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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, P.sub.unadj < 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, P.sub.adj = 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, P.sub.adj = 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., Author(s): Ahmed M. Arzika 1, Amza Abdou 1, Ramatou Maliki 1, Nassirou Beido 1, Boubacar Kadri 1, Abdoul N. Harouna 1, Abdoul N. Galo 1, Mankara K. Alio 1, Elodie [...]

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, Author(s): Ali Sié 1,2,*, Mamadou Ouattara 1, Mamadou Bountogo 1, Clarisse Dah 1, Thierry Ouedraogo 1, Valentin Boudo 1, Elodie Lebas 2, Huiyu Hu 2, Benjamin F. Arnold 2,3,4, Kieran [...]

Background: Trachoma programs use the indicator trachomatous inflammation-—follicular (TF) to monitor indication for and response to treatment for trachoma at the district level. Alternative indicators, including serologic markers, are increasingly being evaluated for trachoma surveillance. We evaluated seroprevalence of IgG antibodies to the Pgp3 antigen in two districts in Maradi, Niger thought to have low TF prevalence. Methods: Data were collected as part of the baseline assessment of the Azithromycin Reduction to Reach Elimination of Trachoma (ARRET) trial in September 2021. A random sample of 80 communities was selected from Mayahi and Guidan Roumdji districts, both of which had TF prevalence <20% at their most recent trachoma impact survey in 2018. A random sample of 50 children per community was sampled. We collected field grades, conjunctival swabs for processing PCR for ocular Chlamydia trachomatis, and dried blood spots for serologic assessment. Results: Of 3,994 children sampled in 80 communities, 49% were female and median age was 4 years. Overall TF prevalence was 4.6% (95% CI 3.5 to 5.8%) and trachomatous inflammation—intense (TI) prevalence was 0.6% (95% 0.3 to 0.9%). The prevalence of ocular chlamydia was 0.03% (95% CI 0.08%). Seroprevalence for Pgp3 antibodies was 6.3% (95% CI 5.5 to 7.1%) in 1–9-year-olds and 3.7% (95% CI 2.9 to 4.4%) in 1–5-year-olds. TF and Pgp3 seroprevalence were better correlated in 1–5-year-olds (correlation coefficient 0.29) compared to 1–9-year-olds (correlation coefficient 0.09). Conclusions: In this low trachoma prevalence setting in Niger, seroprevalence of antibodies to Pgp3 were consistent with little ongoing transmission of C. trachomatis. Author summary: Trachoma is the leading cause of infectious blindness globally and is caused by the bacteria Chlamydia trachomatis. Trachoma programs use the indicator trachomatous inflammation—follicular (TF) to monitor the progress of trachoma control efforts in endemic regions. However, TF is an imperfect indicator of trachoma transmission, and alternative indicators may be useful for monitoring trachoma. We evaluated the prevalence of TF, C. trachomatis as measured by PCR, and serologic markers of trachoma in an area of Niger with low prevalence of TF. We found little evidence of ongoing transmission of C. trachomatis, as evidenced by low prevalence of C. trachomatis and low seroprevalence of trachoma markers, suggesting that ongoing antibiotic distribution for trachoma may not be required in this region. [ABSTRACT FROM AUTHOR]

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 aimed to understand the risk of spillover of antibiotic resistance to nontarget groups in these programs. Methods Data were used from a cluster-randomized trial comparing the effects of biannual azithromycin and placebo distribution to children 1–59 months old on child mortality rates. 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 time point, adjusting for baseline prevalence. Results A total of 1103 children 7–12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). The adjusted mean differences in the prevalence of resistance determinants for macrolides, β-lactams, and tetracyclines were 3.4% (95% confidence interval, −4.1% to 10.8%; P =.37), −1.2% (−7.9% to 5.5%; P =.72), and −3.3% (−9.5% to 2.8%; P =.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 quantify the potential for spillover effects within these programs. [ABSTRACT FROM AUTHOR]

Objectives: A 6‐week course of tetracycline eye ointment is an alternative to single ‐dose oral azithromycin in annual mass drug administration for trachoma control. Compliance with the recommended tetracycline eye ointment regimen has not been well characterised when administered as part of a trachoma control program. Methods: A routine mass drug administration for trachoma was carried out in 40 communities in the Amhara region of Ethiopia. Two tubes of tetracycline eye ointment, to be administered twice daily for 6 weeks, was offered to all children under 6 months of age, to pregnant women who declined to take azithromycin, and to all individuals with a macrolide allergy. Seven weeks following the mass drug administration, a treatment compliance survey was performed for all community members documented to have received tetracycline eye ointment during the mass drug administration. Results: Of the 491 individuals documented as having received tetracycline eye ointment from the treatment records, 367 completed the survey, of which 214 recalled being offered tetracycline eye ointment. A total of 105 (49%) respondents reported taking ≥1 daily dose of tetracycline eye ointment on most days of the week for at least the first week. Only 20 (9%) respondents reported taking at least 1 tetracycline eye ointment dose per week for 6 weeks. The most common reasons for low compliance included 'saving it for a future infection' and 'stopped because I (or my child) seemed healthy'. The odds of low compliance were greater for those who reported not having adequate counselling (e.g., odds ratio [OR] 5.3, 95% CI 2.5–28.9 when low compliance was defined as not taking a tetracycline eye ointment dose for most days of at least the first week). Conclusions: Compliance with tetracycline eye ointment was low when administered by a trachoma program during a routine mass drug administration, especially for those reporting inadequate counselling. Further research with a larger sample size and varied settings is warranted to better understand and improve compliance. [ABSTRACT FROM AUTHOR]

Objective To determine whether a water, sanitation and hygiene intervention could change hygiene behaviours thought to be important for trachoma control. Methods We conducted a cluster-randomized trial in rural Ethiopia from 9 November 2015 to 5 March 2019. We randomized 20 clusters to an intervention consisting of water and sanitation infrastructure and hygiene promotion and 20 clusters to no intervention. All intervention clusters received a primary-school hygiene curriculum, community water point, household wash station, household soap and home visits from hygiene promotion workers. We assessed intervention fidelity through annual household surveys. Findings Over the 3 years, more wash stations, soap and latrines were seen at households in the intervention clusters than the control clusters: risk difference 47 percentage points (95% confidence interval, CI: 41- 53) for wash stations, 18 percentage points (95% CI: 12-24) for soap and 12 percentage points (95% CI: 5-19) for latrines. A greater proportion of people in intervention clusters reported washing their faces with soap (e.g. risk difference 21 percentage points; 95% CI: 15-27 for 0- 5 year-old children) and using a latrine (e.g. risk difference 9 percentage points; 95% CI: 2-15 for 6-9 year-old children). Differences between the intervention and control arms were not statistically significant for many indicators until the programme had been implemented for at least a year; they did not decline during later study visits. Conclusion The community- and school-based intervention was associated with improved hygiene access and behaviours, although changes in behaviour were slow and required several years of the intervention. Objectif Determiner si une intervention au niveau de l'eau, de l'assainissement et de 1'hygiene pourrait avoir une influence sur les comportements en la matiere, consideres comme importants dans la lutte contre le trachome. Methodes Nous avons mene un essai randomise par grappes dans les regions rurales d'Ethiopie entre le 9 novembre 2015 et le 5 mars 2019. Nous avons reparti aleatoirement 20 echantillons ou l'intervention consistait a developper les infrastructures d'assainissement et d'approvisionnement en eau et a promouvoir l'hygiene, et 20 echantillons n'ayant fait l'objet d'aucune intervention. Tous les echantillons du groupe d'intervention ont suivi une formation sur l'hygiene a l'ecole primaire, disposaient d'un point d'eau communautaire, d'un poste de lavage par menage, de savon a domicile, et recevaient des visites de la part de travailleurs charges d'enseigner les bonnes pratiques en matiere d'hygiene. Nous avons evalue le niveau d'observance des mesures en effectuant des enquetes annuelles au sein des foyers. Resultats En l'espace de 3 ans, le nombre de postes de lavage, de savons et de latrines dans les menages a davantage augmente dans le groupe d'intervention que dans le groupe de controle: la difference de risque s'elevait a 47 points de pourcentage (intervalle de confiance de 95%, IC: 41-53) pour les postes de lavage, a 18 points de pourcentage (IC de 95%: 12-24) pour le savon et a 12 points de pourcentage (IC de 95%: 5-19) pour les latrines. La proportion de gens declarant se laver le visage au savon etait plus grande dans le groupe d'intervention (difference de risque de 21 points de pourcentage; IC de 95%: 15-27 pour les enfants de 0 a 5 ans), tout comme celle mentionnant l'usage de latrines (difference de risque de 9 points de pourcentage; IC de 95%: 2-15 pour les enfants de 6 a 9 ans). Pour de multiples indicateurs, il a fallu attendre minimum un an apres l'instauration du programme pour que les variations observees entre les groupes d'intervention et de controle deviennent statistiquement significatives; ces variations se sont ensuite maintenues lors des visites ulterieures. Conclusion Intervenir a l'ecole et au sein de la communaute a permis d'ameliorer l'acces a l'hygiene et les comportements en la matiere. Neanmoins, cette evolution prend du temps et plusieurs annees d'intervention sont necessaires. Objetivo Determinar si una intervencion de agua, saneamiento e higiene cambiaria las practicas de higiene que se consideran importantes para el control del tracoma. Metodos Se realizo un ensayo aleatorizado por grupos en zonas rurales de Etiopia del 9 de noviembre de 2015 al 5 de marzo de 2019. Se asignaron de manera aleatoria 20 grupos a una intervencion que consistia en infraestructura de agua y saneamiento y promocion de la higiene, y 20 grupos a ninguna intervencion. Todos los grupos de intervencion recibieron un programa educativo sobre higiene en la escuela primaria, un punto de abastecimiento de agua en la comunidad, una estacion de lavado en el hogar, jabon en el hogar y visitas a domicilio de profesionales dedicados a la promocion de la higiene. Se evaluo la fidelidad de la intervencion mediante encuestas anuales en los hogares. Resultados Durante los tres anos, se observaron mas estaciones de lavado, jabon y letrinas en los hogares de los grupos de intervencion que en los de control: diferencia de riesgo de 47 puntos porcentuales (intervalo de confianza del 95 %, IC: entre 41 y 53) para las estaciones de lavado, 18 puntos porcentuales (IC del 95 %: entre 12 y 24) para el jabon y 12 puntos porcentuales (IC del 95 %: entre 5 y 19) para las letrinas. Un mayor porcentaje de personas en los grupos de intervencion informo de que se lavaba la cara con jabon (p. ej., diferencia de riesgo de 21 puntos porcentuales; IC del 95 %: entre 15 y 27; para ninos de 0 a 5 anos) y de que usaba una letrina (p. ej., diferencia de riesgo de 9 puntos porcentuales; IC del 95 %: entre 2 y 15; para ninos de 6 a 9 anos). Las diferencias entre los grupos de intervencion y de control no fueron significativas desde el punto de vista estadistico para muchos indicadores hasta que el programa se ejecuto durante al menos un ano; tampoco disminuyeron durante las visitas posteriores del estudio. Conclusion La intervencion en la comunidad y en la escuela se asocio a una mejora del acceso y de las practicas de higiene, aunque los cambios en las practicas fueron lentos y necesitaron varios anos de intervencion., Introduction The World Health Organization recommends improvements in water sources and promotion of facial cleanliness for trachoma elimination. (1) However, very few randomized trials have assessed whether hygiene interventions targeted [...]

Monitoring trachoma transmission with antibody data requires characterization of decay in IgG to Chlamydia trachomatis antigens. In a 3-year longitudinal cohort in a high-transmission setting, we estimated a median IgG half-life of 3 years and a seroreversion rate of 2.5 per 100 person-years (95% confidence interval, 1.6–3.5). Clinical Trials Registration NCT02754583. [ABSTRACT FROM AUTHOR]

Background: Promotion of facial cleanliness is recommended for the elimination of blinding trachoma, largely because of observational studies that have found an association between various measures of facial uncleanliness and trachoma. However, when a field grader assesses both facial cleanliness and trachoma, associations may be biased. Assessment of photographs of the face and conjunctiva by masked graders may provide a less biased estimate of the relationship between facial cleanliness and trachoma. Methods: Face photographs, conjunctival photographs, and conjunctival swabs were obtained on a random sample of 0–9-year-old children from each of 40 communities in Amhara region, Ethiopia. Face photographs were assessed for the presence of seven measures of an unclean face (i.e., wet nasal discharge, dry nasal discharge, wet ocular discharge, dry ocular discharge, food, dust/dirt, and flies) by three independent masked photo-graders. Conjunctival photographs were similarly graded in a masked fashion for signs of clinically active trachoma. Conjunctival swabs were processed for Chlamydia trachomatis DNA. Results: Of 2073 children with complete data, 808 (39%) had evidence of clinically active trachoma, 150 (7%) had evidence of ocular chlamydia infection, and 2524 (91%) had at least one measure of an unclean face. Dry ocular discharge had the strongest association with clinically active trachoma (age- and sex-adjusted prevalence ratio [PR] 1.4, 95% CI 1.2–1.6) and ocular chlamydia infection (PR 1.9, 95%CI 1.3–2.9), although significant associations were observed between each of the measures of facial uncleanliness and trachoma. Conclusions: Masked assessment of face and conjunctival photographs confirmed prior observational studies that have noted associations between various measures of facial uncleanliness and trachoma. The causal relationship between facial uncleanliness and trachoma is unclear since many features used to measure facial cleanliness (e.g., ocular discharge, nasal discharge, and flies) could be consequences of antecedent ocular chlamydia infection. Trial registration: NCT02754583, clinicaltrials.gov. Author summary: We graded face and eye photographs from children in Ethiopia to characterize the relationship between seven measures of an unclean face and several trachoma outcomes. Dry ocular discharge had the strongest associations with trachoma outcomes, and there was a dose-dependent relationship between the seven facial uncleanliness measures and trachoma. Moreover, using a composite measure of facial uncleanliness, such as the presence of nasal discharge, ocular discharge, or flies, had even stronger associations with trachoma. However, it is difficult to determine the importance of these measures of facial uncleanliness as risk factors for trachoma since ocular chlamydia infection can cause ocular discharge and potentially nasal discharge, each of which may in turn attract flies. [ABSTRACT FROM AUTHOR]