Table 1 Cluster randomized controlled trials assessing the impact of MDA-azithromycin on childhood mortality

Trachoma Amelioration in Northern Amhara (TANA) [5]

Ethiopia, 2006‒2007

(1) Annual azithromycin distribution, (2) twice-yearly azithromycin distribution, (3) quarterly azithromycin distribution, and (4) a control group for whom treatment was delayed for 12 months

Arms 1, 2, and 4 included anyone 1 year of age or older, Arm 3 included children 1–9 years of age

Adults were treated with 1 g of azithromycin and children were treated with 20 mg/kg of azithromycin (maximum 1 g)

Mortality in children 1‒9 years of age, as measured at approximately 12 months after initial dosing

49% reduction in death in children aged 1‒9 years (pooled across all treatment arms), compared to placebo

The Partnership for the Rapid Elimination of Trachoma (PRET) [16]

Niger, 2010‒2013

(1) Annual azithromycin distribution, and (2) twice-yearly azithromycin distribution

Arm 1 included the entire community and arm 2 included children 0‒12 years of age

All participants ≥ 6 months of age received 20 mg/kg oral azithromycin (maximum 1 g) and children < 6 months of age, pregnant women, and those allergic to macrolides were offered topical tetracycline ointment (1%) for 6 weeks

Prevalence of ocular chlamydial infection in children aged 0‒5 years, as monitored by polymerase chain reaction at 36 months

Mortality rate was 35.6 deaths per 1000 person-years in the annual arm and 29.0 deaths per 1000 person-years in the twice-yearly arm. The mortality rate ratio comparing children in the twice-yearly arm to the annual arm was 0.81 (95% CI: 0.66‒1.00) [27]

The addition of azithromycin to seasonal malaria chemoprevention [26]

Burkina Faso and Mali, 2014‒2017

(1) Distribution of azithromycin together with sulfadoxine-pyrimethamine plus amodiaquine in four 3-day cycles at monthly intervals for three successive seasons, and (2) a control group receiving a placebo instead of azithromycin with the same combination and schedule

Both arms included children 3 to 59 months of age

Infants 3–11 months of age received a combined 250 mg of sulfadoxine and 12.5 mg of pyrimethamine plus 75 mg of amodiaquine, along with either 100 mg of azithromycin or a matching placebo. Children 1–4 years of age received double these doses

Death or hospital admission for at least 24 h that was not due to trauma or elective surgery

The addition of azithromycin to the antimalarial drugs for chemoprevention did not result in a lower incidence of death or hospital admission in comparison to the placebo group

MORDOR I (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) [8]

Malawi, Niger, and Tanzania, 2014‒2017

(1) Twice-yearly azithromycin distribution, and (2) a control group receiving twice-yearly placebo

Both arms included children 1–59 months of age

Oral azithromycin 20 mg per kilogram of body weight

Aggregate all-cause mortality in study population

Mortality was 13.5% lower overall in communities that received azithromycin. Children in the age group of 1–5 months had the greatest effect from azithromycin (24.9% lower mortality)

MORDOR II [9]* (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance)

Niger, 2017‒2018

The Niger component of the MORDOR I trial in which children 1–59 months old in communities were assigned to four twice-yearly distributions of azithromycin or placebo were all given two additional open-label azithromycin distributions during two additional twice-yearly distributions

Children 1–59 months of age

Oral azithromycin 20 mg per kilogram of body weight

Aggregate all-cause mortality in study population

In communities that had originally received placebo, mortality decreased by 13.3% when the communities received azithromycin. No significant difference was noted in the communities that had originally received azithromycin