To stem the rise in antibiotic resistance, researchers recommend that people only take the drugs after they are diagnosed with a bacterial infection. But a trial involving nearly 200,000 children in Niger, Tanzania and Malawi went against that guidance in an attempt to save youngsters in regions where as many as one in ten die before their fifth birthday.
The results, published on 25 April in The New England Journal of Medicine1, suggest that widespread distribution of antibiotics could prevent thousands of deaths. However, health officials and researchers are wary of implementing a massive drug programme on the basis of the results because it would drive antibiotic resistance.
“It goes against dogma at the moment because everyone else is trying to reduce antibiotic use,” says Per Ashorn, who specializes in paediatric infectious diseases at the World Health Organization (WHO). The study’s results are exciting, he says, but the WHO needs more data to evaluate the approach.
Some officials sound more enthusiastic about the strategy. “As a person who was born in one of the poorest countries in the world, I welcome this,” says Samba Sow, the health minister in Mali, where 11% of children die before age 5. “My older brother died as a child, more than one of my cousins died as a child — children die here, and they die fast.”
Living with resistance
Mass drug administration fell out of favour in the late 1960s, after programmes to prevent malaria through the large-scale distribution of a drug called chloroquine backfired. Drug resistance developed rapidly because thousands of people with insufficient levels of chloroquine in their systems became infected with malaria parasites. Strains that were susceptible to the drug died, but more-resilient ones multiplied. Eventually, chloroquine stopped working.
But opinions on mass drug administration seem to be changing. Since 2012, several African countries have reduced deaths from malaria by pre-emptively treating millions of children during the rainy season. And the WHO now recommends the distribution of some antibiotics to certain populations impacted by neglected tropical diseases — a constellation of illnesses affecting roughly one billion people living in poverty around the world.
The idea for the latest study came from an analysis of the pre-emptive use of the antibiotic azithromycin in Ethiopian communities affected by trachoma — a disease that causes blindness — in the late 2000s. Researchers noticed a drop in overall deaths2, and Thomas Lietman, an infectious-disease researcher at the University of California, San Francisco, and his colleagues followed up with the current trial, dubbed MORDOR (from the French description of the project). The Bill & Melinda Gates Foundation funded the trial with a US$14 million grant and the pharmaceutical company Pfizer donated the antibiotics.
As part of MORDOR, children under five in communities in Niger, Malawi and Tanzania took one dose of azithromycin twice a year for two years. Control populations received a placebo. Childhood mortality rates among treated communities in Niger dropped by 18% compared with control populations; Tanzania had 3% fewer deaths and Malawi saw a 6% reduction.
Pros and cons
Lietman says that Niger likely experienced the greatest benefit from the intervention because it has the highest childhood mortality rate of the three countries. About 9% of children die before the age of 5 in Niger, compared with about 5% in Tanzania and Malawi (see 'Childhood mortality'). Pneumonia and diarrhoea triggered by bacterial infections help to drive up childhood mortality rates, according to a 2017 report from the United Nations. Poor sanitation, unsafe drinking water and malnutrition combine to make children living in poverty especially vulnerable to disease-causing microbes. They’re also more likely to die from curable conditions because health care can be unaffordable or too far away to be of help.
But this antibiotics strategy comes at a cost, says Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics and Policy in Washington DC. If resistance develops against azithromycin, diseases treated by the drug, including gonorrhoea, would become harder to combat. If policymakers decide to implement this approach, he hopes they will target only the populations most in need, and then just for a limited time. Groups supporting this approach should also work to reduce childhood mortality in the same way that the developed world did, he says, through improved sanitation, nutrition and health care.
For now, researchers will continue to study the effects of this antibiotics strategy. Later this year, similar trials funded by the Gates Foundation will launch in Mali and Burkina Faso. And Lietman’s team is evaluating data collected during an extension of its trial to assess how fast antibiotic resistance develops. The WHO plans to release a statement about whether this strategy is justified, and in what circumstances, by the end of 2019.
Nature 557, 14-15 (2018)