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There was no difference in mortality rates among African children who received azithromycin through mass distribution for a third year compared with those who received it for the first time, researchers found.

No significant difference in mortality rates was observed between children who received twice-yearly azithromycin after having previously received placebo (24.o deaths per 1,000 person-years, 95% CI 22.1-26.3) and children who were receiving their third year of azithromycin treatment (23.3 deaths per 1,000, 95% CI 21.4-25.5), reported Thomas Lietman, MD, of the University of California San Francisco, and colleagues.

Moreover, there was no difference in mortality for children receiving their first year of treatment versus those in the intervention group receiving a third year of treatment (3.5% more deaths in communities in their first year of treatment, 95% CI -8.3 to 14, P=0.55), the authors wrote in the

The findings provide some reassurance that mass distribution programs remain effective in Africa, although Lietman and colleagues cautioned that antibiotic resistance is a legitimate concern and should be monitored.

to reduce mortality from trachoma, a form of Chlamydia infection. It proved to be successful; researchers have suggested these programs may also reduce mortality from other infections as well, but some studies have also suggested that these programs have fostered macrolide resistance in other organisms including Streptococcus pneumoniae.

(Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) originally randomized communities of African children in Niger, Malawi, and Tanzania to either mass distribution of azithromycin or placebo, and found the greatest benefit in Niger, with 18% fewer deaths in the treatment group, the authors said.

They also noted that efficacy of azithromycin increased with each distribution during the initial 2 years of the trial, "which suggests the possibility of an enhanced effect with additional treatment," the authors wrote. "Efficacy could improve over time if implementation improves with experience."

In the current study, MORDOR II, azithromycin was provided twice-yearly to children who had originally received placebo, and communities originally receiving the treatment, with the authors stating that this allowed them "to compare the first year of azithromycin treatment with the third year of treatment."

MORDOR II was a continuation study, where children ages 1-59 months from 594 Nigerien communities in MORDOR I all received two additional distributions of open-label azithromycin over the course of a year. The primary outcome was the community-level, all-cause mortality rate as determined through a twice-yearly census (in this case, February to August 2017, September to January 2018, and February to August 2018).

At the start of MORDOR II, groups contained about 33,000 children in the original placebo group and around 38,000 in the original treatment group. Mean azithromycin coverage was 92.0% of the targeted population in those communities receiving azithromycin in MORDOR I, and 91.3% in communities who had originally received placebo, the authors said.

Examining secondary outcomes, twice-yearly distribution of azithromycin in communities in Niger originally receiving placebo was associated with a significant 13.3% decline in mortality (95% CI 5.8-20.2, P=0.007). There was also no significant difference in mortality among children in the treatment group from the first to the third year (-3.6% difference, 95% CI -12.3 to 4.5, P=0.50).

The authors noted that medical review could not determine if any additional serious adverse events were caused by azithromycin.

Study limitations include the fact that it is a "large, simple trial," so there was little information collected on each child. Also, deaths were determined by consecutive censuses, meaning that death rates may be different among children who moved or had unknown status. The authors also said the study was designed to assess a community's prior treatment history, not a child's treatment history.

In an , Naor Bar-Zeev, MBBS and William Moss, MD, both of Johns Hopkins Bloomberg School of Public Health in Baltimore, noted that while the results of the trial seem to suggest "the effect was not diminished by antimicrobial resistance," they raise more questions about this trial, and an earlier study that found no difference in deaths or hospitalizations when azithromycin was added to malaria chemoprevention.

"How should delivery of azithromycin be targeted? Do only some populations benefit? When and why? Should trial end points be more specific or more circumspect?" the editorialists wrote, adding that even if benefits are confirmed for some, antimicrobial resistance could "cause harm to others."

"Perhaps our hopes for azithromycin should be more modest," Bar-Zeev and Moss said.