Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial.
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ABSTRACT:
SUBMITTER: Porco TC
PROVIDER: S-EPMC6541729 | biostudies-literature | 2019 May
REPOSITORIES: biostudies-literature
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Mass Oral Azithromycin for Childhood Mortality: Timing of Death After Distribution in the MORDOR Trial.
Porco Travis C TC Hart John J Arzika Ahmed M AM Weaver Jerusha J Kalua Khumbo K Mrango Zakayo Z Cotter Sun Y SY Stoller Nicole E NE O'Brien Kieran S KS Fry Dionna M DM Vanderschelden Benjamin B Oldenburg Catherine E CE West Sheila K SK Bailey Robin L RL Keenan Jeremy D JD Lietman Thomas M TM
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20190501 12
In a large community-randomized trial, biannual azithromycin distributions significantly reduced postneonatal childhood mortality in sub-Saharan African sites. Here, we present a prespecified secondary analysis showing that much of the protective effect was in the first 3 months postdistribution. Distributing more frequently than biannually could be considered if logistically feasible. Clinical Trials Registration. NCT02047981. ...[more]
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Project description:We examined whether baseline mortality risk, as a function of child age and site, modified the azithromycin mortality-reduction effect in the Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) clinical trial. We used the Cox proportional hazards model with an interaction term. Three models were examined representing three sources for the baseline-risk covariate: two using sources external to MORDOR and the third leveraging data within MORDOR. All three models provided moderate evidence for the effect becoming stronger with increasing baseline mortality (P = 0.02, 0.02, and 0.07, respectively) at the rate of approximately 6-12% additional mortality reduction per doubling of baseline mortality. Etiological and programmatic implications of these findings are discussed.
| S-EPMC7470539 | biostudies-literature
Project description:Recent evidence indicates mass drug administration with azithromycin may reduce child mortality. This study uses verbal autopsy (VA) to investigate the causes of individual deaths during the Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) trial in Malawi. Cluster randomization was performed as part of MORDOR. Biannual household visits were conducted to distribute azithromycin or placebo to children aged 1-59 months and update the census to identify deaths for VA. MORDOR was not powered to investigate mortality effects at individual sites, but the available evidence is presented here for hypothesis generation regarding the mechanism through which azithromycin may reduce child mortality. Automated VA analysis was performed to infer the likely cause of death using two major analysis programs, InterVA and SmartVA. A total of 334 communities were randomized to azithromycin or placebo, with more than 130,000 person-years of follow-up. During the study, there were 1,184 deaths, of which 1,131 were followed up with VA. Mortality was 9% lower in azithromycin-treated communities than in placebo communities (rate ratio 0.91 [95% CI: 0.79-1.05]; P = 0.20). The intention-to-treat analysis by cause using InterVA suggested fewer HIV/AIDS deaths in azithromycin-treated communities (rate ratio 0.70 [95% CI: 0.50-0.97]; P = 0.03) and fewer pneumonia deaths (rate ratio 0.82 [95% CI: 0.60-1.12]; P = 0.22). The use of the SmartVA algorithm suggested fewer diarrhea deaths (rate ratio 0.71 [95% CI: 0.51-1.00]; P = 0.05) and fewer pneumonia deaths (rate ratio 0.58 [95% CI: 0.33-1.00]; P = 0.05). Although this study is not able to provide strong evidence, the data suggest that the mortality reduction during MORDOR in Malawi may have been due to effects on pneumonia and diarrhea or HIV/AIDS mortality.
| S-EPMC7470551 | biostudies-literature
Project description:BackgroundBiannual 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 findingsA 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.ConclusionsAlthough 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 registrationThe MORDOR trial is registered at clinicaltrials.gov NCT02047981.
| S-EPMC7491708 | biostudies-literature
Project description:BACKGROUND:Mass distributions of azithromycin for trachoma have been associated with secondary benefits, including reductions in child mortality. METHODS:In the Partnership for the Rapid Elimination of Trachoma cluster-randomized trial in Niger, 24 communities were randomized to annual treatment of everyone and 24 communities were randomized to biannual treatment of children under 12 for 3 years (clinicaltrials.gov, NCT00792922). Treatment was a single dose of directly observed oral azithromycin (20?mg/kg up to 1?g in adults). Vital status was assessed during annual census and monitoring visits. In this prespecified secondary analysis, we compared the mortality rate among children 6 months to less than 5 years of age by treatment arm using negative binomial regression. RESULTS:Among children 6 months to less than 5 years of age, 404 deaths occurred during the study period. The mortality rate was 35.6 deaths per 1000 person-years (231 deaths, 95% CI: 30.9-40.9) in the annual arm and 29.0 deaths per 1000 person-years (173 deaths, 95% CI: 24.8-33.8) in the biannual arm. The mortality rate ratio comparing children in the biannual arm to the annual arm was 0.81 (95% CI: 0.66-1.00, P = 0.07; primary outcome). The mortality rate ratio comparing children who died from infectious causes in the biannual arm to the annual arm was 0.73 (95% CI: 0.57-0.94; P = 0.02). No adverse events were reported. CONCLUSIONS:This secondary analysis of a cluster-randomized trial found a nonsignificant 19% decrease in mortality among children 6 months to less than 5 years of age who received biannual azithromycin compared with children who received annual azithromycin. This study was conducted in a high mortality, trachoma-endemic area; thus, results may be specific to this environment only. In addition, the trial was neither designed nor powered to detect a mortality effect, and we cannot rule out the possibility that mortality differences resulted from bias.
| S-EPMC6138579 | biostudies-literature
Project description:A cluster-randomized trial demonstrated that mass oral azithromycin distribution reduced childhood mortality 49.6% (Trachoma Amelioration in Northern Amhara [TANA]). The relative risk of childhood mortality was then estimated using two approaches: an expert survey and a Bayesian analysis. The survey asked public health experts to estimate the true effect of mass azithromycin distribution on childhood mortality. The Bayesian estimation used the TANA study's results and prior estimates of the efficacy of other effective population-level interventions. The experts believed mass azithromycin reduces childhood mortality (relative risk = 0.83, 95% credible intervals [CrI] = 0.70-1.00). The Bayesian analysis estimated a relative risk of 0.71 (95% CrI = 0.39-0.93). Both estimates suggest that azithromycin may have a true mortality benefit, though of a smaller magnitude than found in the single available trial. Prior information about nonantibiotic, population-level interventions may have informed the expert's opinions. Additional trials are needed to confirm a mortality benefit from mass azithromycin.
| S-EPMC4703272 | biostudies-literature
Project description:The Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance study showed that administration of biannual, single-dose azithromycin to preschool children reduces mortality. We sought to evaluate its impact on azithromycin resistance. Thirty randomly selected communities in Kilosa district, Tanzania, were randomized to receive 6-monthly single-dose azithromycin (?20 mg/kg) versus placebo treatment of children aged 1-59 months. From each community, 40 children (aged 1-59 months) were randomly selected at baseline, 12 and 24 months. Isolation and resistance testing of Streptococcus pneumoniae and Escherichia coli were evaluated using nasopharyngeal and rectal swabs, respectively. The carriage prevalence and the proportion of azithromycin-resistant isolates were determined using disk diffusion. At baseline, the characteristics of the randomly selected children were similar by treatment arms. Both at baseline and in annual cross-sectional surveys, rates of S. pneumoniae and E. coli isolation between treatment arms were similar. The proportions of azithromycin-resistant S. pneumoniae isolates in the children in communities treated with azithromycin versus placebo at baseline, 12 months, and 24 months were 26.5% (18.1%; P = 0.26), 26.8% (16.5%; P = 0.29), and 13.4% (17.0%; P = 0.57), respectively. The proportions of azithromycin-resistant E. coli isolates at baseline, 12 months, and 24 months in the azithromycin (versus placebo) arms were 14.9% (18.9%; P = 0.16), 21.5% (16.6%; P = 0.10), and 14.9% (14.7%; P = 0.95), respectively. Over the 24 months, the mean treatment coverage for the azithromycin and placebo was 76.9% and 74.8%, respectively (P = 0.49). Biannual administration of single-dose azithromycin to children did not appear to result in excess azithromycin resistance in S. pneumoniae and E. coli isolates over 24 months of follow-up.
| S-EPMC7470586 | biostudies-literature
Project description:Mass azithromycin distributions are used to clear ocular strains of chlamydia that cause trachoma, but treatments may also affect respiratory infections, diarrhea, and malaria. Here, we monitor a large cohort in which almost 90% of individuals received azithromycin. We assess whether receiving treatment is associated with reduced all-cause and infectious childhood mortality.As part of a clinical trial for trachoma, a census was conducted in 24 communities in rural Ethiopia. All individuals ?1 year of age were eligible for single-dose oral azithromycin, although antibiotic coverage was not universal. A follow-up census was performed 26 months after treatment to estimate all-cause mortality among children 1-5 years of age, and verbal autopsies were performed to identify infectious mortality.The cohort included 35,052 individuals ?1 year of age and 5507 children 1-5 years of age, of whom 4914 received a dose of azithromycin. All-cause mortality was significantly lower among those 1-5-year-old children who received azithromycin (odds ratio [OR]=0.35 [95% confidence interval {CI}, 0.17-0.74]), as was infectious mortality (OR=0.20 [95% CI, 0.07-0.58]). When individuals were compared only with members of the same household, azithromycin treatment was still associated with reduced all-cause mortality in children 1-5 years of age (OR=0.40 [95% CI, 0.16-0.96]), although this relationship was not statistically significant for infectious mortality (OR=0.35 [95% CI, 0.10-1.28]).This study demonstrated an association between mass oral azithromycin treatment and reduced all-cause and infectious childhood mortality. This relationship could not be attributed to bias at the level of the household. Mass azithromycin distributions may have benefits unrelated to trachoma.
| S-EPMC3106233 | biostudies-literature
Project description:Mass administration of azithromycin for trachoma has been shown to reduce malarial parasitemia. However, the optimal seasonal timing of such distributions for antimalarial benefit has not been established. We performed numerical analyses on a seasonally forced epidemic model (of Ross-Macdonald type) with periodic impulsive annual mass treatment to address this question. We conclude that when azithromycin-based trachoma elimination programs occur in regions of seasonal malaria transmission, such as Niger, the optimal seasonal timing of mass drug administration (MDA) may not occur during the season of maximum transmission.
| S-EPMC4228890 | biostudies-other
Project description:Background:Mass distributions of oral azithromycin have long been used to eliminate trachoma, and they are now being proposed to reduce childhood mortality. The observed benefit appears to be augmented with each additional treatment, suggesting a possible community-level effect. Here, we assess whether 2 biannual mass treatments of preschool children affect the community's gut microbiome at 6 months after the last distribution. Methods:In this cluster-randomized controlled trial, children aged 1-60 months in the Dossa region of Niger were randomized at the village level to receive a single dose of azithromycin or placebo every 6 months. Fecal samples were collected 6 months after the second treatment for metagenomic deep sequencing. The prespecified primary outcome was the Euclidean PERMANOVA of the gut microbiome, or effectively the distance between the genus-level centroid at the community level, with the secondary outcome being the Simpson's ? diversity. Results:In the azithromycin arm, the gut microbial structures were significantly different than in the placebo arm (Euclidean PERMANOVA, P < .001). Further, the diversity of the gut microbiome in the azithromycin arm was significantly lower than in the placebo arm (inverse Simpson's index, P = .005). Conclusions:Two mass azithromycin administrations, 6 months apart, in preschool children led to long-term alterations of the gut microbiome structure and community diversity. Here, long-term microbial alterations in the community did not imply disease but were associated with an improvement in childhood mortality. Clinical Trials Registration:NCT02048007.
| S-EPMC6101535 | biostudies-literature
Project description:ImportanceMass 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.ObjectiveTo investigate whether biannual mass azithromycin distributions are associated with increased childhood growth.Design, setting, and participantsThis 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.InterventionsParticipants 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 measuresLongitudinal 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.ResultsAmong 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 relevanceThis 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 registrationClinicalTrials.gov Identifier: NCT02048007.
| S-EPMC8719241 | biostudies-literature