Expanding antibiotic treatment in sub-Saharan Africa could save kids’ lives

“We were very surprised that we were able to prove that spillover effect, that treating the older kids actually helped the younger kids,” says epidemiologist Thomas Lietman. “It appears to be the majority of the [antibiotic benefit] is indirect, more than direct.”

Back in 2018, a large trial in Niger, Malawi and Tanzania showed that a single dose of azithromycin twice a year for children under 5 could reduce mortality by almost 14 percent, or from about 165 annual deaths per 10,000 children to about 145. That finding led the World Health Organization, or WHO, to the current recommendation, but they stopped short of suggesting it be given to all children under age 5.

The WHO probably restricted their recommendation to infants because that group has higher mortality rate than preschool-age children, says Lietman, of the University of California, San Francisco. But he and his team suspected that the infants would not fare as well if the older children were not also treated.

Working with a team of healthcare workers in Niger, the researchers conducted a follow-up trial from 2020 through 2023 with more than 380,000 children under age 5. Participants were assigned to one of three groups: infants 1 to 11 months receiving treatment, with the older children receiving a placebo; all children under 5 getting treatment; or all children under 5 receiving a placebo. The results, published August 21 in the New England Journal of Medicine, show that treating all children under 5 reduced mortality for the infants by 17 percent, from roughly 220 annual deaths per 10,000 children to 185.   

Lietman and study coauthor Kieran O’Brien, an epidemiologist also at UC San Francisco, spoke with Science News about the recent findings and their implications. This interview has been edited for length and clarity.

SN: What inspired the first trial back in 2018?

Lietman: It started with trachoma studies [in the early 2000s]. Trachoma is an eye disease caused by chlamydia [that] causes a lot of blindness (SN: 2/20/08). And the WHO has recommended mass azithromycin treatment to entire communities — not just to the preschool kids, but to entire communities — once a year [to treat trachoma]. In one of the trachoma trials in Ethiopia, we found [that communities with widespread antibiotic treatment had lower childhood mortality rates than those that did not. This was surprising because it wasn’t known that widespread antibiotics could reduce childhood mortality until this trial.]

There’s far more childhood mortality in West Africa (for example, in Niger) than there is in East Africa (for example, Ethiopia). So the Gates Foundation decided to fund the MORDOR trial, which is the 2018 study. It found a 13.5 percent reduction in childhood mortality in the communities where they were randomized to give the azithromycin twice a year to the preschool kids.

SN: After the MORDOR trial, how did you feel about the WHO recommendation?

Lietman: The WHO actually made guidelines fairly quickly, I was really impressed. I’ve never seen anything like it happen this quickly. But they’re very concerned about the balance between antibiotic resistance and childhood mortality (SN: 1/24/22). So, they recommended restricting the antibiotics to 1- to 11-month-olds rather than 1- to 59-month-olds, which we’d [studied] in MORDOR.

O’Brien: I think that there was some general disappointment at the release of the guidelines and seeing that restricted age group. And part of the feeling behind that was there are so many fewer children in the 1-to-11-month age group than the 1-to-59-month age group. And so, you end up saving far fewer lives if you only target that small age group.

SN: In this new trial, called AVENIR, did treatment work also for infants in the group where older kids were not treated?

O’Brien: We saw a 6 percent reduction in mortality in the 1-to-11-month group when they alone were treated [compared with 17 percent when all children received antibiotics]. But it wasn’t statistically significant. Unfortunately, we [didn’t have enough participants] to be able to detect an effect as small as 6 percent. 

We do think that these mass drug administration interventions operate in part through the direct effects on the children receiving the drug. But then also through these indirect effects, with the community-wide reduction in transmission of disease. The younger kids are likely benefiting from the older kids, who are active in the community, having this reduced transmission. So, [when the older kids also receive treatment], they’re not getting infected as much from the older kids.

Lietman: We come from the trachoma world, where maybe half the kids are infected with chlamydia [in their eyes] when you start your treatment program. And if you just treat one kid, you’ll probably clear their chlamydia, but they’re just going to get reinfected in a few weeks. So, it’s actually irrelevant; you need to treat all the other kids. As a matter of fact, it’s more important that the other kids are treated than you’re treated. So, we were kind of expecting this indirect effect.

SN: What do you hope will change, given your findings?

O’Brien: I think we would hope to see [the guidelines] updated to recommend treatment to 1-to-59-month-olds, with whatever conditions made sense at the time the guidelines were created. The current guidelines already state that any implementation should be accompanied by monitoring of resistance, and so I would expect fully for that to be in place moving forward.

[Some] of the next questions that I think many researchers are focused on [are]: How do we determine when to stop? How much resistance is too much? What type of impact is resistance having that would cause us to stop treatment? And also, how long do you need to treat in order to see a sustained reduction in mortality? Those are some of the questions that might contribute to better defining some thresholds around the intervention.

Big picture, though, I don’t think anyone anticipates it being a very long-term intervention for any regular area. [The hope is that the treatment could reduce transmission enough to eliminate a future need for mass distribution of antibiotics.]