In the mid-2000s, researchers conducted a clinical trial in Ethiopia to see what it would take to eliminate trachoma, a disease caused by the bacterium Chlamydia trachomatis and the most common cause of blindness from infection worldwide. They randomly gave one- to 10-year-old kids either the antibiotic azithromycin to clear and prevent infection or delayed their treatment until after the trial ended.
There were far fewer cases of trachoma among those treated—but also fewer deaths, even though trachoma is not a lethal disease. “The communities with delayed treatment had twice the childhood mortality as the communities that were treated,” says University of California, San Francisco (UCSF), ophthalmologist Thomas Lietman, the senior author of the 2009 study that reported the unexpected results.
It wasn’t clear how the antibiotic might have been preventing deaths exactly. Because azithromycin is a broad-spectrum antibiotic that is used to treat eye, respiratory, and gastrointestinal infections, the researchers hypothesized that reductions in these infections could be contributing. In 2014, Lietman’s team set out to replicate the experiment in a much larger randomized trial across Niger, Malawi, and Tanzania, in which more than 190,000 children received biannual doses of either azithromycin or a placebo, regardless of trachoma status.
Again, azithromycin seemed to be saving lives, with 13.5 percent fewer deaths in the communities that received the drug.
“Those of us who study child health—specifically, child survival in sub-Saharan Africa—haven’t seen well-done trials showing such a striking mortality benefit in a really long time, so it’s very exciting,” says Patricia Pavlinac, an epidemiologist at the University of Washington who did not participate in the study. “And, of course, [we] are eager to understand why that mortality reduction happened.”
Lietman and his colleagues had that same question in mind when they started the latest trial. At the beginning of the study and six months after the final treatment, they sequenced rectal swabs of 600 children from one to five years old who received four biannual doses of either azithromycin or placebo. All of the children were from Niger, where 10 percent of kids don’t make it to their fifth birthday.
They found a decrease in 35 species of bacteria, including two species of Campylobacter, a genus known to cause diarrhea. Reporting the results in Nature Medicine this week (August 12), they propose that this shift in the composition of the microbiota could be contributing to the lower levels of child mortality after antibiotic administration.
“This study is the first I’ve seen in a while that really gives a compelling mechanism as to why it may be having a mortality benefit in children,” says Pavlinac.
“It seems that biannual mass azithromycin distribution to preschool children—at least in Niger, we can’t really generalize to other countries at this point—reduces [gastrointestinal] pathogens, but it seems to be at the cost of increasing antibiotic resistance,” study coauthor Thuy Doan of UCSF tells The Scientist. Her group also determined that the antibiotic treatment increased the expression of genes conferring resistance to azithromycin and similar antibiotics, while the placebo treatment did not. The threat of increased antibiotic resistance means that adopting policies that recommend mass azithromycin administration would not be without risks.
“There are a lot people who are very concerned with implementing this intervention across countries in Africa because of concern about antibiotic resistance,” Pavlinac tells The Scientist. “There’s an ethical dilemma here. Do you save a child’s life now because we have an intervention that works, but then perhaps run the risk of inducing resistance in a community that means five, ten years down the road this intervention may not save children’s lives? There’s no right answer.”
“We in the Western world have had the advantages of antibiotics for years . . . so who are we to say that kids shouldn’t have access?” asks Ruairi Robertson, a microbiologist affiliated with Queen Mary University London and the University of British Columbia who was not involved in the work. “In the mean time, we need to continue trying to come up with ways to tackle this huge global threat of antimicrobial resistance.”
One possible workaround, according to Doan, is to develop strategies to reduce Campylobacter transmission, instead of using antibiotics to treat it after it’s already present in the gut microbiome.
The team will also further explore how the microbiome changes affect mortality, with the goal of developing tools with a lower risk of increasing antibiotic resistance. “If we could find out in particular . . . what portion of the effect was Campylobacter then we could more specifically target the Campylobacter and select for less resistance in other organisms,” says Lietman.
T. Doan et al., “Gut microbiome alteration in MORDOR I: a community-randomized trial of mass azithromycin distribution,” Nature Medicine, doi:10.1038/s41591-019-0533-0, 2019.
Abby Olena is a freelance journalist based in North Carolina. Find her on Twitter @abbyolena.