Limitations to Life-Saving Effect of Azithromycin in Africa

By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

SYNOPSIS: Twice-yearly oral doses of azithromycin reduce the incidence of potentially blinding trachoma and the incidence of overall death in children in West Africa. However, new data analysis suggests that the favorable effect of azithromycin is limited to children without ready access to healthcare.

SOURCE: Chao DL, Arzika AM, Abdou A, et al. Distance to health centers and effectiveness of azithromycin mass administration for children in Niger: A secondary analysis of the MORDOR cluster randomized trial. JAMA Netw Open 2023;6:e2346840.

Child mortality is still high in sub-Saharan Africa. In Niger, for instance, more than 8% of children die before reaching school age.

West African studies in a previous decade found that intermittent administration of azithromycin effectively prevented blindness due to trachoma. Surprising initially and confirmed since, children who received azithromycin also were more likely to survive childhood. Azithromycin use was associated with reductions in all-cause mortality as well as to disease-specific mortality of malaria, diarrheal diseases, and respiratory infections.

However, the development of antimicrobial resistance to azithromycin occurs with twice-yearly mass administration. In light of known benefits combined with proven resistance risks, the World Health Organization suggested in 2020 that twice-yearly azithromycin be given to children in the highest-risk sub-populations in areas where mortality was particularly high. Practically, twice-yearly azithromycin was recommended for children younger than 5 years of age in areas with greater than 80 under-five deaths per 1,000 population and for children younger than 1 year of age in areas with 60-80 under-five deaths per 1,000 population.

There is evidence that child mortality also relates to the distance between the child’s home and a healthcare facility. Thus, researchers performed fresh analyses of a previous study proving that twice-yearly azithromycin reduced childhood mortality (the MORDOR study, with the abbreviation referring to the study’s title in French — oral macrolides to reduce death with an eye to resistance) to study the relationship between child mortality, residence distance from a healthcare facility, and azithromycin use.

The MORDOR study was done from December 2014 through July 2017 in Niger, Malawi, and Tanzania. For this current analysis, data from 76,092 children from 594 communities served by 51 health centers in Niger were included. The median distance to a healthcare center was 5 km (3.1 miles). There were 3,615 deaths during the two years of treatment and follow-up.

Mortality rates were 22.5 deaths per 1,000 person-years in the azithromycin-treated group and 27.5 deaths per 1,000 person-years in the placebo group. In the placebo group, mortality increased by 5% for each 1 km distance from the health center. In the azithromycin-treated group, there was no statistically significant reduction (compared to placebo) for those living within 3.25 km of the health center, but there was a 16% reduction at 5 km, and a 28% reduction at 10 km. To save one life would require treatment of 223 children living 1 km to 5 km from a health center, 167 children living 5 km to 10 km from a health center, and 72 children living more than 10 km from a health center.

Thus, the extent of the life-saving effect of twice-yearly administration of azithromycin depends on the distance between a child’s residence and the nearest health center. Presumably, the distance between a residence and a healthcare center is a proxy measure for ease (and frequency) of access to preventive and therapeutic interventions. Thus, the amount of routine and as-needed medical care seems to have determined the necessity and effectiveness of preventive azithromycin.

COMMENTARY

Regular twice-yearly oral administration of azithromycin to preschool-age children reduces mortality — in some population groups. These new analyses reveal that the value of azithromycin depends in large measure on the distance from (and, presumably, use of) healthcare facilities. The authors concluded that implementation of twice-yearly azithromycin programs should be prioritized for children with the least access to routine healthcare.

Of course, an alternative conclusion would be that improved access to healthcare should be a first priority.¹ Excessive mortality related to limited access to medical care is not just a problem for rural Africa. Recently, new data were published from the United States showing that mortality from cancer and from motor vehicle crash-related trauma varied with distance from specialized medical care.^2,3

How does proximity to a healthcare center influence the effect of preventive azithromycin? It could be that lives are simply saved (whether azithromycin is given or not) by more ready access to preventive and curative treatments. Or, it could be that children living near healthcare centers were more likely to receive antibiotic treatment for febrile illnesses (whether or not antimicrobial therapy actually was indicated for the acute infections), and that those antibiotic treatments acted, as did azithromycin, to reduce colonization by pathogens that added risk of a subsequent life-threatening infection.

World Health Organization guidelines for the use of twice-yearly azithromycin in high-mortality regions of Africa have yet to be implemented on national levels.¹ While healthcare systems are being improved and while transportation and access to medical care are being enhanced, lives could be saved by providing twice-yearly oral azithromycin to young children in areas of high child mortality. Once children have better access to regular preventive and curative healthcare and the risk of developing azithromycin resistance rises above the benefit of saving lives, mass administration of azithromycin could be discontinued.

In the New England Journal of Medicine issue dated Jan. 18, 2024, Sie and colleagues reported on a prospective study of 32,877 infants in Burkina Faso given either 20 mg/kg azithromycin or placebo as a single oral dose during a well-child visit between 5 and 12 weeks of age. Mortality prior to 6 months of age was not different between the treatment and control groups. The authors postulated that one factor leading to differing results in various studies of the effects of azithromycin on infant mortality could be variations in study subjects’ access to healthcare; this is consistent with the study of Chao and colleagues, as reviewed here.⁴

References

1. Bhutta ZA. Unravelling the potential mortality benefits of mass drug administration with azithromycin in Niger. JAMA Netw Open 2023;6:e2346811.
2. Beckett M, Goethals L, Kraus RD, et al. Proximity to radiotherapy center, population, average income, and health insurance status as predictors of cancer mortality at the county level in the United States. JCO Glob Oncol 2023;9:e2300130.
3. Patel VR, Rozycki G, Jopling J, et al. Association between geospatial access to trauma center care and motor vehicle crash mortality in the United States. J Trauma Acute Care Surg 2023; Dec 6. doi: 10.1097/TA.0000000000004221. [Online ahead of print].
4. Sié A, Ouattara M, Bountogo M, et al. Azithromycin during routine well-infant visits to prevent death. N Engl J Med 2024;390:221-229.