Prolonged mass azithromycin distributions and macrolide resistance determinants among preschool children in Niger: A sub-study of a cluster-randomized trial (MORDOR).

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.

Associations between Antenatal Care Visit Attendance and Infant Mortality and Growth.

This study examines the association between antenatal care (ANC) attendance and infant mortality and growth outcomes. The study used data from the Nouveux-nés et Azithromycine: une Innovation dans le Traitement des Enfants (NAITRE) trial conducted in Burkina Faso. This analysis included 21,795 neonates aged 8 to 27 days who were enrolled in the trial and had ANC data available. Infants were followed until 6 months of age. The analysis adjusted for potential confounders including infant's sex, maternal age, education, urbanicity, geographic region, season (dry versus rainy), pregnancy type (singleton versus multiple), number of previous pregnancies, if the infant was breastfed, and if the facility had an onsite physician to account for level of care. We used logistic and linear regression models to evaluate the association between ANC visits and all-cause infant mortality and infant growth measurements at 6 months. There was no significant association between ANC visits and 6-month mortality. Higher ANC attendance was associated with improved growth outcomes in infants at 6 months of age. After adjusting for potential confounders, each additional ANC visit was associated with a 0.03 kg increase in mean weight, 0.07 cm increase in mean length, 0.04 SD increase in mean mid-upper-arm circumference, 0.04 SD increase in mean height-for-age, 0.04 SD mean weight-for-age, and 0.02 SD mean weight-for-length Z-scores. These mean differences were statistically significant (except for weight-for-length Z-scores) but may not be clinically meaningful. Further research is warranted to explore the relationship between ANC attendance and longer-term health outcomes among infants.

Neonatal anthropometric indicators of infant growth and mortality in Burkina Faso.

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

Mass Azithromycin Distribution to Prevent Child Mortality in Burkina Faso: The CHAT Randomized Clinical Trial.

Importance: Repeated mass distribution of azithromycin has been shown to reduce childhood mortality by 14% in sub-Saharan Africa. However, the estimated effect varied by location, suggesting that the intervention may not be effective in different geographical areas, time periods, or conditions. Objective: To evaluate the efficacy of twice-yearly azithromycin to reduce mortality in children in the presence of seasonal malaria chemoprevention. Design, Setting, and Participants: This cluster randomized placebo-controlled trial evaluating the efficacy of single-dose azithromycin for prevention of all-cause childhood mortality included 341 communities in the Nouna district in rural northwestern Burkina Faso. Participants were children aged 1 to 59 months living in the study communities. Interventions: Communities were randomized in a 1:1 ratio to receive oral azithromycin or placebo distribution. Children aged 1 to 59 months were offered single-dose treatment twice yearly for 3 years (6 distributions) from August 2019 to February 2023. Main Outcomes and Measures: The primary outcome was all-cause childhood mortality, measured during a twice-yearly enumerative census. Results: A total of 34 399 children (mean [SD] age, 25.2 [18] months) in the azithromycin group and 33 847 children (mean [SD] age, 25.6 [18] months) in the placebo group were included. A mean (SD) of 90.1% (16.0%) of the censused children received the scheduled study drug in the azithromycin group and 89.8% (17.1%) received the scheduled study drug in the placebo group. In the azithromycin group, 498 deaths were recorded over 60 592 person-years (8.2 deaths/1000 person-years). In the placebo group, 588 deaths were recorded over 58 547 person-years (10.0 deaths/1000 person-years). The incidence rate ratio for mortality was 0.82 (95% CI, 0.67-1.02; P = .07) in the azithromycin group compared with the placebo group. The incidence rate ratio was 0.99 (95% CI, 0.72-1.36) in those aged 1 to 11 months, 0.92 (95% CI, 0.67-1.27) in those aged 12 to 23 months, and 0.73 (95% CI, 0.57-0.94) in those aged 24 to 59 months. Conclusions and Relevance: Mortality in children (aged 1-59 months) was lower with biannual mass azithromycin distribution in a setting in which seasonal malaria chemoprevention was also being distributed, but the difference was not statistically significant. The study may have been underpowered to detect a clinically relevant difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03676764.

Gut Microbiome Diversity and Antimicrobial Resistance After a Single Dose of Oral Azithromycin in Children: A Randomized Placebo-Controlled Trial.

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.

Azithromycin during Routine Well-Infant Visits to Prevent Death.

BACKGROUND: Mass distribution of azithromycin to children 1 to 59 months of age has been shown to reduce childhood all-cause mortality in some sub-Saharan African regions, with the largest reduction seen among infants younger than 12 months of age. Whether the administration of azithromycin at routine health care visits for infants would be effective in preventing death is unclear. METHODS: We conducted a randomized, placebo-controlled trial of a single dose of azithromycin (20 mg per kilogram of body weight) as compared with placebo, administered during infancy (5 to 12 weeks of age). The primary end point was death before 6 months of age. Infants were recruited at routine vaccination or other well-child visits in clinics and through community outreach in three regions of Burkina Faso. Vital status was assessed at 6 months of age. RESULTS: Of the 32,877 infants enrolled from September 2019 through October 2022, a total of 16,416 infants were randomly assigned to azithromycin and 16,461 to placebo. Eighty-two infants in the azithromycin group and 75 infants in the placebo group died before 6 months of age (hazard ratio, 1.09; 95% confidence interval [CI], 0.80 to 1.49; P = 0.58); the absolute difference in mortality was 0.04 percentage points (95% CI, -0.10 to 0.21). There was no evidence of an effect of azithromycin on mortality in any of the prespecified subgroups, including subgroups defined according to age, sex, and baseline weight, and no evidence of a difference between the two trial groups in the incidence of adverse events. CONCLUSIONS: In this trial conducted in Burkina Faso, we found that administration of azithromycin to infants through the existing health care system did not prevent death. (Funded by the Bill and Melinda Gates Foundation; CHAT ClinicalTrials.gov number, NCT03676764.).

Single-dose azithromycin for infant growth in Burkina Faso: Prespecified secondary anthropometric outcomes from a randomized controlled trial.

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

Distance to Health Centers and Effectiveness of Azithromycin Mass Administration for Children in Niger: A Secondary Analysis of the MORDOR Cluster Randomized Trial.

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.

Comparison of door-to-door and fixed-point delivery of azithromycin distribution for child survival in Niger: A cluster-randomized trial.

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.

Comprehensive Profile of Pathogens and Antimicrobial Resistance in Conjunctivitis Cases from Niger.

Infectious conjunctivitis outbreaks remain a public health burden. This study focuses on the pathogen and antimicrobial resistance (AMR) profiles identified in Niger. Sixty-two patients with acute infectious conjunctivitis who presented to health posts were enrolled from December 2021 to May 2022. Nasal and conjunctival swabs were obtained from each patient. Unbiased RNA deep sequencing (RNA-seq) was used to identify associated pathogens. A pathogen was identified in 39 patients (63%; 95% CI, 50-74). Of those, an RNA virus was detected in 23 patients (59%; 95% CI, 43-73). RNA viruses were diverse and included human coronaviruses (HCoVs): SARS-CoV-2, HCoV-229E, HCoV-HKU1, and HCoV-OC43. A DNA virus was identified in 11 patients (28%; 95% CI, 17-44). Of those, four patients had a coinfection with an RNA virus and two patients had a coinfection with both an RNA virus and a bacterium. DNA viruses were predominantly human herpesvirus (cytomegalovirus, Epstein-Barr virus, human herpesvirus 8) and human adenovirus species B, C, and F. Eighteen patients (46%; 95% CI, 32-61) had a bacteria-associated infection that included Haemophilus influenza, Haemophilus aegyptius, Staphylococcus aureus, Streptococcus pneumoniae, and Moraxella spp. Antimicrobial resistance determinants were detected in either the conjunctiva or nasal samples of 20 patients (32%; 95% CI, 22-45) and were found to be more diverse in the nose (Shannon alpha diversity, 1.12 [95% CI, 1.05-1.26] versus 1.02 [95% CI, 1.00-1.05], P = 0.01). These results suggest the potential utility of leveraging RNA-seq to surveil pathogens and AMR for ocular infections.

Temporal Trends in Phenotypic Macrolide and Nonmacrolide Resistance for Streptococcus pneumoniae Nasopharyngeal Samples Up to 36 Months after Mass Azithromycin Administration in a Cluster-Randomized Trial in Niger.

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 (ß = 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.

Anthropometric Differences in Community- Versus Clinic-Recruited Infants Participating in a Trial of Azithromycin for Prevention of Childhood Mortality in Burkina Faso.

Clinic-based recruitment for preventative interventions for child health may select for healthier populations compared with community-based outreach. Nutritional status during infancy as measured by anthropometry is predictive of mortality, growth faltering later in life, and poor cognitive development outcomes. We evaluated baseline differences in infant nutritional status among children recruited directly in their community versus clinic recruitment among infants participating in a trial of azithromycin compared with placebo for prevention of mortality in three districts of Burkina Faso. Infants between 5 and 12 weeks of age were recruited in their community of residence via vaccine outreach teams or in primary health-care clinics during vaccine clinics. Weight, height, and mid upper arm circumference were measured. We used linear and logistic regression models to compare anthropometric outcomes among community and clinic recruited infants, adjusting for age at enrollment, gender, and season. Among 32,877 infants enrolled in the trial, 21,273 (64.7%) were recruited via community outreach. Mean weight-for-age z-score (WAZ) was -0.60 ± 1.2 (SD), weight-for-length z-score (WLZ) was -0.16 ± 1.5, and length-for-age z-score was-0.53 ± 1.3. Infants enrolled in the community had lower WAZ (mean difference, -0.12; 95% CI, -0.20 to -0.04) and WLZ (mean difference, -0.21; 95% CI, -0.32 to -0.09). Community-recruited infants were more often underweight (WAZ < -2; odds ratio [OR], 1.25; 95% CI, 1.09-1.43) and wasted (WLZ < -2; OR, 1.54; 95% CI, 1.31-1.79). There was no evidence of a difference in height-based measures. Community and clinic recruitment likely reach different populations of children.

Comparison of Population-Based Census versus Birth History for the Estimation of Under-5 Mortality in Niger.

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.

Wastewater-Based Surveillance of Antimicrobial Resistance in Niger: An Exploratory Study.

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.

Infant mortality and growth failure after oral azithromycin among low birthweight and underweight neonates: A subgroup analysis of a randomized controlled trial.

BACKGROUND: Low birthweight (birthweight <2500 grams, g) and underweight (weight-for-age Z-score, WAZ, < -2) infants have higher risk of poor outcomes compared to their well-nourished peers. We evaluated the role of azithromycin for reducing mortality and improving growth outcomes in low birthweight and/or underweight infants. METHODS: Infants aged 8-27 days of age weighing ≥2500 g at enrollment in Burkina Faso were randomized 1:1 to a single, oral dose of azithromycin (20 mg/kg) or matching placebo. We evaluated mortality and anthropometric outcomes in four subgroups: 1) both low birthweight and underweight at enrollment; 2) low birthweight-only; 3) underweight-only; 4) neither low birthweight nor underweight. FINDINGS: Of 21,832 enrolled infants, 21,320 (98%) had birthweight measurements and included in this analysis. Of these, 747 (3%) were both low birthweight and underweight, 972 (5%) were low birthweight-only, 825 (4%) were underweight-only, and 18,776 (88%) were neither low birthweight nor underweight. Infants who were both low birthweight and underweight receiving azithromycin had lower odds of underweight at 6 months compared to placebo (OR 0.65, 95% CI 0.44 to 0.95), but the treatment group by subgroup interaction was not statistically significant (P = 0.06). We did not find evidence of a difference between groups for other outcomes in any subgroup. INTERPRETATION: Azithromycin may have some growth-promoting benefits for the highest risk infants, but we were unable to demonstrate a difference in most outcomes in low birthweight and underweight infants. As a secondary analysis of a trial, this study was underpowered for rare outcomes such as mortality. TRIAL REGISTRATION: ClinicalTrials.gov NCT03682653.

Neonatal Azithromycin Administration and Growth during Infancy: A Randomized Controlled Trial.

Observational studies have linked early-life antibiotic exposure to increased risk of obesity in children in high income settings. We evaluated whether neonatal antibiotic exposure led to changes in infant growth at 6 months of age in Burkina Faso. Neonates aged 8 to 27 days of age who weighed at least 2,500 g at the time of enrollment were randomized in a 1:1 fashion to a single oral 20-mg/kg dose of azithromycin or equivalent volume of placebo from April 2019 through December 2020. Weight, length, and mid-upper-arm circumference (MUAC) were measured at baseline and 6 months of age. Growth outcomes, including weight gain in grams per day, length change in millimeters per day, and changes in weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), length-for-age Z-score (LAZ), and MUAC were compared among neonates randomized to azithromycin compared with placebo. Among 21,832 neonates enrolled in the trial, median age at enrollment was 11 days, and 50% were female. We found no evidence of a difference in weight gain (mean difference -0.009 g/day, 95% confidence interval [CI]: -0.16 to 0.14, P = 0.90), length change (mean difference 0.003 mm/day, 95% CI: -0.002 to 0.007, P = 0.23), or WAZ (mean difference -0.005 SD, 95% CI: -0.03 to 0.02, P = 0.72), WLZ (mean difference -0.01 SD, 95% CI: -0.05 to 0.02, P = 0.39), LAZ (mean difference 0.01, 95% CI: -0.02 to 0.04, P = 0.47), or MUAC (mean difference 0.01 cm, 95% CI: -0.02 to 0.04, P = 0.49). These results do not suggest that azithromycin has growth-promoting properties in infants when administered during the neonatal period. Trial registration: ClinicalTrials.gov NCT03682653.

Influence of maternal age on birth and infant outcomes at 6 months: a cohort study with quantitative bias analysis.

BACKGROUND: Maternal age is increasingly recognized as a predictor of birth outcomes. Given the importance of birth and growth outcomes for children's development, wellbeing and survival, this study examined the effect of maternal age on infant birth and growth outcomes at 6 months and mortality. Additionally, we conducted quantitative bias analysis (QBA) to estimate the role of selection bias and unmeasured confounding on the effect of maternal age on infant mortality. METHODS: We used data from randomized-controlled trials (RCTs) of 21 555 neonates in Burkina Faso conducted in 2019-2020. Newborns of mothers aged 13-19 years (adolescents) and 20-40 years (adults) were enrolled in the study 8-27 days after birth and followed for 6 months. Measurements of child's anthropometric measures were collected at baseline and 6 months. We used multivariable linear regression to compare child anthropometric measures at birth and 6 months, and logistic regression models to obtain the odds ratio (OR) of all-cause mortality. Using multidimensional deterministic analysis, we assessed scenarios in which the difference in selection probability of adolescent and adult mothers with infant mortality at 6 months increased from 0% to 5%, 10%, 15% and 20% if babies born to adolescent mothers more often died during the first week or were of lower weight and hence were not eligible to be included in the original RCT. Using probabilistic bias analysis, we assessed the role of unmeasured confounding by socio-economic status (SES). RESULTS: Babies born to adolescent mothers on average had lower weight at birth, lower anthropometric measures at baseline, similar growth outcomes from enrolment to 6 months and higher odds of all-cause mortality by 6 months (adjusted OR = 2.17, 95% CI 1.35 to 3.47) compared with those born to adult mothers. In QBA, we found that differential selection of adolescent and adult mothers could bias the observed effect (OR = 2.24, 95% CI 1.41 to 3.57) towards the null [bias-corrected OR range: 2.37 (95% CI 1.49 to 3.77) to 2.84 (95% CI 1.79 to 4.52)], whereas unmeasured confounding by SES could bias the observed effect away from the null (bias-corrected OR: 2.06, 95% CI 1.31 to 2.64). CONCLUSIONS: Our findings suggest that delaying the first birth from adolescence to adulthood may improve birth outcomes and reduce mortality of neonates. Babies born to younger mothers, who are smaller at birth, may experience catch-up growth, reducing some of the anthropometric disparities by 6 months of age.

The Association between Malnutrition and Malaria Infection in Children under 5 Years in Burkina Faso: A Longitudinal Study.

The relationship between malaria infection and malnutrition is complex. Using data from a randomized controlled trial of 450 children 0-5 years of age in Burkina Faso, we examined the effect of malaria infection on short-term changes in anthropometric measures, the effect of malnutrition on malaria infection, and whether age modified the effect of baseline anthropometric measures on malaria infection. Malaria infection, assessed by blood smear microscopy and weight, height, mid-upper arm circumference, height-for-age z-score, weight-for-age z-score, and weight-for-height z-score were measured at three time points: baseline, 2 weeks, and 6 months. We used generalized estimating equations adjusted for sex, age, breastfeeding, maternal education, and study treatment (azithromycin versus placebo) for all analyses. Interaction terms were used to assess effect modification by age. Among the 366 children with no malaria infection at baseline, 43 (11.6%) had malaria infection within 6 months. There were no important differences in anthropometric measures at 2 weeks and 6 months between those with and without malaria infection at baseline. There were no significant differences in prevalence of malaria infection by baseline anthropometric measures. Age (0-30 months versus 30-60 months) modified the effect of baseline weight and height on malaria infection. Among those aged 0-30 months, for each kilogram increase in weight, malaria infection increased by 27% (95% CI: 6-53%), and for each centimeter increase in height, it increased by 9% (95% CI: 1-17%), but there were no differences for those aged 30-60 months.

Deep sequencing analysis of acute conjunctivitis in Burkina Faso, Africa.

BACKGROUND: Seasonal and epidemic conjunctivitis (pink eye) infections are highly contagious and impose a significant economic burden worldwide. Long-term visual impairment can occur. METHODS: This study used metagenomic deep sequencing to evaluate pathogens causing acute infectious conjunctivitis in Burkina Faso. RESULTS: We found that pathogens causing conjunctivitis in Burkina Faso are diverse, with human adenoviruses responsible for a small fraction of the samples tested. CONCLUSIONS: These results are unexpected and suggest the importance of regional surveillance.

Gut Microbiome among Children with Uncomplicated Severe Acute Malnutrition in a Randomized Controlled Trial of Azithromycin versus Amoxicillin.

Antibiotics are routinely used as part of the management of severe acute malnutrition and are known to reduce gut microbial diversity in non-malnourished children. We evaluated gut microbiomes in children participating in a randomized controlled trial (RCT) of azithromycin versus amoxicillin for severe acute malnutrition. Three hundred one children aged 6 to 59 months with uncomplicated severe acute malnutrition (mid-upper arm circumference < 11.5 cm and/or weight-for-height Z-score < -3 without clinical complications) were enrolled in a 1:1 RCT of single-dose azithromycin versus a 7-day course of amoxicillin (standard of care). Of these, 109 children were randomly selected for microbiome evaluation at baseline and 8 weeks. Rectal swabs were processed with metagenomic DNA sequencing. We compared alpha diversity (inverse Simpson's index) at 8 weeks and evaluated relative abundance of microbial taxa using DESeq2. Of 109 children enrolled in the microbiome study, 95 were followed at 8 weeks. We found no evidence of a difference in alpha diversity between the azithromycin and amoxicillin groups at 8 weeks controlling for baseline diversity (mean difference -0.6, 95% CI -1.8 to 0.6, P = 0.30). Gut microbiomes did not diversify during the study. Differentially abundant genera at the P < 0.01 level included Salmonella spp. and Shigella spp., both of which were overabundant in the azithromycin compared with amoxicillin groups. We found no evidence to support an overall difference in gut microbiome diversity between azithromycin and amoxicillin among children with uncomplicated severe acute malnutrition, but potentially pathogenic bacteria that can cause invasive diarrhea were more common in the azithromycin group. Trial Registration: ClinicalTrials.gov NCT03568643.