BACKGROUND:Biannual mass azithromycin distribution to children aged 1-59 months reduces all-cause child mortality but selects for antimicrobial resistance (AMR). The World Health Organization (WHO) recommends ongoing surveillance of AMR in the context of azithromycin distribution. We evaluated the impact of twice-yearly distribution of azithromycin compared to placebo on AMR in the gut of children in Burkina Faso. METHODS:The Community Health with Azithromycin Trial (CHAT) was a 1:1 cluster randomized placebo-controlled trial in Nouna District, Burkina Faso, from 2019 to 2023. Communities were randomized in a 1:1 fashion to twice-yearly azithromycin (20 mg/kg) or matching placebo. At 36 months, rectal swabs were collected from a random sample of 15 children per community in 48 communities participating in the trial and assessed for AMR genetic resistance determinants using next-generation DNA sequencing (DNA-seq). We assessed the fold-change in macrolide and nonmacrolide resistance determinants between treatment groups after 36 months. RESULTS:A total of 483 samples from 41 communities were analyzed at 36 months. There was no evidence of a difference in macrolide resistance determinants in the azithromycin group compared to the placebo group (fold-change, 1.21; 95% confidence interval [CI], .96-1.52; P = .62). There was no evidence of a difference in nonmacrolide resistance genes; for example, beta-lactam resistance was similar between treatment groups (fold-change, 1.05; 95% CI, .79-1.40; P = .81). CONCLUSIONS:In this setting in Burkina Faso, twice-yearly azithromycin distributions to children aged 1-59 months did not lead to statistically significant differences in macrolide or nonmacrolide genetic resistance determinants at 36 months. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov NCT03676764.

To assess the benefits of Seasonal Malaria Chemoprevention (SMC)—the monthly administration of sulfadoxine-pyrimethamine and amodiaquine—beyond malaria prevention in real-world program settings. We conducted a pre-post comparison of non-malarial diagnoses (pneumonia, diarrhea, acute malnutrition) and antibiotic prescription rates during SMC administration weeks versus a three-week post-intervention period in rural Burkina Faso. Data was obtained from clinic surveillance at 51 health facilities, a population-based census, and National Malaria Control Program data on SMC timing. Poisson regression models with person-weeks as an offset and standard errors clustered by health post estimated changes in rates. Interaction terms assessed variation across SMC cycles. Positive (malaria diagnoses, antimalarial prescriptions) and negative (injury) control outcomes were used to evaluate potential unmeasured confounding. Compared to administration weeks, modest declines were observed in pneumonia, diarrhea, and acute malnutrition diagnoses, as well as in antibiotic prescription rates during the post-SMC period. Absolute reductions were 0.7 (95

Importance:World Health Organization guidelines on azithromycin mass drug administration for child survival target infants aged 1 to 11 months, although prior studies included those aged 1 to 59 months. The AVENIR trial suggested that infants aged 1 to 11 months have lower mortality if children aged 12 to 59 months in the same household are also included. Objective:To assess the possibility of a spillover effect by examining the association of azithromycin and mortality among children aged 1 to 11 months in subgroups defined by the presence of a child aged 12 to 59 months in the same household. Design, Setting, and Participants:This exploratory secondary analysis of the AVENIR (Azithromycine Pour la Vie des Enfants au Niger: Implementation et Recherche) adaptive cluster-randomized clinical trial was performed in 3000 rural and periurban communities in Niger. AVENIR communities were randomized to 3 arms and followed up for 2 years (November 24, 2020, to July 31, 2023). Study arms consisted of children aged 1 to 59 months receiving azithromycin (child arm); infants aged 1 to 11 months receiving azithromycin with placebo to children aged 12 to 59 months (infant arm); and children aged 1 to 59 months receiving placebo (placebo arm). Participants, investigators, data collectors, and data analysts were masked to randomization. Intervention:A single 20-mg/kg dose of oral azithromycin or placebo administered by study staff biannually. Main Outcomes and Measures:All-cause mortality in infants aged 1 to 11 months (deaths per 1000 person-years) measured through biannual census. Subgroups were defined by the presence of a child aged 12 to 59 months in the household recorded during the census. Results:After exclusions, 2883 communities and 98 969 infants aged 1 to 11 months were included in the analysis. Among the 23 770 infants in allocation 1 at baseline, mean (SD) age was 6.2 (3.1) months and 11 974 (50.4%) were female. Mortality was 18.5 (95% CI, 16.7-20.4) deaths per 1000 person-years in the child arm, 22.3 (95% CI, 20.0-24.7) in the infant arm, and 23.9 (95% CI, 21.6-26.2) in the placebo arm. The incidence rate ratio comparing mortality in the child and infant arms among children with an older sibling was 0.78 (95% CI, 0.65-0.93) compared with 0.91 (95% CI, 0.73-1.15; P = .26 for interaction) among those without. Comparing the infant and placebo arms, the incidence rate ratio among children with an older sibling was 0.96 (95% CI, 0.81-1.14) compared with 0.90 (95% CI, 0.71-1.12; P = .61 for interaction) among those without. Conclusions and Relevance:In this secondary analysis of a cluster-randomized clinical trial, interaction for the presence of a older sibling was not statistically significant, but results were consistent with lower mortality among infants aged 1 to 11 months living with older, treated children. Trial Registration:ClinicalTrials.gov Identifier: NCT04224987.

Objective:Mass treatment with azithromycin (AZ) and administration of seasonal malaria chemoprevention (SMC) are both effective in reducing mortality among children under 5. However, it is not clear whether the benefit of AZ for mortality varies in the presence of routine SMC administration. The objective of this study was to examine whether the effect of mass AZ distribution on all-cause mortality among children less than 5 years of age varies with SMC administration season or SMC coverage. Methods:This was a secondary analysis of the Community Health with Azithromycin Trial (CHAT), a cluster randomized placebo-controlled trial of 341 communities in the Nouna District of Burkina Faso. Communities randomized to intervention received treatment with twice yearly mass AZ while control communities receive placebo. All communities received SMC as standard-of-care. SMC administration and coverage data were provided from National Malaria Control Program. SMC administration season was defined as the period during and immediately following SMC (July-December) versus the months of no SMC (January-June). SMC coverage was assessed as proportion of the population covered and by whether it was below or above a threshold of 80%. We used Poisson regression models with person-time at risk used as an offset and robust standard error to analyze mortality rates by treatment group and SMC subgroups and assessed interaction on both the multiplicative and additive scales. Results:Mortality was higher in SMC seasons for both arms, with a mortality rate of 10.3 per 1,000 person-years (95% CI: 9.0 to 11.6) in SMC seasons and 7.9 (95% CI: 6.9 to 9.0) in non-SMC seasons. Compared to placebo, the mortality rate in AZ clusters was 0.77 (95% CI: 0.60 to 0.98) during SMC season, while it was 0.89 (95% CI: 0.68 to 1.15) during the non-SMC seasons. The effect of AZ compared to placebo in clusters with <80% SMC coverage was 0.73 95%CI (0.56 to 0.96) and in clusters with ≥80% SMC coverage, it was 1.0 95%CI (0.59 to 1.69). The interaction between AZ and SMC season or coverage was not statistically significant on the additive or multiplicative scales. Conclusion:While our findings did not reach statistical significance, they raise the question of whether prioritizing MDA AZ during high transmission periods or in regions with low SMC coverage could be beneficial. Further research is needed to determine if targeting these periods or areas could lead to greater reductions in child mortality. Trial Registration:ClinicalTrials.gov Identifier: NCT03676764.

Background Severe Acute Malnutrition (SAM) is a major cause of morbidity and mortality in children under five, particularly in sub-Saharan Africa. The World Health Organization (WHO) recommends using mid-upper arm circumference (MUAC) for community-based screening due to its simplicity and cost-effectiveness. This study assesses the impact of MUAC-based screening and referral by community health workers (CHWs) on nutritional status and all-cause mortality in Burkina Faso. Methods A prospective regression discontinuity (RD) analysis was nested within the Community Health with Azithromycin Treatment (CHAT) trial, a cluster-randomized controlled trial in Nouna District, Burkina Faso. Children aged 6-59 months were screened using MUAC, and those with MUAC < 11.5 cm were referred for SAM treatment. The effect of referral on subsequent MUAC measurements and 6-month all-cause mortality was analyzed using data near the 11.5 cm threshold. Bandwidths were selected using the Imbens-Kalyanaraman (IK) algorithm to optimize bias-variance tradeoff. Generalized linear mixed-effects models were applied for analysis. Results Out of 65,554 children screened, 226 (0.34%) were referred for SAM. Using the IK-selected bandwidth for MUAC, no significant effects on 6-month MUAC or mortality were observed. The mean MUAC difference was 0.21 cm (95% CI: -0.22 to 0.65 cm), and the mortality odds ratio was 0.95 (95% CI: 0.03 to 31.37). Sensitivity analyses using broader bandwidths yielded consistent results. Conclusions MUAC-based screening and referral did not significantly improve nutritional status or reduce mortality. Improving SAM referral mechanisms and integrating community health support are necessary to improve health outcomes for children with SAM. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT03676764 ### Funding Statement The CHAT study was supported by the Bill and Melinda Gates Foundation (OPP1187628; PI: Lietman). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Board of the University of California, San Francisco and Comite d'Ethique pour la Recherche en Sante in Ouagadougou, Burkina Faso gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced are available online at OSF

There have been significant reductions in the burden of trachoma worldwide. However, some districts have experienced persistently high trachoma prevalence despite many years of intervention. Here, we report the epidemiology of trachoma in Merhabete, Ethiopia, a district in the Amhara Region that has been receiving azithromycin mass drug administration (MDA) since 2009. Data were obtained from the baseline survey of a cluster randomized trial evaluating targeted treatment strategies for trachoma elimination. An enumerative census was conducted in February 2022 to generate lists of children aged 6 months to 9 years in 80 sentinel communities participating in the trial. All children in the sentinel communities who were included in the census were examined. Field grades and conjunctival swabs were collected to assess active trachoma (based on clinical assessment) and ocular chlamydia (based on polymerase chain reaction to identify Chlamydia trachomatis). A total of 5,935 children were examined in 80 communities. The prevalence of trachomatous inflammation-follicular (TF) was 46.6%, trachomatous inflammation-intense (TI) was 17.5%, and ocular chlamydia was 28.0%. The correlation between TF and ocular chlamydia (correlation coefficient 0.54, 95% CI 0.34-0.70) was similar to the correlation between TI and ocular chlamydia (correlation coefficient 0.49, 95% CI 0.30-0.65). The prevalence of ocular chlamydia remained high in this district, which had received more than 10 rounds of azithromycin MDA. Ocular chlamydia was moderately correlated with both TF and TI. Intensive interventions may be required to eliminate trachoma in settings with persistently high ocular chlamydia prevalence despite many years of intervention.

Objective Azithromycin has been shown to reduce all-cause child mortality. This subgroup analysis investigates azithromycin’s mortality impact by underweight status using Azithromycine pour la Vie des Enfants au Niger: Implementation et Recherche (AVENIR) trial data.Design The AVENIR trial randomised communities into three arms: azithromycin for children aged 1–59 months, azithromycin for infants aged 1–11 months or placebo. Weight-for-age z-score was used to categorise children into subgroups of either moderate to severe underweight or not and severe underweight or not.Setting 2880 communities with a population of less than 2500 people in the Dosso and Tahoua regions of Niger that participated in the AVENIR trial were included.Participants 97 572 children aged 1–59 months who had weight captured during at least one census participated.Results Underweight subgroups had higher overall mortality compared with non-underweight subgroups. IRDs of deaths in children aged 1–11 months comparing communities receiving azithromycin to children 1–59 months of age to placebo were −6.2 deaths per 1000 person-years (95% CI −9.3 to −2.6) overall, −8.0 (95% CI −15.9 to −0.4) in the moderate to severe subgroup and −11.2 (95% CI −26.0 to −2.1) in the severe subgroup. Similar trends were noted in the azithromycin 1–11 month comparison. Malnutrition was not a statistically significant effect modifier for either comparison.Conclusions Although analyses suggest the potential for stronger effects in more severe underweight subgroups, we were unable to demonstrate underweight status as an effect modifier. In fact, azithromycin mass drug administration to children 1–59 months old reduced mortality in all subgroups, and, especially as the number of lives saved would be the highest by treating all subgroups, our results do not support restricting eligibility for this intervention.Trial registration number clinicaltrials.gov NCT04224987.

INTRODUCTION:Amoxicillin is recommended for children with uncomplicated severe acute malnutrition (SAM). However, some trials have shown no difference in amoxicillin for nutritional recovery in children with SAM compared with placebo. In addition, amoxicillin treatment requires two times per day dosing for 7 days, which may influence adherence. Azithromycin is a broad-spectrum antibiotic that can be provided as a single dose and has reduced mortality in children aged 1-59 months when provided by mass drug administration. The AMOUR trial is designed to assess amoxicillin, azithromycin and placebo as part of outpatient treatment of uncomplicated SAM. METHODS AND ANALYSIS:This double-masked randomised controlled trial will enrol 3000 children over 3 years in an individually randomised 1:1:1 allocation to azithromycin, amoxicillin or placebo arms and follow them for 12 months. Children eligible to enrol in the study will be aged 6-59 months and have uncomplicated non-oedematous SAM as defined by weight-for-height Z-score <-3 SD and/or mid-upper arm circumference <115 mm. Additionally, the children must not have received antibiotics in the past 7 days and have not received nutritional programme treatment for SAM in the 2 weeks before enrolling in the study. Each participant will receive a 7-day course of treatment or placebo based on the arm they were randomised to; 1 dose of azithromycin plus placebo for consistency in the number of doses, 7 days of amoxicillin or 7 days of placebo, with the first dose directly observed in all arms. The primary endpoint outcome will be weight gain defined by g/kg/day at 8 weeks. Mortality and relapse will be assessed at 8 weeks and 3 months, 6 months, 9 months and 12 months. ETHICS AND DISSEMINATION:Ethical approval was obtained from the Institutional Review Board at the University of California, San Francisco (Protocol 23-39411) and the Comité d'Ethique pour la Recherche en Santé in Ouagadougou, Burkina Faso (Protocol 2024-01-08). The results of this study will be disseminated to the Ministry of Health, community stakeholders and via peer-reviewed publications and academic conferences. TRIAL REGISTRATION NUMBER:NCT06010719.

INTRODUCTION:Malnutrition is a risk factor for child mortality, with around 45% of deaths in children under 5 globally linked to malnutrition. Seasonality of malnutrition has important implications for the timing of child health programme activities, but evidence is mixed on the nature of such patterns. Moreover, the bulk of the existing evidence is focused on wasting and stunting in children 6-59 months, despite increasing evidence that younger children also face a high risk, and that underweight alone is an important predictor of mortality. METHODS:This study used data from the cluster-randomised AVENIR trial which compared the effect of biannual distribution of azithromycin vs placebo on mortality in children 1-59 months old in Niger. AVENIR included a biannual census conducted on a rolling basis over 2 years. A subset of 133 781 infants aged 1-11 months from 2904 communities were included in this study, and weight-for-age z-score (WAZ) was calculated at each census. The exposure for this analysis is the day of the year weight was captured. Harmonic regression was used to determine primary and secondary peaks and nadirs of WAZ over time. RESULTS:Overall, the primary peak of WAZ occurred in late February and the primary nadir occurred in mid-May, aligning with a seasonal temperature increase before the rainy season. A secondary peak in August and a secondary nadir in November were also seen, aligning with the postrainy season. CONCLUSION:The seasonality of WAZ of infants 1-11 months in Niger may have implications for the timing of programmes aiming to decrease malnutrition.

BACKGROUND: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. OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.gov NCT03682654 and NCT03676764.

The twice-yearly mass distribution of azithromycin to children aged 1–59 months reduces all-cause child mortality. It has been suggested in some studies that mass azithromycin distributions may reduce malaria mortality and parasitemia; however, these studies have been conducted in the absence of seasonal malaria chemoprevention (SMC). Here, we evaluate malaria parasitemia in a cluster randomized trial of azithromycin versus a placebo in Burkina Faso, where SMC was being administered. Thin and thick smears were taken from a random sample of 15 children per cluster in 40 clusters that had been receiving twice-yearly azithromycin or a placebo for 36 months (six distributions). We found no evidence of a difference in malaria parasitemia between children in the azithromycin and placebo clusters (mean difference –6% prevalence; 95% CI –17% to 6%; P = 0.33). These results suggest that reductions in malaria parasitemia may not be a major contributor to the effect of azithromycin on child mortality in settings in which SMC is administered.

Biannual azithromycin administration to preschool children in sub-Saharan Africa improved childhood mortality but selected for antibiotic resistance (AMR). WHO guidelines recommended focusing treatment on infants ages 1-11 months old to reduce mortality while minimizing selection of AMR. The Infant Mortality Reduction by the Mass Administration of Azithromycin study was a double-masked, placebo-controlled, cluster-randomized trial that investigated these WHO guidelines. Health centers from three regions of Burkina Faso were randomized in a 2:1 ratio to receive either biannual azithromycin (67%) or placebo (33%) distribution to children 1-11 months old. A total of 3,524 rectal samples from children ages 1-59 months old from 60 randomly selected communities were included in the analysis. The prespecified primary outcome was the community-level fold change in macrolide resistance determinants between arms at the 24-month time point. Macrolide resistance determinants in the gut of children in communities whose infants received azithromycin did not increase compared with those in communities treated with placebo (1.05-fold change). Similarly, the fold changes for resistance determinants for beta-lactams, metronidazole, sulfonamides, tetracycline, and trimethoprim were 0.99-fold, 1.00-fold, 1.22-fold, 0.96-fold, and 0.96-fold, respectively. At 6 months after the fourth treatment, there were no detectable differences in the microbiome structure (Euclidean permutational multivariate analysis of variance) and Shannon diversity index between treatment arms. These results suggest that biannual azithromycin administration to children 1-11 months old did not lead to a significant long-lasting increase in gut AMR or alterations of the gut microbiomes of children 1-59 months old in the community.

Distribution of azithromycin to children ages 0-9 years old is an established strategy for treating and preventing trachoma. Our study aimed to determine whether the order in which children show up for trachoma screening is correlated with their infection status. We used baseline visit data from the study Kebele Elimination of Trachoma for Ocular Health in Ethiopia. All children ages 0-9 years old in 20 randomly selected villages were tested for ocular Chlamydia trachomatis with polymerase chain reaction. We used mixed effects logistic regression to estimate the odds ratio (OR) of trachoma positivity on presentation day 1 versus later, with village as a random effect. There was no statistical difference between infection prevalence among children measured on day 1 versus those measured during the following days (OR = 0.89-fold, 95% CI: 0.65- to 1.21-fold, P = 0.44), indicating that presentation order is not a considerable factor in highly prevalent regions.

World Health Organization guidelines on azithromycin mass drug administration for child survival target infants aged 1 to 11 months, although prior studies included those aged 1 to 59 months. The AVENIR trial suggested that infants aged 1 to 11 months have lower mortality if children aged 12 to 59 months in the same household are also included. To assess the possibility of a spillover effect by examining the association of azithromycin and mortality among children aged 1 to 11 months in subgroups defined by the presence of a child aged 12 to 59 months in the same household. This exploratory secondary analysis of the AVENIR (Azithromycine Pour la Vie des Enfants au Niger: Implementation et Recherche) adaptive cluster-randomized clinical trial was performed in 3000 rural and periurban communities in Niger. AVENIR communities were randomized to 3 arms and followed up for 2 years (November 24, 2020, to July 31, 2023). Study arms consisted of children aged 1 to 59 months receiving azithromycin (child arm); infants aged 1 to 11 months receiving azithromycin with placebo to children aged 12 to 59 months (infant arm); and children aged 1 to 59 months receiving placebo (placebo arm). Participants, investigators, data collectors, and data analysts were masked to randomization. A single 20-mg/kg dose of oral azithromycin or placebo administered by study staff biannually. All-cause mortality in infants aged 1 to 11 months (deaths per 1000 person-years) measured through biannual census. Subgroups were defined by the presence of a child aged 12 to 59 months in the household recorded during the census. After exclusions, 2883 communities and 98 969 infants aged 1 to 11 months were included in the analysis. Among the 23 770 infants in allocation 1 at baseline, mean (SD) age was 6.2 (3.1) months and 11 974 (50.4%) were female. Mortality was 18.5 (95% CI, 16.7-20.4) deaths per 1000 person-years in the child arm, 22.3 (95% CI, 20.0-24.7) in the infant arm, and 23.9 (95% CI, 21.6-26.2) in the placebo arm. The incidence rate ratio comparing mortality in the child and infant arms among children with an older sibling was 0.78 (95% CI, 0.65-0.93) compared with 0.91 (95% CI, 0.73-1.15; P = .26 for interaction) among those without. Comparing the infant and placebo arms, the incidence rate ratio among children with an older sibling was 0.96 (95% CI, 0.81-1.14) compared with 0.90 (95% CI, 0.71-1.12; P = .61 for interaction) among those without. In this secondary analysis of a cluster-randomized clinical trial, interaction for the presence of a older sibling was not statistically significant, but results were consistent with lower mortality among infants aged 1 to 11 months living with older, treated children. ClinicalTrials.gov Identifier: NCT04224987.

The objective of this study was to examine whether the effect of mass Azithromycin (AZ) distribution on all-cause mortality among children under 5 varies with seasonal malaria chemoprevention (SMC) administration season or coverage. This was a secondary analysis of the Community Health with Azithromycin Trial (CHAT), a cluster-randomized, placebo-controlled trial of twice-yearly AZ treatment in 341 communities in the Nouna District, Burkina Faso. All communities received SMC as standard-of-care. SMC administration and coverage data were provided from National Malaria Control Program. SMC season was defined as the period during and following SMC (July-December) versus the no SMC season (January-June). SMC coverage was assessed as proportion of the population covered and by whether it was below or above a threshold of 80%. We used Poisson regression models with person-time at risk as an offset and robust standard error to analyze mortality rates by treatment group and SMC subgroups and assessed interaction on both multiplicative and additive scales. Mortality was higher in SMC seasons for both arms. Compared to placebo, the mortality rate in AZ clusters was 0.77 (95% CI: 0.60 to 0.98) during SMC season, while it was 0.89 (95% CI: 0.68 to 1.15) during the non-SMC seasons. In clusters with <80% SMC coverage, the effect of AZ was 0.73 95%CI (0.56 to 0.96) and in clusters with ≥80% SMC coverage, it was 1.0 95%CI (0.59 to 1.69). The interaction between AZ and SMC season or coverage was not statistically significant on the additive or multiplicative scales. While our findings did not reach statistical significance, they raise the question of whether prioritizing MDA AZ during high transmission periods or in regions with low SMC coverage could be beneficial. Further research is needed to determine if targeting these periods or areas could further reduce child mortality.

Children with acute malnutrition are at high risk of morality. Mass azithromycin distribution reduces all-cause mortality among children aged 1-59 months, and effects may be greater in underweight infants. Here, we evaluate the efficacy of azithromycin for reducing all-cause mortality in children aged 6-59 months with acute malnutrition (mid-upper arm circumference, MUAC, < 12.5 cm). Communities in Nouna District, Burkina Faso were 1:1 randomized to biannual mass distribution of single dose azithromycin or placebo to all children aged 1-59 months. Mortality was assessed during each census and treatment round. MUAC measurements were collected for all children. We evaluated the effect of azithromycin on mortality in subgroups of children aged 6-59 months defined by acute malnutrition (MUAC < 12.5 cm versus MUAC ≥ 12.5 cm). In children with MUAC < 12.5 cm, mortality rates were 51% lower among those living in azithromycin communities compared to placebo (incidence rate ratio 0.49, 95% confidence interval, CI, 0.25 to 0.99; incidence rate difference -18.1 deaths per 1,000 person-years, 95% CI -37.0 to -0.01), which was greater than the reduction in mortality among children with MUAC ≥ 12.5 cm (P-value for interaction on the relative scale = 0.09; P-value for interaction of the additive scale = 0.03). Children with acute malnutrition may benefit from single dose azithromycin above and beyond those without acute malnutrition. Trial registration: ClinicalTrials.gov NCT03676764; https://clinicaltrials.gov/study/NCT03676764.

Mass antibiotic distribution to preschool children resulted in alterations of the gut microbiome months after distribution. This individually randomized, placebo-controlled trial evaluated changes in the gut microbiome and resistome in children aged 8 days to 59 months after one dose of oral azithromycin in Burkina Faso. A total of 450 children were randomized in a 1:1 ratio to either placebo or azithromycin. Rectal samples were collected at baseline, 2 weeks, and 6 months after randomization and subjected to DNA deep sequencing. Gut microbiome diversity and normalized antimicrobial resistance determinants for different antibiotic classes were evaluated. Azithromycin decreased gut bacterial diversity (Shannon P < 0.0001; inverse Simpson P < 0.001) 2 weeks after treatment relative to placebo. Concurrently, the normalized abundance of macrolide resistance genetic determinants was 243-fold higher (95% CI: 76-fold to 776-fold, P < 0.0001). These alterations did not persist at 6 months, suggesting that disruptions were transient. Furthermore, we were unable to detect resistance changes in other antibiotic classes, indicating that co-resistance with a single course of azithromycin when treated at the individual level was unlikely.

Objective: To assess the ongoing population-level impact of Seasonal malaria chemoprevention (SMC) under routine program conditions by evaluating uncomplicated and severe malaria rates following the four rounds of SMC administration. Methods: We used data from a randomized controlled trial (RCT) of 285 villages in Nouna District, Burkina Faso, surveillance data of clinic visits and National Malaria Control Program data on SMC administration to calculate the malaria rates for each epidemiological week in 2021 for each health post in the study area. Negative binomial regression models were used with person-time used as offset and standard errors clustered by health post to obtain incidence rate ratios (IRRs) and rate differences estimating changes in diagnoses. Results: Although SMC was administered during malaria peak weeks, both uncomplicated and severe malaria rates were high through December, after the fourth/last round of SMC. There was substantial reduction in infection rates in the 3 weeks post SMC, with a slight increase in rates around the 3rd week. Uncomplicated malaria rates were lower by 36%, 95%CI (24% - 45%), 37% (27% - 45%) and 23% (12% - 33%) in the first, second and third week after administration, respectively. Severe malaria rates lowered by 41% (14%-59%), 51% (32%-65%) and 25% (5%-40%) in the three weeks post-administration. Conclusion: Under routine program conditions, at the population level, SMC administration was associated with substantial reduction in uncomplicated and severe malaria but only in the immediate weeks post-administration. Assessment of local epidemiology and extension of the areas in which 5 rounds are distributed may be needed to effectively prevent malaria infections in areas with a longer transmission season.

Single-dose azithromycin is being considered by the WHO as an intervention for prevention of child mortality. However, concerns have emerged related to longer term unintended consequences of early life antibiotic use, particularly among infants. We conducted a long-term follow-up in a random sample of children who had been enrolled in a trial of neonatal azithromycin versus placebo for prevention of mortality to assess whether neonatal azithromycin exposure led to differences in child growth up to 4 years of age. We found no evidence of a difference in any anthropometric outcome among children who had received a single oral dose of azithromycin compared with placebo during the neonatal period. These results do not support long-term growth-promoting or deleterious effects of early life azithromycin exposure.