170 research outputs found

    Linear growth in preschool children treated with mass azithromycin distributions for trachoma: A cluster-randomized trial.

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    BackgroundMass azithromycin distributions have been shown to reduce mortality among pre-school children in sub-Saharan Africa. It is unclear what mediates this mortality reduction, but one possibility is that antibiotics function as growth promoters for young children.Methods and findings24 rural Ethiopian communities that had received biannual mass azithromycin distributions over the previous four years were enrolled in a parallel-group, cluster-randomized trial. Communities were randomized in a 1:1 ratio to either continuation of biannual oral azithromycin (20mg/kg for children, 1 g for adults) or to no programmatic antibiotics over the 36 months of the study period. All community members 6 months and older were eligible for the intervention. The primary outcome was ocular chlamydia; height and weight were measured as secondary outcomes on children less than 60 months of age at months 12 and 36. Study participants were not masked; anthropometrists were not informed of the treatment allocation. Anthropometric measurements were collected for 282 children aged 0-36 months at the month 12 assessment and 455 children aged 0-59 months at the month 36 assessment, including 207 children who had measurements at both time points. After adjusting for age and sex, children were slightly but not significantly taller in the biannually treated communities (84.0 cm, 95%CI 83.2-84.8, in the azithromycin-treated communities vs. 83.7 cm, 95%CI 82.9-84.5, in the untreated communities; mean difference 0.31 cm, 95%CI -0.85 to 1.47, P = 0.60). No adverse events were reported.ConclusionsPeriodic mass azithromycin distributions for trachoma did not demonstrate a strong impact on childhood growth.Trial registrationThe TANA II trial was registered on clinicaltrials.gov #NCT01202331

    Effect of Mass Azithromycin Distributions on Childhood Growth in Niger: A Cluster-Randomized Trial.

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

    Biannual azithromycin distribution and child mortality among malnourished children: A subgroup analysis of the MORDOR cluster-randomized trial in Niger.

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

    Mass Azithromycin Distribution to Prevent Childhood Mortality: A Pooled Analysis of Cluster-Randomized Trials.

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

    The efficacy of oral azithromycin in clearing ocular chlamydia: mathematical modeling from a community-randomized trachoma trial.

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    Mass oral azithromycin distributions have dramatically reduced the prevalence of the ocular strains of chlamydia that cause trachoma. Assessing efficacy of the antibiotic in an individual is important in planning trachoma elimination. However, the efficacy is difficult to estimate, because post-treatment laboratory testing may be complicated by nonviable organisms or reinfection. Here, we monitored ocular chlamydial infection twice a year in pre-school children in 32 communities as part of a cluster-randomized clinical trial in Tanzania (prevalence in children was lowered from 22.0% to 4.7% after 3-year of annual treatment). We used a mathematical transmission model to estimate the prevalence of infection immediately after treatment, and found the effective field efficacy of antibiotic in an individual to be 67.6% (95% CI: 56.5-75.1%) in this setting. Sensitivity analyses suggested that these results were not dependent on specific assumptions about the duration of infection. We found no evidence of decreased efficacy during the course of the trial. We estimated an 89% chance of elimination after 10 years of annual treatment with 95% coverage

    Comparison of anthropometric indicators to predict mortality in a population-based prospective study of children under 5 years in Niger.

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    OBJECTIVE: In the present study, we aimed to compare anthropometric indicators as predictors of mortality in a community-based setting. DESIGN: We conducted a population-based longitudinal study nested in a cluster-randomized trial. We assessed weight, height and mid-upper arm circumference (MUAC) on children 12 months after the trial began and used the trial's annual census and monitoring visits to assess mortality over 2 years. SETTING: Niger. PARTICIPANTS: Children aged 6-60 months during the study. RESULTS: Of 1023 children included in the study at baseline, height-for-age Z-score, weight-for-age Z-score, weight-for-height Z-score and MUAC classified 777 (76·0 %), 630 (61·6 %), 131 (12·9 %) and eighty (7·8 %) children as moderately to severely malnourished, respectively. Over the 2-year study period, fifty-eight children (5·7 %) died. MUAC had the greatest AUC (0·68, 95 % CI 0·61, 0·75) and had the strongest association with mortality in this sample (hazard ratio = 2·21, 95 % CI 1·26, 3·89, P = 0·006). CONCLUSIONS: MUAC appears to be a better predictor of mortality than other anthropometric indicators in this community-based, high-malnutrition setting in Niger

    Azithromycin mass drug administration for reducing child mortality in Malawi.

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    BACKGROUND: Child mortality has decreased considerably in recent years but more than one in ten children still die before their fifth birthday in several African countries. The MORDOR study investigated whether azithromycin mass drug administration (MDA) reduces child mortality in three countries in Africa. The study described within this thesis was conducted at the MORDOR-Malawi site and aims to provide additional detail on potential mechanisms of effect of the intervention; macrolide resistance; and cost-effectiveness. METHODS: The study involved cluster randomisation of communities in Mangochi District, Malawi, to biannual azithromycin or placebo MDA. Household visits were conducted to update the census and perform verbal autopsies (VAs) to assess causes of death. Indicators related to healthcare access; malaria risk; and water, sanitation and hygiene were measured. Nasopharyngeal samples were collected to assess macrolide resistance. Cost data were collected for one complete round of fieldwork. RESULTS: The study included 334 clusters. The mortality rate ratio in azithromycin-treated compared to placebo-treated communities was 0.91 (95%CI: 0.79–1.05); P=0.20. There was evidence for an effect of the intervention in infants aged 1-5 months: 0.70 (95%CI: 0.50-0.99); P=0.04; but not in older age groups. The VA analyses suggested possible effects on pneumonia, HIV/AIDS and diarrhoea mortality. The intervention was highly cost-effective according to the WHO’s willingness-to-pay thresholds, costing $898 per death averted. At the 12-month and 24-month follow-up rounds, macrolide resistance in Streptococcus pneumoniae was higher in the azithromycin group compared to placebo. CONCLUSION: The mortality findings at the MORDOR-Malawi site could be explained by the broad spectrum of activity of azithromycin against gut and respiratory organisms, including non-vaccine pneumococcal serotypes and other aetiological causes of pneumonia, sepsis and meningitis. Azithromycin MDA is a feasible short-term intervention to reduce child mortality, whilst longer term sustainable health system improvements are pursued. Vigilance of antibiotic resistance is required

    Characterization of the fecal microbiota of rural Malawian children, associations with biomarkers of environmental enteric dysfunction and the impact of a mass drug administration program

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    Environmental Enteric Dysfunction (EED) is a subclinical condition of the gut characterized by changes in gut morphology and function with underlying chronic inflammatory responses. EED affects more than two-thirds of young children living in low-income settings. EED has been linked with growth faltering in young children living in low-income settings, however, the mechanisms by which EED impacts growth are not well defined. A proposed pathway suggests that ingestion of enteric pathogens and toxins, through contaminated food and water, changes gut microbiota composition and function. This results in intestinal inflammation and changes in the intestinal epithelium structure. There is limited data examining the association between the gut microbiota and EED. The present work was nested in a cluster-randomized trial of mass drug administration of azithromycin and was carried out to characterize composition and diversity of the gut microbiota in rural Malawian children with and without signs of EED. The work also tested for associations between the gut microbiota and stunting. Proteins were extracted from fecal samples and used for the quantification, by ELISA, of neopterin, myeloperoxidase and alpha-1 antitrypsin, which are biomarkers of intestinal inflammation and permeability that have been proposed as potential proxies of EED. Concentrations of the three biomarkers were combined to form a proxy EED score using principal component analysis. Total genomic DNA was also extracted from the fecal samples for V4-16SrRNA sequencing and for species-specific PCR to determine intestinal carriage of bacteria that have previously been shown to be associated with growth in a mouse model. All three biomarkers decreased with age. Faecalibacterium prausnitzii and Dorea formicigenerans were prevalent in over 70% of children while Bifidobacterium longum was the least prevalent of the bacteria assayed. No associations were found between fecal biomarkers of EED or intestinal bacteria carriage and stunting, however, intestinal carriage of D. formicigenerans was associated with normal biomarker concentration. Increased fecal microbiota diversity was associated with a reduction in neopterin concentration. Increased abundance of Succinivibrio was associated with reduced EED scores. Mass treatment with azithromycin appeared to have no long-term impact on alpha diversity of fecal samples but was weakly associated with increased abundance of Prevotella at 24-months follow-up. A negative correlation between age and the three biomarkers of EED was found and confirms trends shown in other children living in similar low-income settings. The association between D. formicigenerans and normal biomarker concentration suggests a potential beneficial role of the bacterium in gut health. An increase in microbiota diversity is potentially associated with reduced intestinal inflammation, but larger studies are needed to confirm this. The association between Succinivibrio and biomarkers of EED shown here is consistent with recent data from another study conducted in Malawi. Succinivibrio plays a role in fiber-degradation and metabolites of fiber-degradation have been shown to inhibit intestinal colonization by pathogenic bacteria, therefore, further studies are needed to investigate the significance of this bacterium in EED. Mass treatment with azithromycin may have long-lasting effects on the abundance of defined bacterial taxa but not overall microbiota diversity

    The impact of antibiotics on growth in children in low and middle income countries: systematic review and meta-analysis of randomised controlled trials

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    Objectives To determine whether antibiotic treatment leads to improvements in growth in prepubertal children in low and middle income countries, to determine the magnitude of improvements in growth, and to identify moderators of this treatment effect.Design Systematic review and meta-analysis.Data sources Medline, Embase, Scopus, the Cochrane central register of controlled trials, and Web of Science.Study selection Randomised controlled trials conducted in low or middle income countries in which an orally administered antibacterial agent was allocated by randomisation or minimisation and growth was measured as an outcome. Participants aged 1 month to 12 years were included. Control was placebo or non-antimicrobial intervention.Results Data were pooled from 10 randomised controlled trials representing 4316 children, across a variety of antibiotics, indications for treatment, treatment regimens, and countries. in random effects models, antibiotic use increased height by 0.04 cm/month (95% confidence interval 0.00 to 0.07) and weight by 23.8 g/month (95% confidence interval 4.3 to 43.3). After adjusting for age, effects on height were larger in younger populations and effects on weight were larger in African studies compared with other regions.Conclusion Antibiotics have a growth promoting effect in prepubertal children in low and middle income countries. This effect was more pronounced for ponderal than for linear growth. the antibiotic growth promoting effect may be mediated by treatment of clinical or subclinical infections or possibly by modulation of the intestinal microbiota. Better definition of the mechanisms underlying this effect will be important to inform optimal and safe approaches to achieving healthy growth in vulnerable populations.Vanier Canada Graduate ScholarshipMcGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, CanadaZvitambo Inst Maternal Child Hlth Res, Harare, ZimbabweQueen Mary Univ London, Blizard Inst, Ctr Paediat, London, EnglandMRC, Clin Trials Unit, London, EnglandJohns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USACornell Univ, Div Nutr Sci, Program Int Nutr, Ithaca, NY 14853 USAWashington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USAUniv Malawi, Blantyre, MalawiUniv Cambridge, Dept Archaeol & Anthropol, Div Biol Anthropol, Cambridge CB2 1TN, EnglandUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilUniv British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, CanadaUniversidade Federal de São Paulo, Escola Paulista Med, São Paulo, BrazilWeb of Scienc
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