Mass Administration of Azithromycin to Prevent Pre-school Childhood Mortality: Boon or Bane?

Summary

A group of American researchers funded by the Bill and Melinda Gates Foundation examined the effect of mass administration of azithromycin, on mortality in pre-school children. This was done through a community-based randomized controlled trial (RCT) designated MORDOR-I, conducted in Malawi, Niger, and Tanzania [1]. MORDOR is an acronym for the French title of the study. Community clusters of children (1 month to 5-year-old) were randomized to receive either azithromycin (single dose 20 mg/kg, administered twice a year for 2 years) or identical placebo (in the same dosage schedule). The overall mortality rate (expressed as deaths per 1000 person years) was 13.5% lower in the treatment arm, with 95% confidence interval 6.7% to 19.8% (hence statistically significant). However, detailed analysis showed that only communities in Niger had statistically significant mortality reduction to the extent of 18% (95% CI 10%, 25.5%), whereas those in Malawi and Tanzania did not. Thus, the overall mortality reduction was largely due to the reduction in Niger. This significant intercountry difference was partly attributed to higher baseline mortality in Niger, and stronger effect of mass azithromycin administration in such settings [2]. The investigators then evaluated the administration of two doses of azithromycin (6 months apart) in children from both groups of communities in Niger only. Thus, communities in the original Azithromycin group (in MORDOR-I) received a total of 6 doses, whereas those in the original placebo group received 2 doses. This part of the study has been designated MORDOR-II [3], and is examined in detail here. Communities in Malawi and Tanzania that did not show mortality decline were not evaluated any further.

The primary outcome in MORDOR-II [3] was the same as in MORDOR-I viz. all-cause mortality at the community level. Secondary outcomes included intra-group comparison of mortality. Although safety data were mentioned in the manuscript [3], the data were not presented. The results showed a comparable mortality rate (expressed as deaths per 1000 person-years) among children who received 6 doses of azithromycin over three years versus those who received 2 doses over 1 year. In contrast, the mortality after administration of 2 doses and 4 doses of azithromycin (versus similar doses of placebo) was 16.0% and 20.3% lower respectively, in the azithromycin group. Intra-group comparison showed that mortality in the original placebo group was 26.3 at the end of year 1 of MORDOR-I, 28.0 at the end of year 2 of MORDOR-I, and 24.0 at the end of MORDOR-II. This translated to an overall (statistically significant) 13.5% reduction in mortality between pre-MORDOR-I and post-MORDOR-II. In contrast, the intra-group comparison in the azithromycin group showed a 3.6% higher mortality after MORDOR-II, compared to before MORDOR-I (although the difference was not statistically significant). The authors reiterated their original conclusion that mass administration of azithromycin reduced mortality among pre-school children in Niger [1,3], and additional administration of two doses did not appear to wane this effect. However, there was no additional benefit on mortality with the third year of mass azithromycin administration.