This cluster-randomized clinical trial in Niger of children ages 6–60 months shows that growth and nutrition are not different in communities randomized to a single mass azithromycin treatment versus communities randomized to two mass azithromycin treatments. We were unable to detect a difference in height, weight, and MUAC in the communities that received a single additional mass treatment.
With the analysis restricting inclusion to participants who received their prescribed antibiotics at baseline, we were unable to show a difference in WHZ scores between communities randomized to annual treatment and communities randomized to biannual treatment. Note that this restriction is a deviation from our primary pre-specified intention-to-treat analysis, where participants were not withdrawn after randomization for any reason. We are aware that withdrawing individuals from the study, even because of non-adherence, may offer bias of unknown magnitude and direction.21
Nevertheless, these restricted analyses can present an estimate of biological efficacy that intention-to-treat analyses may be unable to provide.22
For example, we detected a dose response in those individuals who received their assigned treatment, and each additional treatment (from zero treatments to one treatment and from one treatment to two treatments) resulted in a WHZ score that was approximately 30% higher.
Although we did not detect a difference between annual and biannual mass antibiotic treatments on anthropometry, this finding may be because of the following reasons. First, a single extra mass azithromycin treatment over the course of 1 year may not be sufficient to have an effect on growth. Second, this study was a cross-sectional study and did not follow communities longitudinally; a longitudinal study might be better able to detect a smaller effect size. Third, there is a seasonal component to wasting in Niger, with high prevalence from December to February (after the rainy season) and lower prevalence in October (in the dry season when our study took place).20
Performing a study when wasting is at its lowest might make it more difficult to detect an effect of mass antibiotic treatment.
The outcome measures were performed 1 year after treatment in the annually treated communities and 6 months after treatment in the biannually treated communities by study design. In future studies, we plan to perform outcome measurements at the same time after treatment in compared communities to help with interpretation.
In conventional livestock production, antibiotics have been used to enhance weight gain and promote growth since the early 1950s.23
The use of antibiotics in food-producing animal agriculture results in healthier, more productive animals, lower disease incidence, and reduced morbidity and mortality, although this practice is controversial.24
The biological basis for the growth-promoting effects of oral antibiotics could be a reduction in intestinal microflora, which compete for nutrients,25
or treatment of subclinical infection.26,27
The Animal Health Institute (AHI) estimates that between 9% and 17% of all antibiotics sold in the United States for animals are for growth promotion or improved feed efficiency.23
Antibiotics are not currently prescribed for growth promotion in humans, although treatment of children with deworming drugs has been shown to increase weight in some studies.28
The mechanism for the observed reduction in childhood mortality associated with mass azithromycin treatments is unknown, and it may be, in part, because of improved growth and nutrition.
Antibiotics do not provide a benefit for the treatment of undernutrition based on our study. Mass azithromycin treatments have proven to be very effective in programs for trachoma control, and the treatments are well-tolerated.29
Since 1999, over 225 million treatments of azithromycin have been donated through the International Trachoma Initiative for distribution by local partners in 19 countries.30
Investigation of positive and negative secondary effects associated with these treatments should be part of any mass treatment trial or program, particularly study of emerging antibiotic resistance. Although there is a large increase in the prevalence of resistance in nasopharyngeal pneumococcus after mass antibiotic use,31
this resistance drops quickly when mass distributions are discontinued.32
Nevertheless, a strategy that provides antibiotics to large numbers of children to prevent non-specific infectious diseases to improve growth parameters is currently not advised based on our study.
In summary, we were unable to detect differences in anthropometry measurements in communities randomized to receive an extra mass azithromycin distribution; there were fewer cases of stunting and wasting with the extra treatment, but the result was not significant. There may not be an association between antibiotics and enhanced growth, or this trial may not have been powerful enough to detect an association. Larger studies, longer studies, or longitudinal measurements of growth may be able to find a beneficial effect of antibiotics on growth if it exists.