Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial

Hart, John; Kalua, Khumbo; Keenan, Jeremy D.; Lietman, Thomas M.; Bailey, Robin L.

doi:10.4269/ajtmh.19-0613

Cited by 11 publications

(10 citation statements)

References 39 publications

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“…12 , 13 Malaria was also the commonest inferred cause of death from verbal autopsy in the MORDOR trial in Malawi. 14 Parasitemic children had significantly lower mean hemoglobin levels at all follow-up rounds, consistent with known effects of malaria as a cause of anemia in children. 15 – 17 This analysis provides some validation of the integrity of the data.…”

Section: Discussionsupporting

confidence: 65%

Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial

Hart

Samikwa

Sikina

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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. Reductions in malaria morbidity have been reported following azithromycin mass drug administration (MDA) for trachoma. The recent Macrolides Oraux pour Reduire les Deces avec un Oeil sur la Resistance (MORDOR) trial reported a reduction in child mortality following biannual azithromycin MDA. Here, we investigate the effects of azithromycin MDA on malaria at the MORDOR-Malawi study site. A cluster-randomized double-blind placebo-controlled trial, with 15 clusters per arm, was conducted. House-to-house census was updated biannually, and azithromycin or placebo syrup was distributed to children aged 1–59 months for a total of four biannual distributions. At baseline, 12-month, and 24-month follow-up visits, a random sample of 1,200 children was assessed for malaria with thick and thin blood smears and hemoglobin measurement. In the community-level analysis, there was no difference in the prevalence of parasitemia (1.0% lower in azithromycin-treated communities; 95% CI: −8.2 to 6.1), gametocytemia (0.7% lower in azithromycin-treated communities; 95% CI: −2.8 to 1.5), or anemia (1.7% lower in azithromycin-treated communities; 95% CI: −8.1 to 4.6) between placebo and azithromycin communities. Further interrogation of the data at the individual level, both per-protocol (including only those who received treatment 6 months previously) and by intention-to-treat, did not identify differences in parasitemia between treatment arms. In contrast to several previous reports, this study did not show an effect of azithromycin MDA on malaria parasitemia at the community or individual levels.

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Section: Discussionsupporting

confidence: 65%

Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial

Hart

Samikwa

Sikina

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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“…The following prespecified secondary outcomes assessed in the MORDOR study in Malawi have been published elsewhere: malaria parasitaemia and haemoglobin; 28 cost-effectiveness of the intervention for reducing mortality; 6 and cause-specific mortality rates. 29 The samples have not yet been processed to assess outcomes related to prevalence of macrolide resistance in stool samples and the fraction of conjunctival swabs yielding ocular chlamydia.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015–17

et al. 2022

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Background Azithromycin mass drug administration (MDA) could reduce child mortality. However, macrolide resistance, which has generally been reported to develop after whole-community MDA for trachoma control, is a concern, and it has less commonly been studied in the context of treating children to reduce mortality. Here, we report on macrolide resistance after biannual azithromycin MDA at the Malawi site of the MORDOR study. MethodsIn the MORDOR cluster-randomised trial in Malawi, 30 communities in Mangochi District were randomly selected. Communities were randomly assigned to receive azithromycin or placebo by simple randomisation without stratification. Children aged 1-59 months were administered azithromycin 20 mg/kg or placebo as an oral suspension biannually for a total of four treatments in 2015-17. 1200 children (40 children per community) were randomly selected for nasopharyngeal swabs at baseline, 12 months (6 months after the second treatment visit), and 24 months (6 months after the fourth treatment visit). Samples were processed to culture Streptococcus pneumoniae. The primary outcome was the proportion of S pneumoniae isolates exhibiting macrolide resistance at 12 months and 24 months, assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02048007. Findings At baseline, 3467 (76%) of 4541 eligible children in the azithromycin group and 3107 (72%) of 4308 eligible children in the placebo group were treated. 564 nasopharyngeal swabs were taken from the azithromycin group and 563 from the placebo group, with similar numbers of swabs taken at 12 months and 24 months. In both groups at baseline, carriage of S pneumoniae was greater than 85% and the proportion of strains resistant to macrolides was 28%. At the 12-month follow-up, macrolide resistance was higher in the azithromycin group (36•9%, 95% CI 32•5-41•2) than in the placebo group (21•6%, 17•7-25•4; OR 2•26, 95% CI 1•46-3•49; p=0•0002). At 24 months, macrolide resistance remained higher in the azithromycin group (43•9%, 39•2-48•5) compared with placebo (32•8%, 28•5-37•1; OR 1•66, 1•15-2•40; p=0•0069). Interpretation These findings support previous evidence from trachoma MDA programmes and suggest that monitoring of macrolide resistance should remain a key component of azithromycin interventions for reducing child mortality. Funding Bill & Melinda Gates Foundation.

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“… 12 , 13 Although the mechanism of action of improved survival in mass drug administration trials remains unknown, post hoc subanalyses examining whether prevention of diarrhea and dysentery could have played a role are inconclusive. 26 Secondary analysis of a trial of the mass administration of seasonal malaria prophylaxis plus azithromycin or placebo 27 showed no evidence of a protective effect of azithromycin on hospitalization and deaths, and protection from infectious illnesses was short-lived (2-4 weeks). 28 A trial in Niger is under way to test the effect of age-based targeting of biannual azithromycin on mortality and antimicrobial resistance in children.…”

Section: Discussionmentioning

confidence: 99%

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings

et al. 2021

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IMPORTANCEWorld Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. OBJECTIVE To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. DESIGN, SETTING, AND PARTICIPANTS The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. INTERVENTIONS Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. MAIN OUTCOMES AND MEASURES Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. RESULTS A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and −0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. CONCLUSIONS AND RELEVANCEThe study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin (continued) Key Points Question Does the addition of azithromycin to the standard case management of acute watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished reduce mortality and improve linear growth? Findings This randomized clinical trial of 8266 children was unable to detect a survival benefit for children from the addition of azithromycin to the standard World Health Organization (WHO) case management of acute wat...

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Effect of Mass Treatment with Azithromycin on Causes of Death in Children in Malawi: Secondary Analysis from the MORDOR Trial

Cited by 11 publications

References 39 publications

Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial

Effects of Biannual Azithromycin Mass Drug Administration on Malaria in Malawian Children: A Cluster-Randomized Trial

Prevalence of nasopharyngeal Streptococcus pneumoniae carriage and resistance to macrolides in the setting of azithromycin mass drug administration: analysis from a cluster-randomised controlled trial in Malawi, 2015–17

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings

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