Improving child survival with biannual distribution of azithromycin: an exploration of optimal program design

The Sustainable Development Goals (SDG) aim to eliminate preventable child mortality by 2030. Despite the notable improvement in child survival in sub-Saharan Africa in the past decade overall, progress has been heterogeneous, with some areas experiencing persistently high under-5 mortality. In these settings, unprecedented reductions in child mortality will be required to achieve the SDG target.Biannual azithromycin distribution has been shown to reduce mortality in children under 5, particularly in high mortality settings. As this simple intervention has been implemented in trachoma programs globally for decades, it presents an effective, feasible approach to addressing the child mortality burden. Before implementation of this intervention is considered, however, questions remain about the optimal program design. A major risk of this intervention is the potential to select for antimicrobial resistance, and so implementers must weigh the intervention’s benefits against the risks. In response, this dissertation aims to inform the design of a program to distribute azithromycin to improve child survival while addressing the risk of increasing antimicrobial resistance. This dissertation uses data collected during trachoma and mortality studies assessing azithromycin distribution. Azithromycin has been distributed in community-based programs to control trachoma in endemic areas since the 1990s, and numerous studies have been conducted to evaluate the impact of these programs on a range of outcomes, including antimicrobial resistance. An important gap in understanding of this intervention’s impact in the broader context of child survival is knowledge of its potential to select for antimicrobial resistance. Chapter 1 systematically reviews the literature on macrolide resistance after azithromycin distribution in trachoma programs to characterize the risk of resistance in a variety of settings. To mitigate the risk of antimicrobial resistance, future programs could target vulnerable subgroups of the population, such as malnourished children. This approach would limit the amount of antibiotics distributed, theoretically reducing the risk of selecting for resistance, while focusing the intervention on those at the highest risk of mortality. Chapter 2 explores the potential impact of targeting underweight children by using data from a cluster-randomized trial of the efficacy of azithromycin distribution in reducing child mortality to evaluate whether the effect of the intervention differs by nutritional status. Finally, existing estimates of the effect of this intervention on mortality are based on intention-to-treat estimates, which might not capture the full population-level impact of the intervention, particularly in real-world settings that might experience varying patterns of intervention uptake. Using data from the same trial, Chapter 3 estimates the effect of the intervention among eligible treated children to estimate the per protocol effect and among eligible untreated children to determine the presence of spillover effects from treated to untreated subgroups. Overall, these findings contribute to the global discussion on approaches to improving child survival and could inform the direction of both future research in this area and implementation of this intervention