About 5.3 million children under the age of five died in 20181. Most of these deaths occurred in lowincome countries, with the highest risk of death in sub-Saharan Africa (69 deaths per 1000 live births). Sustainable Development Goal (SDG) 3 aims to end all preventable deaths of newborns and children under the age of five by 2030, with all countries aiming to reduce under-five mortality to at least as low as 25 deaths per 1000 live births. In contrast, 2018 estimates of child mortality for sub-Saharan Africa stand at 78 per 1000 live births. There is a need to identify simple, feasible and cost-effective interventions to reduce child mortality in low- and middle-income countries (LMICs). Mass drug administration of azithromycin (MDA-azithromycin) has been effective in containing trachoma2. Recent studies have suggested that MDA-azithromycin can reduce child mortality rates3,4. Azithromycin is an effective antibiotic for the treatment of acute lower respiratory tract and enteric infections. Although the exact mechanism(s) through which MDA-azithromycin reduces child mortality has not been clearly elucidated, it has been postulated that one route may be through a reduction in the incidence of these infections5,6,7. In addition, azithromycin offers short-term protection against P. falciparum infection8. By decreasing the incidence of these three major causes of mortality, MDA-azithromycin may have an impact on overall child mortality, especially in countries with high under-five mortality and a heavy burden of morbidity due to diarrhoea, pneumonia and malaria.

Guideline purpose and scope:

The purpose of the guideline was to provide an evidence-informed recommendation on whether mass drug administration of azithromycin, as a public health intervention for the reduction of under-five mortality, should (a) be rolled out universally in low-and middle-income countries, (b) be applied only in some situational contexts in low- and middle-income countries or (c) not be used at all.

Guideline development process:

In March 2018, the World Health Organization’s department of Maternal, Newborn, Child and Adolescent Health (MCA) convened a meeting of technical experts to review newly available evidence on the effect of MDA-azithromycin on child mortality. Details of this meeting are provided in Annex 5. The MORDOR Trial reported a large and statistically significant reduction (13.5%) in overall under-five mortality across its three trial sites (in Niger, Malawi and Tanzania)4. This scientific consultation weighed all the available evidence on the effects of MDA-azithromycin on child survival and concluded that the weight of evidence was such that guidance should be provided by WHO for this intervention. WHO/MCA therefore decided to initiate a formal guideline development process towards making a recommendation for or against MDA-azithromycin. This evidence-informed process was developed using the procedures outlined in the WHO handbook for guideline development. Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology was followed to prepare evidence profiles related to preselected topics which were based on up-to-date systematic reviews9. Developing and Evaluating Communication Strategies to support Informed Decisions and Practice based on Evidence (DECIDE), an evidence-to-decision tool that includes intervention effects, values, resources, equity, acceptability and feasibility criteria, was used to guide how the recommendations were formulated by the Guideline Development Group. Guideline scoping and outcome prioritization were carried out by the Guideline Development Group (members are listed in Annex 4). Evidence-informed recommendations were developed and finalized at a meeting of the guideline development group in Geneva (30 January–1 February 2019). Sixteen external experts served as technical peer reviewers for the preliminary version of this guideline. Details on the guideline development process are provided in a subsequent section.

Available evidence:

The WHO Steering Committee commissioned three systematic reviews to synthesize the evidence relating to (1) overall efficacy and in terms of factors which might modify the effect of the intervention; (2) antimicrobial resistance (AMR); and (3) adverse effects, dose strength and regimen, and potential mechanisms of action whereby MDA-azithromycin is likely to reduce mortality.