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Villages in Niger were randomly assigned to offer azithromycin or placebo to children 1 to 59 months of age every 6 months for 4 years. Stool samples collected at 36 and 48 months showed that antibiotic resistance was more common among children living in villages that received azithromycin than among children living in villages that received placebo.

The MORDOR trial in Niger, Malawi, and Tanzania found that biannual mass distribution of azithromycin to children younger than 5 years led to a 13.5% reduction in all-cause mortality (NCT02048007). To help elucidate the mechanism for mortality reduction, we report IgG responses to 11 malaria, bacterial, and protozoan pathogens using a multiplex bead assay in pre-specified substudy of 30 communities in the rural Niger placebo-controlled trial over a three-year period ( n  = 5642 blood specimens, n  = 3814 children ages 1–59 months). Mass azithromycin reduces Campylobacter spp. force of infection by 29% (hazard ratio = 0.71, 95% CI: 0.56, 0.89; P  = 0.004) but serological measures show no significant differences between groups for other pathogens against a backdrop of high transmission. Results align with a recent microbiome study in the communities. Given significant sequelae of Campylobacter infection among preschool aged children, our results support an important mechanism through which biannual mass distribution of azithromycin likely reduces mortality in Niger. In a randomized placebo-controlled trial in rural Niger, biannual azithromycin distribution to children 1-59 months reduced all-cause mortality. Based on serology, Arzika et al . here report a reduction of Campylobacter infection, supporting one mechanism for the intervention’s impact on mortality.

In the MORDOR I study, mortality was lower in communities in Niger that received single-dose azithromycin twice yearly for 2 years than in communities that received placebo. In this open-label extension study, MORDOR II, the effect on mortality persisted through a third year and was seen in the MORDOR I placebo group that was now treated with azithromycin.

In 2023, the World Health Organization (WHO) revised its guidelines for management of severe acute malnutrition (SAM). The revised guidelines include a focus on infants at risk of poor growth and development. The guideline identifies evaluation of routine antibiotics for these infants as a priority research area. We pooled data from two large randomized controlled trials evaluating azithromycin for prevention of infant mortality in Burkina Faso to assess whether azithromycin reduces mortality or wasting in this subgroup. Infants in the two trials were 1-12 weeks of age at enrollment. Infants were considered at risk of poor risk of growth and development per WHO: underweight (weight-for-age Z-score, WAZ < -2), wasted (weight-for-length Z-score, WLZ < -2), or MUAC < 11.0 cm among infants ≥6 weeks of age. Infants were randomized to a single oral (20 mg/kg) dose of azithromycin or matching placebo and were followed until 6 months of age. We evaluated vital status, underweight (WAZ < -2), wasting (WLZ < -2), and stunting (length-for-age Z-score, LAZ) at 6 months among infants at risk of poor growth and development based on WHO single measurement criteria. A total of 54,709 infants were enrolled in the two trials. Of these, 9,728 were at risk of poor growth and development based on baseline WAZ (N = 5,385), WLZ (N = 6,022), or MUAC (N = 1,541). We found no evidence of a difference in mortality (1.3% vs 1.1%, odds ratio, OR, 1.19, 95% confidence interval, CI, 0.82 to 1.72) or wasting (20.6% vs 20.2%, OR 1.03, 95% CI 0.92 to 1.14) at 6 months among infants receiving azithromycin versus placebo. In infants aged 1-12 weeks at risk of poor growth and development, we do not have evidence that single dose azithromycin reduces mortality or improves growth outcomes. ClinicalTrials.gov NCT03682654 and NCT03676764.

Antibiotic use during early infancy has been linked to childhood obesity in high-income countries. We evaluated whether a single oral dose of azithromycin administered during infant-well visits led to changes in infant growth outcomes at 6 months of age in a setting with a high prevalence of undernutrition in rural Burkina Faso. Infants were enrolled from September 25, 2019, until October 22, 2022, in a randomized controlled trial designed to evaluate the efficacy of a single oral dose of azithromycin (20 mg/kg) compared to placebo when administered during well-child visits for prevention of infant mortality. The trial found no evidence of a difference in the primary endpoint. This paper presents prespecified secondary anthropometric endpoints including weight gain (g/day), height change (mm/day), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and mid-upper arm circumference (MUAC). Infants were eligible for the trial if they were between 5 and 12 weeks of age, able to orally feed, and their families were planning to remain in the study area for the duration of the study. Anthropometric measurements were collected at enrollment (5 to 12 weeks of age) and 6 months of age. Among 32,877 infants enrolled in the trial, 27,298 (83%) were followed and had valid anthropometric measurements at 6 months of age. We found no evidence of a difference in weight gain (mean difference 0.03 g/day, 95% confidence interval (CI) -0.12 to 0.18), height change (mean difference 0.004 mm/day, 95% CI -0.05 to 0.06), WAZ (mean difference -0.004 SD, 95% CI -0.03 to 0.02), WLZ (mean difference 0.001 SD, 95% CI -0.03 to 0.03), LAZ (mean difference -0.005 SD, 95% CI -0.03 to 0.02), or MUAC (mean difference 0.01 cm, 95% CI -0.01 to 0.04). The primary limitation of the trial was that measurements were only collected at enrollment and 6 months of age, precluding assessment of shorter-term or long-term changes in growth. Single-dose azithromycin does not appear to affect weight and height outcomes when administered during early infancy. ClinicalTrials.gov NCT03676764.

Most evidence supporting screening for undernutrition is for children aged 6-59 months. However, the highest risk of mortality and highest incidence of wasting occurs in the first 6 months of life. We evaluated relationships between neonatal anthropometric indicators, including birth weight, weight-for-age -score (WAZ), weight-for-length Z-score (WLZ), length-for-age -score (LAZ) and mid-upper arm circumference (MUAC) and mortality and growth at 6 months of age among infants in Burkina Faso. Data arose from a randomised controlled trial evaluating neonatal azithromycin administration for the prevention of child mortality. We evaluated relationships between baseline anthropometric measures and mortality, wasting (WLZ < -2), stunting (LAZ < -2) and underweight (WAZ < -2) at 6 months of age were estimated using logistic regression models adjusted for the child's age and sex. Five regions of Burkina Faso. Infants aged 8-27 d followed until 6 months of age. Of 21 832 infants enrolled in the trial, 7·9 % were low birth weight (<2500 g), 13·3 % were wasted, 7·7 % were stunted and 7·4 % were underweight at enrolment. All anthropometric deficits were associated with mortality by 6 months of age, with WAZ the strongest predictor (WAZ < -2 to ≥ -3 at enrolment . WAZ ≥ -2: adjusted OR, 3·91, 95 % CI, 2·21, 6·56). Low WAZ was also associated with wasting, stunting, and underweight at 6 months. Interventions for identifying infants at highest risk of mortality and growth failure should consider WAZ as part of their screening protocol.

Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting. The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability. In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored. NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Background Delays in care-seeking for childhood illness may lead to more severe outcomes. We evaluated whether community distance from a primary healthcare facility was associated with decreased healthcare utilization in a rural district of northwestern Burkina Faso. Methods We conducted passive surveillance of all government-run primary healthcare facilities in Nouna District, Burkina Faso from March 1 through May 31, 2020. All healthcare visits for children under 5 years of age were recorded on a standardized form for sick children. We recorded the age, sex, and community of residence of the child as well as any diagnoses and treatments administered. We calculated healthcare utilization per 100 child-months by linking the aggregate number of visits at the community level to the community’s population of children under 5 months per a census that was conducted from August 2019 through February 2020. We calculated the distance between each community and its corresponding healthcare facility and assessed the relationship between distance and the rate of healthcare utilization. Results In 226 study communities, 12,676 primary healthcare visits were recorded over the three-month period. The median distance between the community and primary healthcare facility was 5.0 km (IQR 2.6 to 6.9 km), and median number of healthcare visits per 100 child-months at the community level was 6.7 (IQR 3.7 to 12.3). The rate of primary healthcare visits declined with increasing distance from clinic (Spearman’s rho − 0.42, 95% CI − 0.54 to − 0.31, P  < 0.0001). This relationship was similar for cause-specific clinic visits (including pneumonia, malaria, and diarrhea) and for antibiotic prescriptions. Conclusions We documented a distance decay effect between community distance from a primary healthcare facility and the rate of healthcare visits for children under 5. Decreasing distance-related barriers, for example by increasing the number of facilities or targeting outreach to more distant communities, may improve healthcare utilization for young children in similar settings.

To examine how child mortality among children aged 1-59 months varies by asset-based wealth status in rural Burkina Faso, and to assess the interaction between mass azithromycin (AZ) distribution and wealth status on child mortality at both the household and community levels. We used data from a cluster-randomized trial and population census data on household characteristics and assets. A wealth index score for each household, used to classify the population by wealth, was generated using principal component analysis. We used the Relative Index of Inequality (RII), the Slope Index of Inequality (SII), and the concentration index to assess wealth-related inequalities in mortality, and the Gini Index to assess variability in child mortality across households and communities. Poisson regression models were used, with person-time at risk included as an offset, and robust standard error to estimate changes in mortality rates by wealth and treatment arm. Interaction was assessed on both the multiplicative and additive scales. Mortality declined with increasing wealth at both the household and community levels, with a significant gradient at the community level (RII = 1.17, 95% CI: 1.05-1.29; SII = 2.3 per 1,000 person-years, 95% CI: 0.2-4.4), reflecting higher mortality among the poorest. The effect of AZ did not vary significantly by wealth index, and changes in mortality rates across wealth levels were similar between the two treatment arms. There was no evidence of a statistically significant interaction between AZ and asset-based wealth on either the multiplicative or additive scale at the household or cluster level. Our findings demonstrate a wealth gradient in child mortality, with the highest mortality rates observed among households and communities in the lowest wealth quintiles. These disparities were consistent across both AZ-treated and placebo groups, suggesting that the role of AZ in health disparities may be limited to addressing gaps in treatment access rather than broader wealth-related disparities. While the study may have been underpowered to detect modest interaction effects, AZ appeared to offer similar benefits across economically diverse communities, with no evidence suggesting enhanced benefits for disadvantaged communities or for prioritizing treatment based on wealth status. Further work is needed to address the wealth-related disparities in child mortality in these communities. ClinicalTrials.gov NCT03676764.

Background While Seasonal Malaria Chemoprevention (SMC) has been adopted as a malaria control strategy in regions with seasonal transmission, continued monitoring and evaluation of its effectiveness across diverse ecological, epidemiological, and healthcare settings remain critical for optimizing the intervention. This study aims to assess the ongoing population-level impact of SMC under routine programme conditions by evaluating rates of uncomplicated and severe malaria following four rounds of administration. Methods A pre-post analysis was conducted using real-world surveillance data from clinic visits in 285 villages in Nouna District, Burkina Faso, along with National Malaria Control Programme data on SMC administration. Estimates of the population used for person-time calculations were derived from a census conducted as part of a randomized controlled trial. Malaria rates for children under 5 were analyzed for each epidemiological week in 2021, for each health post in the study area. Negative binomial regression models were used, with person-time at risk used as an offset and standard errors clustered by health post, to obtain incidence rate ratios (IRRs) and rate differences. Changes in diagnoses were estimated from the administration weeks to each of the three weeks post- administration within the same population. Injury rates were used as a negative control outcome to assess potential unmeasured confounding. Results Although SMC was administered during peak malaria transmission weeks within each cycle, both uncomplicated and severe malaria rates remained high through December, following the fourth and final round of SMC. There was a substantial reduction in infection rates in the 3 weeks post SMC, with gradual increases in rates across the three weeks. The rates of uncomplicated and severe malaria per 1000 person-weeks in the administration weeks were 8.5 (95% CI 7.0 to 10.1) and 0.31 (95% CI 0.22 to 0.40), respectively. Uncomplicated malaria rates were lower by 41%, 95%CI (31–50%), 34% (23–43%) and 22% (12–31%) in the first, second and third weeks after administration, respectively. Severe malaria rates declined by 47% (21–64%), 47% (31–59%) and 34% (17–47%) in the three weeks post-administration. Injury rates, the negative control outcome, did not change significantly across the three weeks. Conclusion In programme settings, at the population level, SMC administration was associated with a substantial reduction in uncomplicated and severe malaria, though this effect was limited to the immediate weeks following administration. The gradual increase in malaria rates by the third week suggests a shorter duration of protection than previously observed. Extending the areas where 5 rounds of distribution occur may be necessary to effectively prevent malaria infections in regions with a longer transmission season. Regular evaluation of local malaria trends and impact of SMC can help further tailor and optimize SMC programmes for specific regional contexts.