Safety of azithromycin in infants under six months of age in Niger: A community randomized trial

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Abstract

Background

Mass azithromycin distribution reduces under-5 child mortality. Trachoma control programs currently treat infants aged 6 months and older. Here, we report findings from an infant adverse event survey in 1–5 month olds who received azithromycin as part of a large community-randomized trial in Niger.

Methods and principal findings

Active surveillance of infants aged 1–5 months at the time of treatment was conducted in 30 randomly selected communities from within a large cluster randomized trial of biannual mass azithromycin distribution compared to placebo to assess the potential impact on child mortality. We compared the distribution of adverse events reported after treatment among azithromycin-treated versus placebo-treated infants. From January 2015 to February 2018, the caregivers of 1,712 infants were surveyed. Approximately one-third of caregivers reported at least one adverse event (azithromycin: 29.6%, placebo: 34.3%, risk ratio [RR] 0.86, 95% confidence interval [CI] 0.68 to 1.10, P = 0.23). The most commonly reported adverse events included diarrhea (azithromycin: 19.3%, placebo: 28.1%, RR 0.68, 95% CI 0.49 to 0.96, P = 0.03), vomiting (azithromycin: 15.9%, placebo: 21.0%, RR 0.76, 95% CI 0.56 to 1.02, P = 0.07), and skin rash (azithromycin: 12.3%, placebo: 13.6%, RR 0.90, 95% CI 0.59 to 1.37, P = 0.63). No cases of infantile hypertrophic pyloric stenosis were reported.

Conclusions

Azithromycin given to infants aged 1–5 months appeared to be safe. Inclusion of younger infants in larger azithromycin-based child mortality or trachoma control programs could be considered if deemed effective.

Trial registration

ClinicalTrials.gov NCT02048007.

Author summary

Trachoma control programs currently treat all adults and children age 6 months and older in communities endemic for trachoma. If shown to be safe, programs could consider inclusion of younger children in mass treatment programs. Here, we evaluated adverse events in infants aged 1–5 months who were participating in a placebo-controlled trial of mass azithromycin for the reduction of child mortality in Niger. Overall, there was no difference in the frequency of adverse events among children treated with azithromycin compared to placebo. Common adverse events in both arms included diarrhea, vomiting, and skin rash. Azithromycin distribution to children between 1 and 5 months of age appeared to be safe. Inclusion of younger children in azithromycin-based trachoma and child mortality programs could be considered.

Related collections

Most cited references 28

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Mass azithromycin distribution for reducing childhood mortality in sub-Saharan Africa

Jeremy D. Keenan, Robin L Bailey, Sheila K. West … (2018)

Background. Interventions to reduce under-5 mortality can either target the vulnerable or include all children regardless of state of health. Here, we assess whether mass distribution of a broad-spectrum antibiotic to pre-school children reduces mortality in sub-Saharan Africa. Methods. MORDOR was a large simple trial that randomized communities in Malawi, Niger, and Tanzania to 4 biannual mass distributions of either oral azithromycin or placebo. Children aged 1-59 months were enumerated and offered treatment. Vital status was assessed at the subsequent biannual census. The primary outcome was aggregate all-cause mortality, with country-specific rates as pre-specified subgroup analyses. Results. In total, 1533 communities were randomized, 190,238 children censused at baseline, and 323,302 person-years monitored. Mean antibiotic coverage over the 4 biannual distributions was 90.4% (SD 10.4%) of the censused population. The overall annual mortality rate in placebo- treated communities was 16.5 per 1000 person-years (9.6 per 1000 person-years in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Antibiotic-treated communities had an estimated 13.5% lower mortality overall (95% CI 6.7%—19.8%, P<0.001). Mortality was 5.7% lower in Malawi (CI - 9.7%—18.9%, P=0.45), 18.1% lower in Niger (CI 10.0%—25.5%, P<0.001), and 3.4% lower in Tanzania (CI -21.2%—23.0%, P=0.77). The greatest reduction was observed in 1-5 month-old children (24.9% lower, CI 10.6%—37.0%, P=0.001). Conclusions. Mass azithromycin distribution to post-neonatal, pre-school children may reduce childhood mortality in sub-Saharan Africa, particularly in high mortality areas such as Niger. Any implementation would need to consider selection for antibiotic resistance.

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Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial.

Kausik K Ray, Berhan Ayele, Zhaoxia Zhou … (2009)

Mass oral azithromycin distribution to affected communities is a cornerstone of the World Health Organization's trachoma elimination program. Antibiotics are provided to target the ocular strains of chlamydia that cause trachoma, but may also be efficacious against respiratory disease, diarrhea, and malaria--frequent causes of childhood mortality in trachoma-endemic areas. To compare mortality rates of participants aged 1 to 9 years in treated communities with those in untreated communities. We conducted a cluster-randomized clinical trial of mass azithromycin administration for trachoma control. Forty-eight communities (known as subkebeles) were randomized into 1 of 3 treatment schedules (annual treatment of all residents [15,902 participants], biannual treatment of all residents [17,288 participants], or quarterly treatment of children only [14,716 participants]) or into 1 group for which treatment was delayed by 1 year (control, 18,498 participants). Twelve subkebeles were randomized to each of the 4 schedules with all children in each of the 3 communities being eligible for treatment. The trial was conducted in a field setting in rural Ethiopia, May 2006 to May 2007. A single dose of oral azithromycin (adults, 1 g; children, 20 mg/kg) was administered for treatment of ocular Chlamydia trachomatis infection. Antibiotic coverage levels for children aged 1 to 9 years exceeded 80% at all visits. The main outcome measure was the community-specific mortality risk for children aged 1 to 9 years over the course of 1 year. Mortality was measured by enumerative census at baseline and again after 1 year. Comparison of the risk of mortality was a prespecified outcome for the clinical trial. The odds ratio for childhood mortality in the intervention communities was 0.51 (95% confidence interval, 0.29-0.90; P = .02; clustered logistic regression) compared with the control group. In the treated communities, the estimated overall mortality rate during this period for children aged 1 to 9 years in the untreated group was 8.3 per 1000 person-years (95% confidence interval, 5.3-13.1), while among the treated communities, the estimated overall mortality rate was 4.1 per 1000 person-years (95% confidence interval, 3.0-5.7) for children aged 1 to 9 years. In a trachoma-endemic area, mass distribution of oral azithromycin was associated with reduced mortality in children. clinicaltrials.gov Identifier: NCT00322972.

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Mass treatment with single-dose azithromycin for trachoma.

Anthony W. Solomon, Martin Holland, Neal D.E. Alexander … (2004)

Trachoma, caused by repeated ocular infection with Chlamydia trachomatis, is an important cause of blindness. Current recommended dosing intervals for mass azithromycin treatment for trachoma are based on a mathematical model. We collected conjunctival swabs for quantitative polymerase-chain-reaction assay of C. trachomatis before and 2, 6, 12, 18, and 24 months after mass treatment with azithromycin in a Tanzanian community in which trachoma was endemic. For ethical reasons, at 6, 12, and 18 months, we gave tetracycline eye ointment to residents who had clinically active trachoma. At baseline, 956 of 978 residents (97.8 percent) received either one oral dose of azithromycin or (if azithromycin was contraindicated) a course of tetracycline eye ointment. The prevalence of infection fell from 9.5 percent before mass treatment to 2.1 percent at 2 months and 0.1 percent at 24 months. The quantitative burden of ocular C. trachomatis infection in the community was 13.9 percent of the pretreatment level at 2 months and 0.8 percent at 24 months. At each time point after baseline, over 90 percent of the total community burden of C. trachomatis infection was found among subjects who had been positive the previous time they were tested. The prevalence and intensity of infection fell dramatically and remained low for two years after treatment. One round of very-high-coverage mass treatment with azithromycin, perhaps aided by subsequent periodic use of tetracycline eye ointment for persons with active disease, can interrupt the transmission of ocular C. trachomatis infection. Copyright 2004 Massachusetts Medical Society.

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Author and article information

Contributors

Catherine E. Oldenburg:

ORCID: http://orcid.org/0000-0002-0763-399X

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draft

Ahmed M. Arzika: Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Ramatou Maliki: Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Mohamed Salissou Kane: Role: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Elodie Lebas: Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing

Kathryn J. Ray: Role: Data curationRole: Formal analysisRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing

Catherine Cook: Role: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing

Sun Y. Cotter: Role: Data curationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing

Zhaoxia Zhou: Role: Data curationRole: Project administrationRole: ValidationRole: Writing – review & editing

Sheila K. West: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Robin Bailey: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Travis C. Porco: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: ValidationRole: Writing – review & editing

Jeremy D. Keenan: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing

Thomas M. Lietman: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – original draft

Krithivasan Sankaranarayanan: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date (Electronic): 12 November 2018

Publication date Collection: November 2018

Volume: 12

Issue: 11

Electronic Location Identifier: e0006950

Affiliations

[1 ] Francis I. Proctor Foundation, University of California, San Francisco, San Francisco, California, United States of America

[2 ] Department of Ophthalmology, University of California, San Francisco, San Francisco, California, United States of America

[3 ] Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America

[4 ] The Carter Center Niger, Niamey, Niger

[5 ] The Dana Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America

[6 ] Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom

University of Oklahoma, UNITED STATES

Author notes

The authors have declared that no competing interests exist.

¶ Membership of the MORDOR Study Group is listed in S1 Appendix.

* E-mail: tom.lietman@ 123456ucsf.edu

Author information

Catherine E. Oldenburg http://orcid.org/0000-0002-0763-399X

Article

Publisher ID: PNTD-D-18-00962

DOI: 10.1371/journal.pntd.0006950

PMC ID: 6258425

PubMed ID: 30419040

SO-VID: b0c2a1e6-9a08-46d1-b6d6-76ca206c974e

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 19 June 2018

Date accepted : 27 October 2018

Page count

Figures: 1, Tables: 3, Pages: 11

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;

Award ID: OPP1032340

Award Recipient : Thomas M. Lietman

The Bill and Melinda Gates Foundation provided the funding for the trial (OPP1032340). Pfizer Inc. (New York City) provided both the azithromycin and the placebo oral suspensions. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Custom metadata

PLOS Publication Stage vor-update-to-uncorrected-proof

Publication Update 2018-11-26

Data Availability All data underlying these analyses can be found at: https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/MQYM5S.

ScienceOpen disciplines: Infectious disease & Microbiology

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

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Safety of azithromycin in infants under six months of age in Niger: A community randomized trial

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Abstract

Background

Methods and principal findings

Conclusions

Trial registration

Author summary

Related collections

Point-of-Care Testing for Infectious Diseases Super Collection

Most cited references 28

Mass azithromycin distribution for reducing childhood mortality in sub-Saharan Africa

Effect of mass distribution of azithromycin for trachoma control on overall mortality in Ethiopian children: a randomized trial.

Mass treatment with single-dose azithromycin for trachoma.

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