Life-saving drug for African children may drive antimicrobial resistance?

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Editorial reviews azithromycin as a life-saving option for African children—but at the risk of increasing antimicrobial resistance.

In a co-written editorial published in The New England Journal of Medicine by Professor Kathryn Maitland, lead of Institute of Global Health Innovation’s Centre of African Research and Engagement (ICCARE), discusses the use of azithromycin—an antibiotic commonly recommended for treating trachoma in African children.

The piece examines previous research on azithromycin, followed by the results from the latest 'Azithromycin for Life' trial, which considers the drug’s dramatic impact on all-cause childhood mortality, as well as concerns regarding antibiotic resistance.

Innovative medicine that prevents blindness and lowers mortality

Azithromycin is an antibiotic medicine which was originally developed to treat trachoma, an infection caused by the bacterium Chlamydia trachomatis that affects the eyes.

Trachoma is the leading infectious cause of irreversible blindness worldwide. It is most commonly present in areas of extreme poverty, making the rural and most isolated communities of sub-Saharan Africa particularly vulnerable, with an enormous economic burden due to loss of productivity.

To tackle this issue, about 15 years ago, a study was conducted in Ethiopia which involved the administration of a single dose of azithromycin to children between one and nine years of age to prevent trachoma.

Unexpectedly, a single dose on Azithromycin was effective not only against trachoma prevention but against illness and deaths from respiratory disease, diarrhoea, and malaria—frequent causes of childhood mortality in sub-Saharan Africa. Specifically, the study showed a significant reduction (49%) in the risk of dying from any cause among these children. Moreover, this reduction was sustained over two years following the mass distribution.

Mixed results when combined with other prevention programmes

The findings were remarkable, considering that one in ten children do not reach the age of five in some parts of Sub-Saharan Africa so mortality rates are tragically high.

This led to several subsequent trials in various African countries investigating the effects of azithromycin child mortality, alone and in combination with seasonal malaria prophylaxis to prevent infection in areas of Africa with endemic trachoma. The results from these studies were mixed.

For example, the MORDOR trial showed a positive impact on all-cause mortality rates in the countries involved, especially in Niger, where baseline mortality rates were high and specifically in very young children aged one to five months.

By contrast, another trial demonstrated no additional benefits for childhood survival when azithromycin was added to a malaria prevention strategy. However, the authors did report reductions in gastrointestinal infections, respiratory infections, and other conditions.

Fears of antimicrobial resistance

These conflicting results have also raised concerns about antimicrobial resistance associated with the mass distribution of antibiotics such as azithromycin.

In the most recent systematic review, the World Health Organization (WHO) evaluated the existing evidence, weighing the benefits of this drug against the potential harms of adverse effects.

The WHO strongly recommended against its routine use for reducing mortality due to concerns about antimicrobial resistance developing in these children. However, they made an exception for recommended use in babies between one month and 11 months of age in areas with very high death rates, despite low quality of evidence. In addition, it required continuous monitoring of infant and child mortality and antimalarial resistance.

Professor Kathryn Maitland commented:

“This set the bar very high for any future implementation, where epidemiological frameworks for monitoring both of these criteria are rarely present in countries where trachoma is endemic.’’

Ethical and scientific dilemmas

The Azithromycin ‘’for life’’(AVENIR) trial, published in August 2024, was initiated by a group of researchers from Niger who challenged the WHO recommendations and conducted a trial to assess the effects of the drug administered to 382,000 children twice annually.

The study divided participants into three groups: (1) children aged one to 59 months receiving azithromycin, (2) infants aged 1 to 11 months receiving azithromycin, with older children up to 59 months receiving a placebo, and (3) children aged one to 59 months receiving a placebo.

The results showed a significant 14% reduction in all-cause mortality in the communities where both infants and children were given prophylaxis with azithromycin, suggesting its effectiveness in preventing infections and other causes of death. However, no benefit was observed in communities when only infants when only were given prophylaxis – contradicting the basis of WHO recommendations. The findings suggest that treating all children, not just infants, provides a community-wide mortality benefit.

Professor Kathryn Maitland reflects on this topic in the NEJM editorial:

“This situation creates ethical and scientific dilemmas, since the AVENIR study has not yet reported its effect on antimicrobial resistance and how this affects treatment of other common childhood conditions. Whilst azithromycin is not frequently used to treat childhood infections, it can cause cross resistance in other classes of antibiotics that are widely used in these countries.’’  

“Further deliberations for guideline recommendations weighing the risks and benefits of mass distribution of azithromycin for communities and individual persons should not overlook the disease it was originally intended to control — trachoma eye infection, which affects millions of people worldwide, especially in sub-Saharan Africa. Trachoma causes lifelong effects on health including blindness, disability with severe economic consequences for communities most affected.’’

Trachoma prevention programmes that provide azithromycin distribution to the whole population, in which strict prevalence conditions are met, will continue to provide indirect survival benefits to children.