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Background: Twice-yearly mass distribution of azithromycin to children is a promising intervention to reduce childhood mortality in sub-Saharan Africa. The World Health Organization recommended restricting distribution to infants 1 to 11 months of age to mitigate antimicrobial resistance, although this more limited treatment had not yet been tested., Methods: We randomly assigned rural communities in Niger to four twice-yearly distributions of azithromycin for children 1 to 59 months of age (child azithromycin group), four twice-yearly distributions of azithromycin for infants 1 to 11 months of age and placebo for children 12 to 59 months of age (infant azithromycin group), or placebo for children 1 to 59 months of age. Census workers who were not aware of the group assignments monitored mortality twice yearly over the course of 2 years. We assessed three primary community-level mortality outcomes (deaths per 1000 person-years), each examining a different age group and pairwise group comparison., Results: A total of 1273 communities were randomly assigned to the child azithromycin group (1229 were included in the analysis), 773 to the infant azithromycin group (751 included in the analysis), and 954 to the placebo group (929 included in the analysis). Among 382,586 children, 419,440 person-years and 5503 deaths were recorded. Lower mortality among children 1 to 59 months of age was observed in the child azithromycin group (11.9 deaths per 1000 person-years; 95% confidence interval [CI], 11.3 to 12.6) than in the placebo group (13.9 deaths per 1000 person-years; 95% CI, 13.0 to 14.8) (representing 14% lower mortality with azithromycin; 95% CI, 7 to 22; P<0.001). Mortality among infants 1 to 11 months of age was not significantly lower in the infant azithromycin group (22.3 deaths per 1000 person-years; 95% CI, 20.0 to 24.7) than in the placebo group (23.9 deaths per 1000 person-years; 95% CI, 21.6 to 26.2) (representing 6% lower mortality with azithromycin; 95% CI, -8 to 19). Five serious adverse events were reported: three in the placebo group, one in the infant azithromycin group, and one in the child azithromycin group., Conclusions: Azithromycin distributions to children 1 to 59 months of age significantly reduced mortality and was more effective than treatment of infants 1 to 11 months of age. Antimicrobial resistance must be monitored. (Funded by the Bill and Melinda Gates Foundation; AVENIR ClinicalTrials.gov number, NCT04224987.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs., Methods: Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence., Results: 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4% (95% CI -4.1% to 10.8%, P-value 0.37), -1.2% (95% CI -7.9% to 5.5%, P-value 0.72), and -3.3% (95% CI -9.5% to 2.8%, P-value 0.61), respectively., Conclusions: We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: 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., Methods and Findings: 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., Conclusions: 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., Trial Registration: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arzika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Importance: The MORDOR (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) trial demonstrated that mass azithromycin administration reduced mortality by 18% among children aged 1 to 59 months in Niger. The identification of high-risk subgroups to target with this intervention could reduce the risk of antimicrobial resistance., Objective: To evaluate whether distance to the nearest primary health center modifies the effect of azithromycin administration to children aged 1 to 59 months on child mortality., Design, Setting, and Participants: The MORDOR cluster randomized trial was conducted from December 1, 2014, to July 31, 2017; this post hoc secondary analysis was conducted in 2023 among 594 clusters (communities or grappes) in the Boboye and Loga departments in Niger. All children aged 1 to 59 months in eligible communities were evaluated., Interventions: Biannual (twice-yearly) administration of a single dose of oral azithromycin or matching placebo over 2 years., Main Outcomes and Measures: A population-based census was used to monitor mortality and person-time at risk (trial primary outcome). Community distance to a primary health center was calculated as kilometers between the center of each community and the nearest health center. Negative binomial regression was used to evaluate the interaction between distance and the effect of azithromycin on the incidence of all-cause mortality among children aged 1 to 59 months., Results: Between December 1, 2014, and July 31, 2017, a total of 594 communities were enrolled, with 76 092 children (mean [SD] age, 31 [2] months; 39 022 [51.3%] male) included at baseline, for a mean (SD) of 128 (91) children per community. Median (IQR) distance to the nearest primary health center was 5.0 (3.2-7.1) km. Over 2 years, 145 693 person-years at risk were monitored and 3615 deaths were recorded. Overall, mortality rates were 27.5 deaths (95% CI, 26.2-28.7 deaths) per 1000 person-years at risk in the placebo arm and 22.5 deaths (95% CI, 21.4-23.5 deaths) per 1000 person-years at risk in the azithromycin arm. For each kilometer increase in distance in the placebo arm, mortality increased by 5% (adjusted incidence rate ratio, 1.05; 95% CI, 1.03-1.07; P < .001). The effect of azithromycin on mortality varied significantly by distance (interaction P = .02). Mortality reduction with azithromycin compared with placebo was 0% at 0 km from the health center (95% CI, -19% to 17%), 4% at 1 km (95% CI, -12% to 17%), 16% at 5 km (95% CI, 7% to 23%), and 28% at 10 km (95% CI, 17% to 38%)., Conclusions and Relevance: In this secondary analysis of a cluster randomized trial of mass azithromycin administration for child mortality, children younger than 5 years who lived farthest from health facilities appeared to benefit the most from azithromycin administration. These findings may help guide the allocation of resources to ensure that those with the least access to existing health resources are prioritized in program implementation., Trial Registration: ClinicalTrials.gov Identifier: NCT02047981.

Recent evidence indicates mass azithromycin distribution reduces under-5 mortality. This intervention is being considered for child survival programs in high mortality sub-Saharan African settings. The delivery approach used in prior studies required a full-time census and distribution team, which is not feasible for most programs. To determine the optimal programmatic approach to delivery, this study aimed to compare treatment coverage, costs, and acceptability of different delivery approaches with existing community health workers (CHWs). This cluster-randomized trial included rural and peri-urban communities in Dosso, Niger (clinicaltrials.gov, NCT04774991). A random sample of 80 eligible communities was randomized 1:1 to biannual door-to-door or fixed-point delivery of oral azithromycin to children 1-59 months old over 1 year. Data analysts alone were masked given the nature of the intervention. The primary outcome was community-level treatment coverage defined as the number of children treated recorded by CHWs divided by the number of eligible children determined using a post-distribution census. Costs were monitored through routine administrative data collection and micro-costing. The census included survey questions on intervention acceptability among caregivers, community leaders, and CHWs. After randomization, 1 community was excluded due to inaccuracies in available administrative data, resulting in 39 communities receiving door-to-door delivery. At the second distribution, community-level mean treatment coverage was 105% (SD 44%) in the door-to-door arm and 92% (SD 20%) in the fixed-point arm (Mean difference 13%, 95% CI -2% to 28%, P-value = 0.08). The total cost per dose delivered was $1.91 in the door-to-door arm and $2.51 in the fixed-point arm. Indicators of acceptability were similar across stakeholder groups in both arms, with most respondents in each group indicating a preference for door-to-door. Overall, door-to-door delivery is the preferred approach to azithromycin distribution in this setting and might reach more children at a lower cost per dose delivered than fixed-point. Trial Registration: clinicaltrials.gov NCT04774991., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Arzika et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The WHO guidelines on mass distribution of azithromycin for child survival recommend monitoring of mortality to evaluate effectiveness. Trials that contributed evidence to these guidelines used a population-based census to monitor vital status, requiring census workers to visit each household biannually (twice yearly). Birth history is an alternative to the census approach that may be more feasible because it decreases the time and labor needed for mortality monitoring. This study aimed to compare the population-based census (reference standard) and birth history (index test) approaches to estimating mortality among children 1 to 59 months old using data from the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial. Sixteen communities that received 5 years of biannual census in the MORDOR trial were selected randomly also to receive birth history surveys. The census approach recorded more participants and households than birth history, with correlations more than 0.94 for each. The correlation between number of deaths in each community was 0.84 (95% CI, 0.59-0.94). A comparison of the mortality incidence rate estimated from the census against the under-5 mortality rate estimated from the birth history resulted in a correlation of 0.60 (95% CI, 0.15-0.84). Of the 47% of children who were linked individually to compare vital status from each method, the death status of children had a sensitivity of 80% (95% CI, 73-89) and a specificity of 98% (95% CI, 98-99), comparing birth history to census. Overall birth histories were found to be a reasonable alternative to biannual census for tracking vital status.

Azithromycin mass drug administration decreases child mortality but also selects for antibiotic resistance. Herein, we evaluate macrolide resistance of nasopharyngeal Streptococcus pneumoniae after azithromycin MDA. In a cluster-randomized trial, children 1-59 months received azithromycin or placebo biannually. Fifteen villages from each arm were randomly selected for antimicrobial resistance testing, and 10-15 randomly selected swabs from enrolled children at each village were processed for S. pneumoniae isolation and resistance testing. The primary prespecified outcome was macrolide resistance fraction for azithromycin versus placebo villages at 36 months. Secondary non-prespecified outcomes were comparisons of azithromycin and placebo for: 1) macrolide resistance at 12, 24, and 36 months; 2) nonmacrolide resistance at 36 months; and 3) suspected-erm mutation. At 36 months, 423 swabs were obtained and 322 grew S. pneumoniae, (azithromycin: 146/202, placebo: 176/221). Mean resistance prevalence was non-significantly higher in treatment than placebo (mixed-effects model: 14.6% vs. 8.9%; OR = 2.0, 95% CI: 0.99-3.97). However, when all time points were evaluated, macrolide resistance prevalence was significantly higher in the azithromycin group (β = 0.102, 95% CI: 0.04-0.167). For all nonmacrolides, resistance prevalence at 36 months was not different between the two groups. Azithromycin and placebo were not different for suspected-erm mutation prevalence. Macrolide resistance was higher in the azithromycin group over all time points, but not at 36 months. Although this suggests resistance may not continue to increase after biannual MDA, more studies are needed to clarify when MDA can safely decrease mortality and morbidity in lower- and middle-income countries.

Wastewater-based surveillance is increasingly recognized as an important approach to monitoring population-level antimicrobial resistance (AMR). In this exploratory study, we examined the use of metagenomics to evaluate AMR using untreated wastewater samples routinely collected by the Niger national polio surveillance program. Forty-eight stored samples from two seasons each year over 4 years (2016-2019) in three regions were selected for inclusion in this study and processed using unbiased DNA deep sequencing. Normalized number of reads of genetic determinants for different antibiotic classes were compared over time, by season, and by location. Correlations in resistance were examined among classes. Changes in reads per million per year were demonstrated for several classes, including decreases over time in resistance determinants for phenicols (-3.3, 95% CI: -8.7 to -0.1, P = 0.029) and increases over time for aminocoumarins (3.8, 95% CI: 0.0 to 11.4, P = 0.043), fluoroquinolones (6.8, 95% CI: 0.0 to 20.5, P = 0.048), and beta-lactams (0.85, 95% CI: 0.1 to 1.7, P = 0.006). Sulfonamide resistance was higher in the post-rainy season compared with the dry season (5.2-fold change, 95% CI: 3.4 to 7.9, P < 0.001). No differences were detected when comparing other classes by season or by site for any antibiotic class. Positive correlations were identified in genetic determinants of resistance among several antibiotic classes. These results demonstrate the potential utility of leveraging existing wastewater sample collection in this setting for AMR surveillance.

Trachoma, caused by ocular Chlamydia trachomatis infection, is targeted for global elimination as a public health problem by 2030. To provide evidence for use of antibodies to monitor C. trachomatis transmission, we collated IgG responses to Pgp3 antigen, PCR positivity, and clinical observations from 19,811 children aged 1-9 years in 14 populations. We demonstrate that age-seroprevalence curves consistently shift along a gradient of transmission intensity: rising steeply in populations with high levels of infection and active trachoma and becoming flat in populations near elimination. Seroprevalence (range: 0-54%) and seroconversion rates (range: 0-15 per 100 person-years) correlate with PCR prevalence (r: 0.87, 95% CI: 0.57, 0.97). A seroprevalence threshold of 13.5% (seroconversion rate 2.75 per 100 person-years) identifies clusters with any PCR-identified infection at high sensitivity ( >90%) and moderate specificity (69-75%). Antibody responses in young children provide a robust, generalizable approach to monitor population progress toward and beyond trachoma elimination., (© 2023. The Author(s).)

Background: Biannual azithromycin distribution to children 1-59 months old reduced all-cause mortality by 18% [incidence rate ratio (IRR) 0.82, 95% confidence interval (CI): 0.74, 0.90] in an intention-to-treat analysis of a randomized controlled trial in Niger. Estimation of the effect in compliance-related subgroups can support decision making around implementation of this intervention in programmatic settings., Methods: The cluster-randomized, placebo-controlled design of the original trial enabled unbiased estimation of the effect of azithromycin on mortality rates in two subgroups: (i) treated children (complier average causal effect analysis); and (ii) untreated children (spillover effect analysis), using negative binomial regression., Results: In Niger, 594 eligible communities were randomized to biannual azithromycin or placebo distribution and were followed from December 2014 to August 2017, with a mean treatment coverage of 90% [standard deviation (SD) 10%] in both arms. Subgroup analyses included 2581 deaths among treated children and 245 deaths among untreated children. Among treated children, the incidence rate ratio comparing mortality in azithromycin communities to placebo communities was 0.80 (95% CI: 0.72, 0.88), with mortality rates (deaths per 1000 person-years at risk) of 16.6 in azithromycin communities and 20.9 in placebo communities. Among untreated children, the incidence rate ratio was 0.91 (95% CI: 0.69, 1.21), with rates of 33.6 in azithromycin communities and 34.4 in placebo communities., Conclusions: As expected, this analysis suggested similar efficacy among treated children compared with the intention-to-treat analysis. Though the results were consistent with a small spillover benefit to untreated children, this trial was underpowered to detect spillovers., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: To facilitate mass distribution of azithromycin, trachoma control programmes use height instead of weight to determine dose for children 6 months to 15 years old. WHO has recommended azithromycin distribution to children 1-11 months old to reduce mortality in high mortality settings under carefully monitored conditions. Weight was used to determine dose in children 1-5 months old in studies of azithromycin distribution for child survival, but a simplified approach using age or height for all aged 1-11 months old could increase programme efficiency in real-world settings., Methods: This secondary analysis used data from two cluster randomised trials of azithromycin distribution for child mortality in Niger and Burkina Faso. An exhaustive search algorithm was developed to determine the optimal dose for different age groups, using tolerance limits of 10-20 mg/kg for children 1-2 months old and 15-30 mg/kg for children 3-11 months old. Height-based dosing was evaluated against the existing trachoma dosing pole and with a similar exhaustive search., Results: The optimal two-tiered age-based approach suggested a dose of 80 mg (2 mL) for children 1-2 months old and 160 mg (4 mL) for children 3-11 months old. Under this schedule, 89%-93% of children would have received doses within tolerance limits in both study populations. Accuracy was 93%-94% with a three-tiered approach, which resulted in doses of 80 mg (2 mL), 120 mg (3 mL) and 160 mg (4 mL) for children 1-2, 3-4 and 5-11 months old, respectively. For children 1-5 months old, the existing height pole would result in 70% of doses within tolerance limits. The optimisation identified height-based dosing options with 95% accuracy, although this would require changes to the existing dosing pole as well as additional training to measure infants lying flat., Conclusions: Overall, an age-based approach with two age tiers resulted in high accuracy while considering both concerns about overdosing in this young population and simplicity of field operations., Competing Interests: Competing interests: CK is affiliated with Pfizer, which supplied the azithromycin and placebo used in the trials that generated the data analysed in this manuscript., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

We analyzed samples obtained at baseline and 24 months in a mass azithromycin administration trial in Niger using quantitative polymerase chain reaction. In villages randomized to azithromycin, Shigella was the only pathogen reduced at 24 months (prevalence ratio, 0.36 [95% confidence interval: .17-.79]; difference in log quantity, -.42 [-.75 to -.10])., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)

Importance: Because transmission of ocular strains of Chlamydia trachomatis is greatest among preschool-aged children, limiting azithromycin distributions to this age group may conserve resources and result in less antimicrobial resistance, which is a potential advantage in areas with hypoendemic trachoma and limited resources., Objective: To determine the efficacy of mass azithromycin distributions to preschool-aged children as a strategy for trachoma elimination in areas with hypoendemic disease., Design, Setting, and Participants: In this cluster randomized clinical trial performed from November 23, 2014, until July 31, 2017, thirty rural communities in Niger were randomized at a 1:1 ratio to biannual mass distributions of either azithromycin or placebo to children aged 1 to 59 months. Participants and study personnel were masked to treatment allocation. Data analyses for trachoma outcomes were performed from October 19, 2021, through June 10, 2022., Interventions: Every 6 months, a single dose of either oral azithromycin (20 mg/kg using height-based approximation for children who could stand or weight calculation for small children) or oral placebo was provided to all children aged 1 to 59 months., Main Outcomes and Measures: Trachoma was a prespecified outcome of the trial, assessed as the community-level prevalence of trachomatous inflammation-follicular and trachomatous inflammation-intense through masked grading of conjunctival photographs from a random sample of 40 children per community each year during the 2-year study period. A secondary outcome was the seroprevalence of antibodies to C trachomatis antigens., Results: At baseline, 4726 children in 30 communities were included; 1695 children were enrolled in 15 azithromycin communities and 3031 children were enrolled in 15 placebo communities (mean [SD] proportions of boys, 51.8% [4.7%] vs 52.0% [4.2%]; mean [SD] age, 30.8 [2.8] vs 30.6 [2.6] months). The mean coverage of study drug for the 4 treatments was 79% (95% CI, 75%-83%) in the azithromycin group and 82% (95% CI, 79%-85%) in the placebo group. The mean prevalence of trachomatous inflammation-follicular at baseline was 1.9% (95% CI, 0.5%-3.5%) in the azithromycin group and 0.9% (95% CI, 0-1.9%) in the placebo group. At 24 months, trachomatous inflammation-follicular prevalence was 0.2% (95% CI, 0-0.5%) in the azithromycin group and 0.8% (95% CI, 0.2%-1.6%) in the placebo group (incidence rate ratio adjusted for baseline: 0.18 [95% CI, 0.01-1.20]; permutation P = .07)., Conclusions and Relevance: The findings of this trial do not show that biannual mass azithromycin distributions to preschool-aged children were more effective than placebo, although the underlying prevalence of trachoma was low. The sustained absence of trachoma even in the placebo group suggests that trachoma may have been eliminated as a public health problem in this part of Niger., Trial Registration: ClinicalTrials.gov Identifier: NCT02048007.

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., (© 2022. The Author(s).)

Importance: Mass azithromycin distributions may decrease childhood mortality, although the causal pathway is unclear. The potential for antibiotics to function as growth promoters may explain some of the mortality benefit., Objective: To investigate whether biannual mass azithromycin distributions are associated with increased childhood growth., Design, Setting, and Participants: This cluster-randomized trial was performed from December 2014 until March 2020 among 30 rural communities in Boboye and Loga departments in Niger, Africa, with populations from 200 to 2000 individuals. Communities were randomized in a 1:1 ratio to biannual mass distributions of azithromycin or placebo for children ages 1 to 59 months. Participants, field-workers, and study personnel were masked to treatment allocation. Height and weight changes from baseline to follow-up at 4 years were compared between groups. Data were analyzed from June through November 2021., Interventions: Participants received azithromycin at 20 mg/kg using height-based approximation or by weight for children unable to stand every 6 months at the participants' households. Placebo contained the vehicle of the azithromycin suspension., Main Outcomes and Measures: Longitudinal anthropometric assessments were performed on a random sample of children before the first treatment and then annually for 5 years. Height and weight were the prespecified primary outcomes., Results: Among 3936 children enrolled from 30 communities, baseline characteristics were similar between 1299 children in the azithromycin group and 2637 children in the placebo group (mean 48.2% [95% CI, 45.5% to 50.8%] girls vs 48.0% [95% CI, 45.7% to 50.3%] girls; mean age, 30.8 months [95% CI, 29.5 to 32.0 months] vs 30.6 months [95% CI, 29.2 to 31.6 months]). Baseline anthropometric assessments were performed among 2230 children, including 985 children in the azithromycin group and 1245 children in the placebo group, of whom follow-up measurements were available for 789 children (80.1%) and 1063 children (85.4%), respectively. At the prespecified 4-year follow-up visit, children in the azithromycin group gained a mean 6.7 cm (95% CI, 6.5 to 6.8 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year and children in the placebo group gained a mean 6.6 cm (95% CI, 6.4 to 6.7 cm) in height and 1.7 kg (95% CI, 1.7 to 1.8 kg) in weight per year. Height at 4 years was not statistically significantly different between groups when adjusted for baseline height (0.08 cm [95% CI, -0.12 to 0.28 cm] greater in the azithromycin group; P = .45), and neither was weight when adjusted for height and baseline weight (0.02 kg [95% CI, -0.10 to 0.06 kg] less in the azithromycin group; P = .64). However, among children in the shortest quartile of baseline height, azithromycin was associated with a 0.4 cm (95% CI, 0.1 to 0.7 cm) increase in height compared with placebo., Conclusions and Relevance: This study did not find evidence of an association between mass azithromycin distributions and childhood growth, although subgroup analysis suggested some benefit for the shortest children. These findings suggest that the mortality benefit of mass azithromycin distributions is unlikely to be due solely to growth promotion., Trial Registration: ClinicalTrials.gov Identifier: NCT02048007.

We evaluated the gut resistome of children from communities treated with 10 twice-yearly azithromycin distributions. Although the macrolide resistance remained higher in the azithromycin arm, the selection of non-macrolide resistance observed at earlier time points did not persist. Longitudinal resistance monitoring should be a critical component of mass distribution programs., Clinical Trials Registration: NCT02047981., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Antibiotics are recommended by the WHO as part of the management of uncomplicated severe acute malnutrition in children. We evaluated whether azithromycin, an antibiotic with antimalarial properties, improved malarial parasitemia outcomes in children with severe acute malnutrition compared with amoxicillin, an antibiotic commonly used for severe acute malnutrition that does not have antimalarial properties. Total of 301 children were randomized (1:1) to a single oral dose of azithromycin or a 7-day course of amoxicillin and followed for 8 weeks. We found no significant evidence that children receiving azithromycin had improved parasitemia outcomes relative to amoxicillin. Although azithromycin may have advantages over amoxicillin in terms of dosing and administration for uncomplicated severe acute malnutrition, it may not yield additional benefit for malaria outcomes.

Background: Biannual distribution of azithromycin to children 1-59 months old reduced mortality by 14% in a cluster-randomized trial. The World Health Organization has proposed targeting this intervention to the subgroup of children 1-11 months old to reduce selection for antimicrobial resistance. Here, we describe a trial designed to determine the impact of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance., Methods: AVENIR is a cluster-randomized, placebo-controlled, double-masked, response-adaptive large simple trial in Niger. During the 2.5-year study period, 3350 communities are targeted for enrollment. In the first year, communities in the Dosso region will be randomized 1:1:1 to 1) azithromycin 1-11: biannual azithromycin to children 1-11 months old with placebo to children 12-59 months old, 2) azithromycin 1-59: biannual azithromycin to children 1-59 months old, or 3) placebo: biannual placebo to children 1-59 months old. Regions enrolled after the first year will be randomized with an updated allocation based on the probability of mortality in children 1-59 months in each arm during the preceding study period. A biannual door-to-door census will be conducted to enumerate the population, distribute azithromycin and placebo, and monitor vital status. Primary mortality outcomes are defined as all-cause mortality rate (deaths per 1000 person-years) after 2.5 years from the first enrollment in 1) children 1-59 months old comparing the azithromycin 1-59 and placebo arms, 2) children 1-11 months old comparing the azithromycin 1-11 and placebo arm, and 3) children 12-59 months in the azithromycin 1-11 and azithromycin 1-59 arms. In the Dosso region, 50 communities from each arm will be followed to monitor antimicrobial resistance. Primary resistance outcomes will be assessed after 2 years of distributions and include 1) prevalence of genetic determinants of macrolide resistance in nasopharyngeal samples from children 1-59 months old, and 2) load of genetic determinants of macrolide resistance in rectal samples from children 1-59 months old., Discussion: As high-mortality settings consider this intervention, the results of this trial will provide evidence to support programmatic and policy decision-making on age-based strategies for azithromycin distribution to promote child survival., Trial Registration: This trial was registered on January 13, 2020 (clinicaltrials.gov: NCT04224987 ).

Background: Given the high risk of infectious mortality among children with severe acute malnutrition (SAM), the World Health Organization recommends routine administration of a broad-spectrum antibiotic like amoxicillin as part of the management of uncomplicated SAM. However, evidence for the efficacy of amoxicillin to improve nutritional recovery or reduce mortality has been mixed. With a long half-life and evidence of efficacy to reduce mortality in high-risk populations, azithromycin is a potential alternative to amoxicillin in the management of SAM. In this pilot study, we aim to compare the efficacy of azithromycin to amoxicillin to improve nutritional outcomes in children with uncomplicated SAM., Methods: This pilot randomized controlled trial will enroll 300 children with uncomplicated SAM from 6 Centre de Santé et de Promotion Sociale in the Boromo health district in Burkina Faso. Eligible children are randomized to receive a single directly observed dose of oral azithromycin or a 7-day course of oral amoxicillin in addition to the standard package of care for uncomplicated SAM. Enrolled children are followed weekly until nutritional recovery, and all children return for a final study visit at 8 weeks after enrollment. Anthropometric indicators, vital status, and clinical outcomes are monitored at each visit and compared by arm. Primary feasibility outcomes include enrollment potential, refusals, loss to follow-up, and completeness of data collection. The primary clinical outcome is weight gain (g/kg/day) over the 8-week study period., Discussion: This pilot trial will establish the feasibility of conducting a full-scale randomized controlled trial to evaluate alternative antibiotics in this setting and provide preliminary evidence for the efficacy of azithromycin compared to amoxicillin to improve outcomes for children with SAM., Trial Registration: This trial was first registered on clinicaltrials.gov on 26 June 2018 ( NCT03568643 ).

Background: The World Health Organization (WHO) recommends annual mass azithromycin distribution until districts drop below 5% prevalence of trachomatous inflammation-follicular (TF). Districts with very low TF prevalence may have little or no transmission of the ocular strains of Chlamydia trachomatis that cause trachoma, and additional rounds of mass azithromycin distribution may not be useful. Here, we describe the protocol for a randomized controlled trial designed to evaluate whether mass azithromycin distribution can be stopped prior to the current WHO guidelines., Methods: The Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) study is a 1:1 community randomized non-inferiority trial designed to evaluate whether mass azithromycin distribution can be stopped in districts with baseline prevalence of TF under 20%. Communities in Maradi, Niger are randomized after baseline assessment either to continued annual mass azithromycin distribution or stopping annual azithromycin distribution over a 3-year period. We will compare the prevalence of ocular C. trachomatis (primary outcome), TF and other clinical signs of trachoma, and serologic markers of trachoma after 3 years. We hypothesize that stopping annual azithromycin distribution will be non-inferior to continued annual azithromycin distributions for all markers of trachoma prevalence and transmission., Discussion: The results of this trial are anticipated to provide potentially guideline-changing evidence for when mass azithromycin distributions can be stopped in low TF prevalence areas. TRIAL REGISTRATION NUMBER: This study is registered at clinicaltrials.gov ( NCT04185402 ). Registered December 4, 2019; prospectively registered pre-results.

There is a lack of empirical, prospective human data on the gut microbiome and its relationship with growth, especially in low- and middle-income countries. We prospectively assessed the association between gut microbial diversity and short-term growth in a cohort of preschool children in Burkina Faso to better characterize whether there is any evidence that changes in gut microbial diversity may affect growth. Data were obtained from a randomized controlled trial evaluating the effect of antibiotic administration on gut microbial diversity in preschool children. We followed up the enrolled children for 35 days, with anthropometric measurements at baseline and day 35 and microbial diversity measured at baseline and day 9 (analytic sample, N = 155). We estimated linear mixed-effects regression models with household random intercepts to assess the association of Simpson's and Shannon's alpha diversity with measures of change in anthropometry (e.g., ponderal growth since baseline) and absolute anthropometric measurements (e.g., day 35 weight). We did not find evidence that alpha gut microbial diversity was associated with growth or absolute anthropometric measurements after adjusting for confounding variables. Effect estimates were close to the null ( P ≥ 0.15 for all fully adjusted comparisons), with the association between Simpson's alpha diversity and day 35 height (cm) farthest from the null (coefficient = -0.03, 95% CI: -0.07, 0.01). The change in gut microbial diversity also was not associated with the change in anthropometry in crude or adjusted models. Future research is needed to explore whether gut diversity has an impact on growth over a longer time period, in both healthy and malnourished children.

We evaluated the potential antiviral effects of azithromycin on the nasopharyngeal virome of Nigerien children who had received multiple rounds of mass drug administration. We found that the respiratory burden of non-severe acute respiratory syndrome coronaviruses was decreased with azithromycin distributions. Clinical Trials Registration. NCT02047981., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear., Methods: We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months., Results: Over the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa., Conclusions: Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.)., (Copyright © 2020 Massachusetts Medical Society.)

Background: Biannual azithromycin distribution has been shown to reduce child mortality as well as increase antimicrobial resistance. Targeting distributions to vulnerable subgroups such as malnourished children is one approach to reaching those at the highest risk of mortality while limiting selection for resistance. The objective of this analysis was to assess whether the effect of azithromycin on mortality differs by nutritional status., Methods and Findings: A large simple trial randomized communities in Niger to receive biannual distributions of azithromycin or placebo to children 1-59 months old over a 2-year timeframe. In exploratory subgroup analyses, the effect of azithromycin distribution on child mortality was assessed for underweight subgroups using weight-for-age Z-score (WAZ) thresholds of -2 and -3. Modification of the effect of azithromycin on mortality by underweight status was examined on the additive and multiplicative scale. Between December 2014 and August 2017, 27,222 children 1-11 months of age from 593 communities had weight measured at their first study visit. Overall, the average age among included children was 4.7 months (interquartile range [IQR] 3-6), 49.5% were female, 23% had a WAZ < -2, and 10% had a WAZ < -3. This analysis included 523 deaths in communities assigned to azithromycin and 661 deaths in communities assigned to placebo. The mortality rate was lower in communities assigned to azithromycin than placebo overall, with larger reductions among children with lower WAZ: -12.6 deaths per 1,000 person-years (95% CI -18.5 to -6.9, P < 0.001) overall, -17.0 (95% CI -28.0 to -7.0, P = 0.001) among children with WAZ < -2, and -25.6 (95% CI -42.6 to -9.6, P = 0.003) among children with WAZ < -3. No statistically significant evidence of effect modification was demonstrated by WAZ subgroup on either the additive or multiplicative scale (WAZ < -2, additive: 95% CI -6.4 to 16.8, P = 0.34; WAZ < -2, multiplicative: 95% CI 0.8 to 1.4, P = 0.50, WAZ < -3, additive: 95% CI -2.2 to 31.1, P = 0.14; WAZ < -3, multiplicative: 95% CI 0.9 to 1.7, P = 0.26). The estimated number of deaths averted with azithromycin was 388 (95% CI 214 to 574) overall, 116 (95% CI 48 to 192) among children with WAZ < -2, and 76 (95% CI 27 to 127) among children with WAZ < -3. Limitations include the availability of a single weight measurement on only the youngest children and the lack of power to detect small effect sizes with this rare outcome. Despite the trial's large size, formal tests for effect modification did not reach statistical significance at the 95% confidence level., Conclusions: Although mortality rates were higher in the underweight subgroups, this study was unable to demonstrate that nutritional status modified the effect of biannual azithromycin distribution on mortality. Even if the effect were greater among underweight children, a nontargeted intervention would result in the greatest absolute number of deaths averted., Trial Registration: The MORDOR trial is registered at clinicaltrials.gov NCT02047981., Competing Interests: The authors have declared that no competing interests exist.

Mass azithromycin distribution has been shown to reduce all-cause mortality in preschool children in sub-Saharan Africa. However, substantial heterogeneity in the apparent effect has been noted across geographic settings, suggesting a greater relative benefit in higher mortality settings. Here, we evaluated the relationship between the underlying mortality rate and the efficacy of azithromycin for the prevention of child mortality using data from multiple sites in Ethiopia, Malawi, Niger, and Tanzania. Between regions, we find no strong evidence of effect modification of the efficacy of azithromycin distribution for the prevention of child mortality by the underlying mortality rate ( P = 0.12), although a modest effect is consistent with our findings. Higher mortality settings could be prioritized, however, because of the larger number of deaths which could be averted with azithromycin distribution.

The relationship between malaria and malnutrition is complicated, and existence of one may predispose or exacerbate the other. We evaluated the relationship between malaria parasitemia and nutritional status in children living in communities participating in a cluster-randomized trial of biannual azithromycin compared with placebo for prevention of childhood mortality. Data were collected during the low malaria transmission and low food insecurity season. Parasitemia was not associated with weight-for-height Z -score (24 months: P = 0.11 azithromycin communities, P = 0.75 placebo communities), weight-for-age Z -score (24 months: P = 0.83 azithromycin, P = 0.78 placebo), height-for-age Z -score (24 months: P = 0.30 azithromycin, P = 0.87 placebo), or mid-upper arm circumference (24 months: P = 0.12 azithromycin, P = 0.56 placebo). There was no statistically significant evidence of a difference in the relationship in communities receiving azithromycin or placebo. During the low transmission season, there was no evidence that malaria parasitemia and impaired nutritional status co-occur in children.

Though bulk stool remains the gold standard specimen type for enteropathogen diagnosis, rectal swabs may offer comparable sensitivity with greater ease of collection for select pathogens. This study sought to evaluate the validity and reproducibility of rectal swabs as a sample collection method for the molecular diagnosis of Giardia duodenalis. Paired rectal swab and bulk stool samples were collected from 86 children ages 0-4 years living in southwest Niger, with duplicate samples collected among a subset of 50 children. Infection was detected using a previously validated real-time PCR diagnostic targeting the small subunit ribosomal RNA gene. Giardia duodenalis was detected in 65.5% (55/84) of bulk stool samples and 44.0% (37/84) of swab samples. The kappa evaluating test agreement was 0.81 (95% CI: 0.54-1.00) among duplicate stool samples ( N = 49) and 0.75 (95% CI: 0.47-1.00) among duplicate rectal swabs ( N = 48). Diagnostic sensitivity was 93% (95% CI: 84-98) by bulk stool and 63% (95% CI: 49-75) by rectal swabs. When restricting to the lowest three quartiles of bulk stool quantitation cycle values (an indication of relatively high parasite load), sensitivity by rectal swabs increased to 78.0% (95% CI: 64-89, P < 0.0001). These findings suggest that rectal swabs provide less sensitive and reproducible results than bulk stool for the real-time PCR diagnosis of G. duodenalis. However, their fair sensitivity for higher parasite loads suggests that swabs may be a useful tool for detecting higher burden infections when stool collection is excessively expensive or logistically challenging.

We examined whether baseline mortality risk, as a function of child age and site, modified the azithromycin mortality-reduction effect in the Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) clinical trial. We used the Cox proportional hazards model with an interaction term. Three models were examined representing three sources for the baseline-risk covariate: two using sources external to MORDOR and the third leveraging data within MORDOR. All three models provided moderate evidence for the effect becoming stronger with increasing baseline mortality ( P = 0.02, 0.02, and 0.07, respectively) at the rate of approximately 6-12% additional mortality reduction per doubling of baseline mortality. Etiological and programmatic implications of these findings are discussed.

Biannual mass azithromycin distribution to children younger than 5 years has been shown to reduce all-cause mortality in sub-Saharan Africa. Antibiotic-sparing approaches to azithromycin distribution, such as targeting to younger children who are at higher risk of mortality, are being considered by policymakers. We evaluated the absolute number of deaths averted in the Macrolides Oraux pour Réduire le Décès avec un Oeil sur la Résistance study in three age-groups: 1-5 months, 1-11 months, and 1-59 months. The number of deaths averted decreased from 729 (95% CI 492 to 966) in children aged 1-59 months to 297 (95% CI 168 to 427) and 126 (95% CI 43 to 209) in the 1- to 11-month and 1- to 5-month groups, respectively. Limiting antibiotic treatment to a subgroup of higher risk children may result in fewer deaths averted compared with treating all preschool children.

Eukaryotic parasites are significant contributors to childhood illness in Niger. While helminthiases have received national attention through mass deworming efforts, the epidemiology of intestinal protozoa in Niger remains underexamined. This study employed real-time PCR diagnostics to describe the prevalence of two schistosomes, four soil-transmitted helminths, and one protozoan parasite in Boboye Department, Dosso Region. Prevalence was assessed using bulk stool specimens collected from a population-based sample of 86 children residing in 9 communities. Anthropometric measurements were used to calculate child growth z -scores and stool consistency was graded. Helminths were absent from the study population, with the exception of a single Schistosoma haematobium infection (1/86; 1.2%). Giardia duodenalis was the only protozoa present, detected in 65% (56/86) of children. Prevalence of G. duodenalis peaked in 2-year-olds with 88% (15/17) positivity. The population was generally undernourished, though growth indices did not differ significantly between children with and without G. duodenalis infection., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Aiemjoy K et al.)

Eukaryotic parasites are significant contributors to childhood illness in Niger. While helminthiases have received national attention through mass deworming efforts, the epidemiology of intestinal protozoa in Niger remains underexamined. This study employed real-time PCR diagnostics to describe the prevalence of two schistosomes, four soil-transmitted helminths, and one protozoan parasite in Boboye Department, Dosso Region. Prevalence was assessed using bulk stool specimens collected from a population-based sample of 86 children residing in 9 communities. Anthropometric measurements were used to calculate child growth z -scores and stool consistency was graded. Helminths were absent from the study population, with the exception of a single Schistosoma haematobium infection (1/86; 1.2%). Giardia duodenalis was the only protozoa present, detected in 65% (56/86) of children. Prevalence of G. duodenalis peaked in 2-year-olds with 88% (15/17) positivity. The population was generally undernourished, though growth indices did not differ significantly between children with and without G. duodenalis infection., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Aiemjoy K et al.)

Background: The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial found that biannual mass distribution of azithromycin to children younger than 5 years in Niger reduced the primary outcome of all-cause mortality by 18%. We aimed to determine the causes of mortality among deceased children using verbal autopsy., Methods: In this 2-year cluster-randomised controlled trial, 594 community clusters in Niger were randomly allocated (1:1 ratio) to receive biannual mass distributions of either oral azithromycin (approximately 20 mg per kg of bodyweight) or placebo targeted to children aged 1-59 months. Participants, study investigators, and field workers were masked to treatment allocation. Between Nov 23, 2014, and July 31, 2017, 3615 child deaths were recorded by use of biannual house-to-house censuses, and verbal autopsies were done between May 26, 2015, and May 17, 2018, to identify cause of death. Cause-specific mortality, as assessed by verbal autopsy, was a prespecified secondary outcome. This trial is completed and is registered with ClinicalTrials.gov, NCT02047981., Findings: Between Nov 23, 2014, and July 31, 2017, 303 communities (n=40 375 children at baseline) in Niger received mass azithromycin and 291 communities (n=35 747 children at baseline) received placebo. Treatment coverage was 90·3% (SD 10·6) in the azithromycin group and 90·4% (10·1) in the placebo group. No communities were lost to follow-up. In total, 1727 child deaths in the azithromycin group and 1888 child deaths in the placebo group were reported from the population censuses. Of these, the cause of death for 1566 (90·7%) children in the azithromycin group and 1735 (91·9%) children in the placebo group were ascertained by verbal autopsy interviews. In the azithromycin group, 437 (27·9%) deaths were due to malaria, 252 (16·1%) deaths were due to pneumonia, and 234 (14·9%) deaths were due to diarrhoea. In the placebo group, 493 (28·4%) deaths were due to malaria, 275 (15·9%) deaths were due to pneumonia, and 251 (14·5%) deaths were due to diarrhoea. Relative to communities that received placebo, child mortality in communities that received azithromycin was lower for malaria (incidence rate ratio 0·78, 95% CI 0·66-0·92; p=0·0029), dysentery (0·65, 0·44-0·94; p=0·025), meningitis (0·67, 0·46-0·97; p=0·036), and pneumonia (0·83, 0·68-1·00; p=0·051). The distribution of causes of death did not differ significantly between the two study groups (p=0·98)., Interpretation: Mass azithromycin distribution resulted in approximately a third fewer deaths in children aged 1-59 months due to meningitis and dysentery, and a fifth fewer deaths due to malaria and pneumonia. The lack of difference in the distribution of causes of death between the azithromycin and placebo groups could be attributable to the broad spectrum of azithromycin activity and the study setting, in which most childhood deaths were due to infections., Funding: Bill & Melinda Gates Foundation., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Community-level interventions in cluster randomized controlled trials may alter the gut microbiome of individuals. The current method of estimating community diversities uses microbiome data obtained from multiple individual's specimens. Here we propose randomly pooling a number of microbiome samples from the same community into one sample before sequencing to estimate community-level microbiome diversity., Methods: We design and analyze an experiment to compare community microbiome diversity (gamma-diversity) estimates derived from 16S rRNA gene sequencing of 1) individually sequenced specimens vs. 2) pooled specimens collected from a community. Pool sizes of 10, 20, and 40 are considered. We then compare the gamma-estimates using Pearson's correlation as well as using Bland and Altman agreement analysis for three established diversity indices including richness, Simpson's and Shannon's., Results: The gamma-diversity estimates are highly correlated, with most being statistically significant. All correlations between all three diversity estimates are significant in the 10-pooled data. Pools comprising 40 specimens are closest to the line of agreement, but all pooled samples and individual samples fall within the 95% limits of agreement., Conclusions: Pooling microbiome samples before DNA amplification and metagenomics sequencing to estimate community-level diversity is a viable measure to consider in population-level association research studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The MORDOR I trial 1 , conducted in Niger, Malawi and Tanzania, demonstrated that mass azithromycin distribution to preschool children reduced childhood mortality 1 . However, the large but simple trial design precluded determination of the mechanisms involved. Here we examined the gut microbiome of preschool children from 30 Nigerien communities randomized to either biannual azithromycin or placebo. Gut microbiome γ-diversity was not significantly altered (P = 0.08), but the relative abundances of two Campylobacter species, along with another 33 gut bacteria, were significantly reduced in children treated with azithromycin at the 24-month follow-up. Metagenomic analysis revealed functional differences in gut bacteria between treatment groups. Resistome analysis showed an increase in macrolide resistance gene expression in gut microbiota in communities treated with azithromycin (P = 0.004). These results suggest that prolonged mass azithromycin distribution to reduce childhood mortality reduces certain gut bacteria, including known pathogens, while selecting for antibiotic resistance.

Background: Mass azithromycin distributions have been shown to reduce mortality in preschool children, although the factors mediating this mortality reduction are not clear. This study was performed to determine whether mass distribution of azithromycin, which has modest antimalarial activity, reduces the community burden of malaria., Methods and Findings: In a cluster-randomized trial conducted from 23 November 2014 until 31 July 2017, 30 rural communities in Niger were randomized to 2 years of biannual mass distributions of either azithromycin (20 mg/kg oral suspension) or placebo to children aged 1 to 59 months. Participants, field staff, and investigators were masked to treatment allocation. The primary malaria outcome was the community prevalence of parasitemia on thick blood smear, assessed in a random sample of children from each community at study visits 12 and 24 months after randomization. Analyses were performed in an intention-to-treat fashion. At the baseline visit, a total of 1,695 children were enumerated in the 15 azithromycin communities, and 3,029 children were enumerated in the 15 placebo communities. No communities were lost to follow-up. The mean prevalence of malaria parasitemia at baseline was 8.9% (95% CI 5.1%-15.7%; 52 of 552 children across all communities) in the azithromycin-treated group and 6.7% (95% CI 4.0%-12.6%; 36 of 542 children across all communities) in the placebo-treated group. In the prespecified primary analysis, parasitemia was lower in the azithromycin-treated group at month 12 (mean prevalence 8.8%, 95% CI 5.1%-14.3%; 51 of 551 children across all communities) and month 24 (mean 3.5%, 95% CI 1.9%-5.5%; 21 of 567 children across all communities) than it was in the placebo-treated group at month 12 (mean 15.3%, 95% CI 10.8%-20.6%; 81 of 548 children across all communities) and month 24 (mean 4.8%, 95% CI 3.3%-6.4%; 28 of 592 children across all communities) (P = 0.02). Communities treated with azithromycin had approximately half the odds of parasitemia compared to those treated with placebo (odds ratio [OR] 0.54, 95% CI 0.30 to 0.97). Parasite density was lower in the azithromycin group than the placebo group at 12 and 24 months (square root-transformed outcome; density estimates were 7,540 parasites/μl lower [95% CI -350 to -12,550 parasites/μl; P = 0.02] at a mean parasite density of 17,000, as was observed in the placebo arm). No significant difference in hemoglobin was observed between the 2 treatment groups at 12 and 24 months (mean 0.34 g/dL higher in the azithromycin arm, 95% CI -0.06 to 0.75 g/dL; P = 0.10). No serious adverse events were reported in either group, and among children aged 1 to 5 months, the most commonly reported nonserious adverse events (i.e., diarrhea, vomiting, and rash) were less common in the azithromycin-treated communities. Limitations of the trial include the timing of the treatments and monitoring visits, both of which took place before the peak malaria season, as well as the uncertain generalizability to areas with different malaria transmission dynamics., Conclusions: Mass azithromycin distributions were associated with a reduced prevalence of malaria parasitemia in this trial, suggesting one possible mechanism for the mortality benefit observed with this intervention., Trial Registration: The trial was registered on ClinicalTrials.gov (NCT02048007)., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TML has received a research grant from the Bill & Melinda Gates Foundation for this project and from the National Institutes of Health and private foundations for unrelated projects. The other authors have declared that no competing interests exist.

Background: The MORDOR I trial (Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance) showed that in Niger, mass administration of azithromycin twice a year for 2 years resulted in 18% lower postneonatal childhood mortality than administration of placebo. Whether this benefit could increase with each administration or wane owing to antibiotic resistance was unknown., Methods: In the Niger component of the MORDOR I trial, we randomly assigned 594 communities to four twice-yearly distributions of either azithromycin or placebo to children 1 to 59 months of age. In MORDOR II, all these communities received two additional open-label azithromycin distributions. All-cause mortality was assessed twice yearly by census workers who were unaware of participants' original assignments., Results: In the MORDOR II trial, the mean (±SD) azithromycin coverage was 91.3±7.2% in the communities that received twice-yearly azithromycin for the first time (i.e., had received placebo for 2 years in MORDOR I) and 92.0±6.6% in communities that received azithromycin for the third year (i.e., had received azithromycin for 2 years in MORDOR I). In MORDOR II, mortality was 24.0 per 1000 person-years (95% confidence interval [CI], 22.1 to 26.3) in communities that had originally received placebo in the first year and 23.3 per 1000 person-years (95% CI, 21.4 to 25.5) in those that had originally received azithromycin in the first year, with no significant difference between groups (P = 0.55). In communities that had originally received placebo, mortality decreased by 13.3% (95% CI, 5.8 to 20.2) when the communities received azithromycin (P = 0.007). In communities that had originally received azithromycin and continued receiving it for an additional year, the difference in mortality between the third year and the first 2 years was not significant (-3.6%; 95% CI, -12.3 to 4.5; P = 0.50)., Conclusions: We found no evidence that the effect of mass administration of azithromycin on childhood mortality in Niger waned in the third year of treatment. Childhood mortality decreased when communities that had originally received placebo received azithromycin. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02047981.)., (Copyright © 2019 Massachusetts Medical Society.)

In a large community-randomized trial, biannual azithromycin distributions significantly reduced postneonatal childhood mortality in sub-Saharan African sites. Here, we present a prespecified secondary analysis showing that much of the protective effect was in the first 3 months postdistribution. Distributing more frequently than biannually could be considered if logistically feasible. Clinical Trials Registration. NCT02047981., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Mass drug administration (MDA) with azithromycin may reduce under-5 child mortality (U5M) in sub-Saharan Africa. Here, we conducted a pooled analysis of all published cluster-randomized trials evaluating the effect of azithromycin MDA on child mortality. We pooled data from cluster-randomized trials randomizing communities to azithromycin MDA versus control. We calculated mortality rates in the azithromycin and control arms in each study, and by country for multisite studies including multiple countries. We conducted a two-stage individual community data meta-analysis to estimate the effect of azithromycin for prevention of child mortality. Three randomized controlled trials in four countries (Ethiopia, Malawi, Niger, and Tanzania) were identified. The overall pooled mortality rate was 15.9 per 1,000 person-years (95% confidence interval [CI]: 15.5-16.3). The pooled mortality rate was lower in azithromycin-treated communities than in placebo-treated communities (14.7 deaths per 1,000 person-years, 95% CI: 14.2-15.3 versus 17.2 deaths per 1,000 person-years, 95% CI: 16.5-17.8). There was a 14.4% reduction in all-cause child mortality in communities receiving azithromycin MDA (95% CI: 6.3-21.7% reduction, P = 0.0007). All-cause U5M was lower in communities receiving azithromycin MDA than in control communities, suggesting that azithromycin MDA could be a new tool to reduce child mortality in sub-Saharan Africa. However, heterogeneity in effect estimates suggests that the magnitude of the effect may vary in time and space and is currently not predictable.

Cohabiting children may share components of their intestinal microbiome. We evaluated whether receipt of azithromycin in one sibling confers changes to the intestinal microbiome in an untreated sibling compared with placebo in a randomized controlled trial. We found no evidence of an indirect effect of antibiotic use in cohabiting children. Clinical Trials Registrations: NCT03187834.

Background: Mass azithromycin distribution reduces under-5 child mortality. Trachoma control programs currently treat infants aged 6 months and older. Here, we report findings from an infant adverse event survey in 1-5 month olds who received azithromycin as part of a large community-randomized trial in Niger., Methods and Principal Findings: Active surveillance of infants aged 1-5 months at the time of treatment was conducted in 30 randomly selected communities from within a large cluster randomized trial of biannual mass azithromycin distribution compared to placebo to assess the potential impact on child mortality. We compared the distribution of adverse events reported after treatment among azithromycin-treated versus placebo-treated infants. From January 2015 to February 2018, the caregivers of 1,712 infants were surveyed. Approximately one-third of caregivers reported at least one adverse event (azithromycin: 29.6%, placebo: 34.3%, risk ratio [RR] 0.86, 95% confidence interval [CI] 0.68 to 1.10, P = 0.23). The most commonly reported adverse events included diarrhea (azithromycin: 19.3%, placebo: 28.1%, RR 0.68, 95% CI 0.49 to 0.96, P = 0.03), vomiting (azithromycin: 15.9%, placebo: 21.0%, RR 0.76, 95% CI 0.56 to 1.02, P = 0.07), and skin rash (azithromycin: 12.3%, placebo: 13.6%, RR 0.90, 95% CI 0.59 to 1.37, P = 0.63). No cases of infantile hypertrophic pyloric stenosis were reported., Conclusions: Azithromycin given to infants aged 1-5 months appeared to be safe. Inclusion of younger infants in larger azithromycin-based child mortality or trachoma control programs could be considered if deemed effective., Trial Registration: ClinicalTrials.gov NCT02048007., Competing Interests: The authors have declared that no competing interests exist.

Antibiotics improve both weight and height gain in randomized trials of preschool children with preexisting morbidity. Here, we assess the effect of a short course of three different antibiotics (amoxicillin, azithromycin, and cotrimoxazole) on short-term linear and ponderal growth in a population-based sample of preschool children in rural Burkina Faso. We randomized households with at least two children in the Nouna district, Burkina Faso, to a 5-day course of amoxicillin, azithromycin, cotrimoxazole, or placebo. Within each antibiotic-randomized household, one child was randomly assigned to receive the antibiotic and the other to receive the placebo. Weight and height measurements were taken at baseline and 30 days following the last study medication dose. Weight-for-height Z (WHZ), height-for-age Z (HAZ), and weight-for-age Z (WAZ) scoreswere calculated based on the 2006 World Health Organization standards. Of the 124 households and 248 children enrolled, 229 had anthropometry measurements at 1 month and were analyzed. Children randomized to amoxicillin gained significantly more weight compared with both the placebo household (mean difference 317 g, 95% confidence interval [CI]: 115-519 g) and placebo sibling (mean difference 315 g, 95% CI: 147-482 g) controls. Growth velocity in g/kg/day, and WHZ and WAZ scores were higher in amoxicillin-treated children compared with placebo households and siblings. There were no differences in weight gain in children randomized to azithromycin or cotrimoxazole compared with placebo households or placebo siblings. There were no differences in height gain or HAZ across any of the study arms. Amoxicillin may have short-term growth-promoting effects in healthy children.

Background: Mass distributions of oral azithromycin have long been used to eliminate trachoma, and they are now being proposed to reduce childhood mortality. The observed benefit appears to be augmented with each additional treatment, suggesting a possible community-level effect. Here, we assess whether 2 biannual mass treatments of preschool children affect the community's gut microbiome at 6 months after the last distribution., Methods: In this cluster-randomized controlled trial, children aged 1-60 months in the Dossa region of Niger were randomized at the village level to receive a single dose of azithromycin or placebo every 6 months. Fecal samples were collected 6 months after the second treatment for metagenomic deep sequencing. The prespecified primary outcome was the Euclidean PERMANOVA of the gut microbiome, or effectively the distance between the genus-level centroid at the community level, with the secondary outcome being the Simpson's α diversity., Results: In the azithromycin arm, the gut microbial structures were significantly different than in the placebo arm (Euclidean PERMANOVA, P < .001). Further, the diversity of the gut microbiome in the azithromycin arm was significantly lower than in the placebo arm (inverse Simpson's index, P = .005)., Conclusions: Two mass azithromycin administrations, 6 months apart, in preschool children led to long-term alterations of the gut microbiome structure and community diversity. Here, long-term microbial alterations in the community did not imply disease but were associated with an improvement in childhood mortality., Clinical Trials Registration: NCT02048007.

Background: Burkina Faso has a seasonal malnutrition pattern, with higher malnutrition prevalence during the rainy season when crop yields are low. We investigated the association between dietary diversity and nutritional status among children aged 6-59 mo during the low crop yield season in rural Burkina Faso to assess the role of dietary diversity during the lean season on childhood nutritional status., Methods: Caregivers reported the dietary diversity of the past 7 d, consisting of 11 food groups, summed into a scale. Anthropometric measurements were taken from all children. Height-for-age (HAZ), weight-for-height (WHZ) and weight-for-age (WAZ) z-scores were calculated based on 2006 WHO standards. Stunting, wasting and underweight were defined as HAZ, WHZ and WAZ <-2 SD, respectively. Multivariable regression models adjusting for potential confounders including household food insecurity and animal ownership were used to assess the relationship between anthropometric indices and dietary diversity., Results: Of 251 children enrolled in the study, 20.6% were stunted, 10.0% wasted and 13.9% underweight. Greater dietary diversity was associated with greater HAZ (SD 0.14, 95% CI 0.04 to 0.25) among all children. There was no association between dietary diversity and wasting or mid-upper arm circumference in this study., Conclusions: Increasing dietary diversity may be an approach to reduce the burden of stunting and chronic malnutrition among young children in regions with seasonal food insecurity.

Background: We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations., Methods: In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice-yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses., Results: A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (±SD) azithromycin and placebo coverage over the four twice-yearly distributions was 90.4±10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing., Conclusions: Among postneonatal, preschool children in sub-Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .).

Background: Antibiotic exposure can alter the gut microbiome. We evaluate the effects of azithromycin on the gut microbiome diversity of children from an antibiotic-naive community in Niger., Methods: A population-based sample of 80 children aged 1-60 months in the Dosso region of Niger was randomized to receive a single dose of either oral azithromycin or placebo. Fecal samples were collected immediately before treatment and 5 days after treatment for 16S rRNA gene sequencing. The prespecified outcome was α-diversity (inverse Simpson's α-diversity index), with secondary outcomes of β and γ Simpson's and Shannon's diversities., Results: At 5 days after treatment, 40 children aged 1-60 months were analyzed in the azithromycin-treated group and 40 children in the placebo-treated group. Diversity of the gut microbiome was significantly lower in the treated group (inverse Simpson's α-diversity, 5.03; 95% confidence interval [CI], 4.08-6.14) than in the placebo group (6.91; 95% CI, 5.82-8.21; P = .03). Similarly, the Shannon's α-diversity was lower in the treated group (10.60; 95% CI, 8.82-12.36) than the placebo group (15.42; 95% CI, 13.24-17.80; P = .004). Simpson's community-level (γ) diversity decreased with azithromycin exposure from 17.72 (95% CI, 13.80-20.21) to 10.10 (95% CI, 7.80-11.40; P = .00008), although β-diversity was not significantly reduced (2.56, 95% CI, 1.88-3.12; to 2.01, 95% CI, 1.46-2.51; P = .26)., Conclusions: Oral administration of azithromycin definitively decreases the diversity of the gut microbiome of children in an antibiotic-naive community., Clinical Trials Registration: NCT02048007., (Published by Oxford University Press for the Infectious Diseases Society of America 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.)