023.
Niger, which saw the biggest reduction in mortality in the 2018 MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial, was selected because it has high under-5 mortality rates.
In 1,273 communities, all children ages 1 to 59 months received twice-yearly oral doses of azithromycin (the child azithromycin group). In 773 communities, azithromycin was given only to children ages 1 to 11 months (the infant azithromycin group). In 954, children ages 1 to 59 months received placebo (the placebo group. The primary outcome was all-cause mortality after 2 years of azithromycin distribution.
O'Brien said the trial ultimately had a few goals. One was to see if the researchers could replicate the findings of the MORDOR trial, which found that twice-yearly azithromycin distribution reduced mortality in rural communities in Niger, Tanzania, and Malawi by 14%. But the investigators also wanted to directly test the efficacy of the WHO recommendations—which have never been studied—by including a group in which only 1- to 11-month-olds received azithromycin and then comparing the results with the placebo group.
"I think there was some disappointment in the [WHO] guidelines, since the 1- to 59-month group overall is at a high risk of mortality," she said. "There's a lot more children in the 12- to 59-month age group than there are in the 1- to 11-month age group, and many more lives could be saved if you included that full 1- to 59-month group."
Among the 382,586 children included in the AVENIR trial, there were 5,503 deaths. In children 1 to 59 months, mortality was 14% lower in the child azithromycin group (11.9 deaths per 1,000 person-years at risk) than in the placebo group (13.9 deaths/1,000 person-years at risk). But in infants ages 1 to 11 months, mortality in the infant azithromycin group (22.3 deaths/1,000 person-years at risk) was only 6% lower than in the placebo group (23.9 deaths/1,000 person-years at risk)—a difference not considered statistically significant.
And when the investigators compared mortality among infants ages 1 to 11 months in the child azithromycin group (18.5 deaths/1,000 person-years at risk) with those in the infant azithromycin group (22.3 deaths/1,000 person-years at risk), they found a 17% reduction.
"We think that this is evidence that the 1- to 59-month treatment, to achieve the mortality benefits that were originally posited in the WHO guidelines, would make sense," O'Brien said.
The authors also note that the trial showed that mass azithromycin distribution maintains its impact on childhood mortality even in the presence of seasonal malaria chemoprevention, which contains the antibiotic sulfadoxine and is routinely given to children ages 3 to 59 months in the trial area. A previous trial, conducted in Mali and Burkina Faso, found that mass azithromycin distribution alongside seasonal malaria chemoprevention had no additional impact on mortality.
Antimicrobial resistance remains a concern
The question that remains, however, is what effect routine, twice-yearly distribution of azithromycin in children under 5 might have on antimicrobial resistance (AMR). Analysis of microbiologic data from children in the MORDOR trial found that mass azithromycin distribution did increase the prevalence of macrolide resistance in Streptococcus pneumoniae over 2 to 3 years. And it increased the presence of genetic resistance mechanisms in gut bacteria, as well.
But Tom Lietman, MD, an ophthalmologist at UCSF who was involved in both the MORDOR and AVENIR trials, says he theorizes that the resistance levels could plateau, because kids will no longer receive the antibiotic after they reach 59 months and the new children who age into the program will have not been exposed to azithromycin.
"I think that would alleviate a little bit of the concern if we select for resistance, but it appears to plateau rather than just continually going up," Lietman said.
Lietman also noted that, unlike mass azithromycin distribution programs for trachoma, which target all members of a community, the intervention studied in MORDOR and AVENIR targets only preschool-aged children.
"Our theory is that, because we're targeting just the preschool kids rather than the whole community, like with trachoma, that maybe there's less antibiotic pressure," he said.
O'Brien said the resistance data from the AVENIR trial still need to be analyzed, and she expects that WHO experts will wait until those data, and data from a few other trials of the intervention, are available before they decide whether to update the guidelines.
We think that this is evidence that the 1- to 59-month treatment, to achieve the mortality benefits that were originally posited in the WHO guidelines, would make sense.
But at a time when the WHO and health officials around the world are increasingly concerned about AMR and the threat of a post-antibiotic world, is mass distribution of azithromycin to children a good idea?
For O'Brien and Lietman, the effectiveness of the strategy ultimately highlights the lack of access to healthcare in places like rural Niger, which plays a significant role in high childhood mortality. Until these communities have stronger healthcare systems and better access to effective antibiotics when they're needed, they say, strategies like mass azithromycin distribution may be necessary to help reduce what Lietman calls "unacceptably high" childhood mortality rates.
"That's where we think that there may be sort of a niche for this intervention," Lietman said. "It wouldn't be forever."
