From Pages to Practice
Trachoma leads to ocular scarring and blindness from repeated infection with Chlamydia trachomatis. This is a public health concern in many poor, rural communities that lack access to clean water and adequate sanitation. The fight against trachoma and global campaigns to control, and ultimately eradicate the disease, include distribution of oral azithromycin in endemic communities. Studies indicate that widespread distribution of oral azithromycin is effective against trachoma and suggest benefits against malaria, diarrhea, and pneumonia, and a potential role in reducing childhood mortality.
In this week’s issue of NEJM,Keenan et al. examined whether biannual mass distribution of azithromycin reduced mortality in children aged 1–59 months in the MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial. In this randomized controlled trial, children in 1533 communities with populations between 200 and 2000 inhabitants in Malawi, Niger and Tanzania were randomized to receive either azithromycin (20 mg/kg) or placebo biannually for 2 years.
The primary outcome of aggregate all-cause mortality was assessed in 190,238 children over 323,302 person-years. The annual all-cause mortality rate was 16.5 per 1000 person-years in placebo-treated communities versus 14.6 per 1000 person-years in antibiotic-treated communities. Antibiotic-treated communities in Niger derived the greatest benefit from azithromycin treatment, with an 18.1% reduction in mortality (P<0.001), Redictions were 5.7% in Malawi (P=0.45) and 3.4% in Tanzania (P=0.77). Azithromycin was associated with the greatest reduction in mortality in children aged 1–5 months, preventing 1 in 4 deaths. No data were available on the emergence of antimicrobial resistance in the participating communities during this period.
The mechanism by which azithromycin reduces mortality remains unclear, although experts postulate a protective effect due to reductions in respiratory infections, diarrhea, or malaria (in that order), or the induction of beneficial alterations in the microbiome. Interestingly, the significant reduction in childhood mortality from azithromycin observed in children aged 1–5 months challenges current recommendations: The U.S. Food and Drug Administration has not approved azithromycin for children in this age group and the World Health Organization does not recommend inclusion of azithromycin in distributions to control trachoma. However, the finding that only one of the three sites demonstrated a significant reduction in mortality suggests that the results are not generalizable to all geographic regions. The risk of inducing antibiotic resistance with the broad use of antibiotics must also be carefully considered. Repeated mass distribution of azithromycin for trachoma control can select for macrolide resistance in nasopharyngeal strains of Streptococcus pneumoniae and rectal Escherichia coli. and curb or even reverse any potential mortality benefit, although this was not observed in the present study.
NEJM Deputy Editor Dr. Lindsey Baden noted, “These data are extremely exciting and the potential to significantly reduce childhood mortality is a terrific result. However, we need to better understand the variability in the observed effect across the three communities studied, and more work is needed to understand the mechanism of this benefit. Of course, we need to be mindful of the potential for the induction and amplification of antimicrobial resistance and strategies to define this risk are needed.”
Given the observed reduction in childhood mortality, these data will spur discussions on potentially implementing mass distribution of azithromycin, at least in countries and communities similar to those studied in Niger. Further implementation will require careful consideration of the effect on antibiotic resistance.