Longer-Term Assessment of Azithromycin for Reducing Childhood Mortality in Africa

Abstract

Background: The MORDOR I trial (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) showed that in Niger, mass administration of azithromycin twice a year for 2 years resulted in 18% lower postneonatal childhood mortality than administration of placebo. Whether this benefit could increase with each administration or wane owing to antibiotic resistance was unknown.

Methods: In the Niger component of the MORDOR I trial, we randomly assigned 594 communities to four twice-yearly distributions of either azithromycin or placebo to children 1 to 59 months of age. In MORDOR II, all these communities received two additional open-label azithromycin distributions. All-cause mortality was assessed twice yearly by census workers who were unaware of participants' original assignments.

Results: In the MORDOR II trial, the mean (±SD) azithromycin coverage was 91.3±7.2% in the communities that received twice-yearly azithromycin for the first time (i.e., had received placebo for 2 years in MORDOR I) and 92.0±6.6% in communities that received azithromycin for the third year (i.e., had received azithromycin for 2 years in MORDOR I). In MORDOR II, mortality was 24.0 per 1000 person-years (95% confidence interval [CI], 22.1 to 26.3) in communities that had originally received placebo in the first year and 23.3 per 1000 person-years (95% CI, 21.4 to 25.5) in those that had originally received azithromycin in the first year, with no significant difference between groups (P = 0.55). In communities that had originally received placebo, mortality decreased by 13.3% (95% CI, 5.8 to 20.2) when the communities received azithromycin (P = 0.007). In communities that had originally received azithromycin and continued receiving it for an additional year, the difference in mortality between the third year and the first 2 years was not significant (-3.6%; 95% CI, -12.3 to 4.5; P = 0.50).

Conclusions: We found no evidence that the effect of mass administration of azithromycin on childhood mortality in Niger waned in the third year of treatment. Childhood mortality decreased when communities that had originally received placebo received azithromycin. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02047981.).

Figure 1

In MORDOR I, communities were enrolled and randomly assigned to 4 biannual distributions of azithromycin or placebo. In MORDOR II, these same communities were followed, with both arms offered 2 biannual distributions of azithromycin. Distribution by randomization unit is expressed as the estimated mean (±SD) for the population. No communities were lost to follow-up during MORDOR I or MORDOR II.

Figure 2

All-cause mortality rate in 1-59 month old children over time in communities randomized to 2 years of treatment with biannual placebo and the third year with biannual azithromycin (blue, with 95% CI in lighter blue), and in communities randomized to 3 years of biannual azithromycin (red, with 95% CI in lighter red). In MORDOR II, we were unable to show a statistically signficant difference between the 2 arms in year 3 (p=0.55). Mortality did decrease significantly in the originally placebo-treated communities (-13.0%, 95% CI, -21.5% to -3.7%, p=0.008). In the communities originally receiving azithromycin, mortality was not significantly different in a third year of azithromycin (2.1%, 95% CI, -7.6 to 12.6%, p=0.69). Note that the annual mortality rates used in this study are expected to be several fold lower than the Under 5 Mortality Rate (U5MR), which is the number of live births that do not survive till their fifth birthday.