In MORDOR I, twice-yearly oral azithromycin administered for 2 years to postneonatal preschool children resulted in significantly lower all-cause mortality (by 18%) in Niger than administration of placebo.9 In MORDOR II, both groups of Niger communities from MORDOR I (communities that had received azithromycin and those that had received placebo) received twice-yearly doses of azithromycin during the third year; this design allowed us to compare a third year of treatment with the first year of treatment. We found no evidence that the benefit of azithromycin waned in the third year. Some experts had hypothesized that there would be a decrease in efficacy of azithromycin with more distributions owing to the selection of antibiotic-resistant bacteria.11-13 Repeated mass azithromycin distributions for trachoma have indeed selected for macrolide resistance in nasopharyngeal S. pneumoniae and rectal E. coli.1-3,6,14 Resistance was noted in the nasopharynx and stool in children in Niger in MORDOR I (unpublished data). Resistance emerging during mass azithromycin distributions could theoretically have curbed or even reversed any potential survival benefit in this community.

We also found no evidence that the effect of azithromycin was enhanced with additional distributions. Enhancement was possible since the overall benefit in the three sites of MORDOR I increased from 7% to 22% with each of the first four twice-yearly distributions; however, that apparent increase was not statistically significant.9 Here, the comparison between the first and third years of treatments did not support either an increasing or decreasing effect on mortality with additional rounds of azithromycin. Longer follow-up will be necessary to determine whether the mortality effect is sustained past the third year of distributions and whether potential side effects, such as increased colonization with antibiotic-resistant bacteria, cause negative health outcomes.

The communities receiving their first year of treatment had 13% lower mortality than they had in the previous 2 years during which they had received placebo. Although this longitudinal analysis was not a randomized comparison and is therefore subject to confounding, the result does support the original MORDOR I finding of a reduction in mortality in the Niger analysis. Mortality decreased with the first of the two additional distributions, which suggests that cumulative treatments are not necessary to achieve efficacy. This is consistent with a secondary analysis of MORDOR I in which the number of deaths was relatively lower in the first 3 months after a twice-yearly distribution of azythromycin.15 The convergence of mortality rates in the two groups in MORDOR II — when both groups of communities received the same treatment — bolsters the argument that the difference in MORDOR I was caused by intervention and not by imbalanced randomization.

The study has a number of limitations. Because it is a large, simple trial, little information was collected on each child and community.10 Deaths were determined by consecutive censuses. Children who were born and died between censuses did not contribute to either the number of deaths or the person-time at risk for the primary outcome. Death rates may have differed among children who moved away or had an unknown census status. Although the comparison assessed whether a community’s prior treatment history affected the results, it was not designed to analyze a child’s prior treatment history. Communities in Malawi and Tanzania (part of MORDOR I) were not studied in MORDOR II, since the mortality rates were lower in those communities. Cluster-randomized trials run the risk of contamination between groups, which could dampen the observed effect. Although the intervention itself was not subject to contamination in MORDOR II, since all communities were given the same treatment, infections could spread between nearby communities and cause contamination. Although this could theoretically explain the MORDOR II findings, contamination did not prevent a highly significant result in MORDOR I, so invoking this explanation would require contamination in the third year only. No child in MORDOR I and II had ever received azithromycin as part of a trachoma program, but macrolide use outside the study was not recorded. Since distributions were offered only twice yearly, a child’s first treatment might not be until 7 months of age. Supplementary treatments given during a scheduled vaccination visit to a health clinic might prove to be a more reliable way of reaching younger infants. The assessments of years 1 and 2 as compared with year 3 were longitudinal within each group, and not randomized between groups. Conditions may have changed between these time periods. This study did not investigate whether morbidity increased or decreased with azithromycin. The study also did not evaluate the mechanism by which azithromycin reduced mortality, although its antimicrobial effect presumably plays a role, since a majority of child deaths in the geographic area of the trial are attributed to infectious disease.16 Smaller parallel trials with detailed microbiologic and anthropometric assessments were conducted, and these may provide insight into mechanism of action.17,18 Azithromycin has been linked to cardiac death in adults, although epidemiologic results are mixed and may not be relevant to children in this setting.19-22 Later development of atopic disease has been associated with infant antibiotic use in general, and macrolides in particular.23 Rare side effects or those apparent only later in life would be difficult to assess with this study design.

The International Trachoma Initiative has now distributed more than 800 million doses of oral azithromycin in the trachoma control programs sponsored by the World Health Organization.24 Azithromycin has proved quite effective in reducing the prevalence of, and in some cases completely eliminating, the strains of ocular chlamydia that cause trachoma.2,4,6,25-27 Annual trachoma case distribution numbers are now declining as countries continue to meet control criteria.24 Trachoma is no longer endemic — or never was — in many regions with high childhood mortality. Thus, the majority of children now being born in areas with the highest mortality among those younger than 5 years of age will not receive azithromycin as part of trachoma programs.28 The treatment regimen for trachoma and the regimen used in the MORDOR studies differed; the regimen for trachoma is annual mass azithromycin treatment of children 6 months of age or older, whereas the regimen in MORDOR I and II was twice-yearly distributions targeted to children 1 to 59 months of age. The MORDOR studies distributed approximately one third as many doses of azithromycin per community per year as would a trachoma program. If azithromycin for childhood mortality were targeted to areas with very high mortality, such as Niger, only a fraction of the total antibiotics used in trachoma programs would be required in those areas.

In summary, this study showed no evidence that the beneficial effect of mass twice-yearly azithromycin distribution on childhood mortality waned in the third year of distribution as compared with the first year. However, twice-yearly oral azithromycin distribution in year 3 resulted in significantly reduced mortality in communities that had previously received 2 years of twice-yearly placebo distributions in MORDOR I. This longitudinal observation supports the original MORDOR I community-randomized trial results. Selection of antibiotic-resistant strains of pathogenic bacteria may eventually reduce efficacy and should continue to be monitored with longer follow-up.