Researchers pursuing a simple, cheap way to dramatically reduce childhood deaths in sub-Saharan Africa released some promising new results Thursday — but it’s still unclear whether their approach might ultimately put more children at a disadvantage in fighting off serious diseases.
The story starts in 2009, when a group of ophthalmologists from the University of California, San Francisco published some surprising results from a study they had conducted in Ethiopia on trachoma, an eye infection that is the world’s leading cause of preventable blindness. The eye doctors knew that the antibiotic azithromycin was effective in fighting the disease and had administered it to tens of thousands of children there, ages 1 to 9. Meanwhile, they wanted to keep watch on whether the drug seemed to have any other beneficial effects on the children’s health.
What they found was remarkable: Mass azithromycin treatment, administered two times a year, seemed to have an almost miraculous ability to reduce childhood deaths. In Ethiopia, 58 babies per 1,000 births don’t survive past the age of 5. That’s lower than the sub-Saharan Africa average of 76 but still far higher than in Europe or the U.S. (where the rate is around 6 per 1,000). But in groups of children treated with azithromycin, the mortality rate was half that of untreated groups.
“It seemed almost unbelievable,” says Jeremy Keenan, a UCSF ophthalmologist who was not involved with the study but had watched it with interest. In the following years, Keenan joined the research team as it secured funding from the Gates Foundation (which also supports this blog) and set out to attempt to replicate the results elsewhere, with azithromycin donated by the pharmaceutical giant Pfizer, which manufactures it. That effort, in which the antibiotic was administered to nearly 200,000 children in Tanzania, Malawi and Niger, published its first findings last year. While they weren’t as shocking as in Ethiopia, they were still impressive: a 14% mortality reduction in Tanzania and Malawi, and 18% in Niger.
The study doesn’t address the question of what, exactly, causes that reduction, although researchers suspect that the antibiotic provides a kind of broad defense against the myriad gastrointestinal and respiratory bugs that commonly afflict young children in developing countries and can sometimes be fatal if untreated.
But despite its apparent success, the study raised concern among global health specialists: Couldn’t such widespread use of an antibiotic in healthy children increase the likelihood that infectious bacteria would develop antibiotic resistance, making the germs harder to beat when kids inevitably get sick? In other words, could this seemingly silver-bullet solution actually trigger an evolutionary arms race that would eventually leave more children less capable of fighting back?
Keenan and his colleagues put forward a mixed answer to that question Thursday, with the publication of a second round of findings in the peer-reviewed New England Journal of Medicine. They found that in Niger, even after three years of twice-yearly azithromycin treatment, the childhood mortality reduction stayed about the same, suggesting that the antibiotic continued to be effective and didn’t lose steam over time against resistant bugs.
But a separate study by the same team tested the study participants for pneumococcus, a bacterium that causes pneumonia and sinus infections. In the treated group, they found evidence of significantly higher levels of pneumococcus that was resistant to macrolides (the class of antibiotics that includes azithromycin) than in a group given a placebo. In other words, signs of antibiotic resistance were already beginning to appear in the group that had been given azithromycin.
The increase in macrolide-resistant bacteria was expected, Keenan says, and was not as pronounced as it has been in other areas where azithromycin has been widely distributed to fight trachoma. Overall, the results are encouraging, he says: They offer further proof that azithromycin can be a potent weapon against childhood mortality, and the increase in antibiotic resistance doesn’t seem to be enough to change that.
“Our group definitely thinks antimicrobial resistance is still a big issue,” he says. “But if it’s the case that there’s more resistance and the mortality benefit goes away over time, we should be able to see that.”
Other public health experts remain skeptical.
“It doesn’t really alleviate my concerns about the potential for antibiotic resistance,” says Nicola Low, an epidemiologist at the Institute of Social and Preventive Medicine at the University of Bern in Switzerland.
Low says she has followed the UCSF team’s work for years and been impressed by the “really striking” reductions it has achieved in child mortality. But she worries that the trial doesn’t go far enough to truly measure the side effects of mass azithromycin distribution. By design, the researchers only tracked childhood deaths and not other cases of nonfatal infection (the rationale being that if they continually monitored their study group for illnesses, they would be obliged to treat them, which could muddle measurements of fatality). So other impacts may be lurking in the shadows, Low says.
“Most of the infections kids get are not fatal,” she says. “So even if there is resistance circulating, you would need to have a massive impact on death for it to be measurable.”
In any case, monitoring signs of antibiotic resistance within the study group itself is only part of the equation, says Marc Lipsitch, an epidemiologist at Harvard’s T.H. Chan School of Public Health. Children in the study group could easily pass antibiotic-resistant bugs on to their older siblings, parents, or others. And those people could be in trouble if azithromycin or another macrolide is the usual treatment for that bug, he says, “so you have to sample more people to see the effect.”
Azithromycin is not commonly used in Niger for routine infections, and so far Keenan and his colleagues haven’t found signs of resistance to penicillin or other more prevalent antibiotics among the study group. Even if they did, Lipsitch says, that wouldn’t necessarily be a reason to scrap the treatment. Antibiotics may be worth the risk in a place like Niger, which has one of the highest childhood mortality rates in the world and has struggled to implement improvements like clean water infrastructure and rural primary care that would help save children’s lives.
“I can’t think of anything better to do with antibiotics than to save lives, and there are very few cases where you can clearly see in a randomized trial that it’s saving lives,” he says. “So the real question is whether the consequences for human health [of antibiotic resistance] are very severe, and if so are they severe enough to compete with the impressive benefit the treatment has.”
At the same time, Keenan says, “antibiotics are always an add-on. They can never replace vaccinations, clean water or primary care. But with an antibiotic you get a big bang for your buck.”
So far, community leaders in the villages where the trial was conducted seem to agree, says Ahmed Arzika, a Nigerien public health researcher with the U.S. nonprofit Carter Center, who coordinated the field work on behalf of the UCSF researchers. Out of hundreds of villages that were initially invited to participate, only one declined, he says, and several that were left out of the randomized selection later contacted him to ask to be included.
“We shared the results with local authorities, and they appreciated what is being done and they want to continue helping us,” he says. “Because of what it does for the kids, they’re very happy about it.”
The research isn’t over yet: Keenan and his colleagues hope to extend the trial to infants younger than 1 month, for whom deaths from infections are even more common.
Aaron Milstone, an epidemiologist at the Bloomberg School of Public Health at Johns Hopkins, says it will take many more years to gauge the extent to which antibiotic resistance may become a problem for communities in the trial.
“They haven’t completely reassured that this has long-term safety. There’s a lot of concern about early childhood antibiotic exposure, how might that set you up for other diseases later in life,” he says. “But if I lived there and had to take the risk, now versus later in life, I’d take the azithromycin.”