Dataset Information

Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.

ABSTRACT:

Background

Antibiotic use by one individual may affect selection for antimicrobial resistance in close contacts. Here we evaluated whether oral antibiotic treatment of one child within a household affected the gut resistome of an untreated cohabiting child.

Methods

Households with at least two children <5 y of age were randomized in a 1:1 fashion to a 5d course of azithromycin or placebo. To evaluate indirect effects of azithromycin treatment on the gut resistome, we randomly assigned one child in the house to azithromycin and one to placebo. In placebo households, each child received placebo. We performed DNA sequencing of rectal swabs collected 5 d after the last antibiotic dose. We estimated risk ratios for the presence of genetic resistance determinants at the class level using modified Poisson models for children in azithromycin households compared with placebo households and assessed the composition of the resistome using permutational analysis of variance (PERMANOVA).

Results

Of 58 children (n = 30 azithromycin households, n = 28 placebo households) with post-treatment rectal swabs, genetic resistance determinants were common but there was no significant difference at the class (p = 0.54 for macrolides) or gene (p = 0.94 for structure by PERMANOVA, p = 0.94 for diversity) level between untreated children in azithromycin households compared with placebo households.

Conclusions

The results are encouraging that one child's antibiotic use may not influence the resistome of another child. Trial registration: ClinicalTrials.gov NCT03187834.

SUBMITTER: Oldenburg CE

PROVIDER: S-EPMC7902679 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.

Oldenburg Catherine E CE Hinterwirth Armin A Worden Lee L Sié Ali A Dah Clarisse C Ouermi Lucienne L Coulibaly Boubacar B Zhong Lina L Chen Cindi C Ruder Kevin K Lietman Thomas M TM Keenan Jeremy D JD Doan Thuy T

International health 20210201 2

<h4>Background</h4>Antibiotic use by one individual may affect selection for antimicrobial resistance in close contacts. Here we evaluated whether oral antibiotic treatment of one child within a household affected the gut resistome of an untreated cohabiting child.<h4>Methods</h4>Households with at least two children <5 y of age were randomized in a 1:1 fashion to a 5d course of azithromycin or placebo. To evaluate indirect effects of azithromycin treatment on the gut resistome, we randomly assi ...[more]

PMID: 32556194

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Project description:BackgroundAzithromycin is a broad-spectrum antibiotic that has moderate antimalarial activity and has been shown to reduce all-cause mortality when biannually administered to children under five in high mortality settings in sub-Saharan Africa. One potential mechanism for this observed reduction in mortality is via a reduction in malaria transmission.MethodsWe evaluated whether a single oral dose of azithromycin reduces malaria positivity by rapid diagnostic test (RDT). We conducted an individually randomized placebo-controlled trial in Burkina Faso during the high malaria transmission season in August 2020. Children aged 8 days to 59 months old were randomized to a single oral dose of azithromycin (20 mg/kg) or matching placebo. At baseline and 14 days following treatment, we administered a rapid diagnostic test (RDT) to detect Plasmodium falciparum and measured tympanic temperature for all children. Caregiver-reported adverse events and clinic visits were recorded at the day 14 visit.ResultsWe enrolled 449 children with 221 randomized to azithromycin and 228 to placebo. The median age was 32 months and 48% were female. A total of 8% of children had a positive RDT for malaria at baseline and 11% had a fever (tympanic temperature ≥ 37.5 °C). In the azithromycin arm, 8% of children had a positive RDT for malaria at 14 days compared to 7% in the placebo arm (P = 0.65). Fifteen percent of children in the azithromycin arm had a fever ≥ 37.5 °C compared to 21% in the placebo arm (P = 0.12). Caregivers of children in the azithromycin group had lower odds of reporting fever as an adverse event compared to children in the placebo group (OR 0.41, 95% CI 0.18-0.96, P = 0.04). Caregiver-reported clinic visits were uncommon, and there were no observed differences between arms (P = 0.32).ConclusionsWe did not find evidence that a single oral dose of azithromycin reduced malaria positivity during the high transmission season. Caregiver-reported fever occurred less often in children receiving azithromycin compared to placebo, indicating that azithromycin may have some effect on non-malarial infections. Trial registration Clinicaltrials.gov NCT04315272, registered 19/03/2020.

Project description:BackgroundMacrolides are commonly prescribed for respiratory infections and asthma-like episodes in children. While their clinical benefits have been proved, concerns regarding the side-effects of their therapeutic use have been raised. Here we assess the short- and long-term impacts of azithromycin on the gut microbiota of young children.MethodsWe performed a randomized, double-blind, placebo-controlled trial in a group of children aged 12-36 months, diagnosed with recurrent asthma-like symptoms from the COPSAC2010 cohort. Each acute asthma-like episode was randomized to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo. Azithromycin reduced episode duration by half, which was the primary end-point and reported previously. The assessment of gut microbiota after treatment was the secondary end-point and reported in this study. Fecal samples were collected 14 days after randomization (N = 59, short-term) and again at age 4 years (N = 49, long-term, of whom N = 18 were placebo treated) and investigated by 16S rRNA gene amplicon sequencing.FindingsShort-term, azithromycin caused a 23% reduction in observed richness and 13% reduction in Shannon diversity. Microbiota composition was shifted primarily in the Actinobacteria phylum, especially a reduction of abundance in the genus Bifidobacterium. Long-term (13-39 months after treatment), we did not observe any differences between the azithromycin and placebo recipients in their gut microbiota composition.InterpretationAzithromycin treatment induced a perturbation in the gut microbiota 14 days after randomization but did not have long-lasting effects on the gut microbiota composition. However, it should be noted that our analyses included a limited number of fecal samples for the placebo treated group at age 4 years. FUND: Lundbeck Foundation, Danish Ministry of Health, Danish Council for Strategic Research, Capital Region Research Foundation, China Scholarship Council.

Project description: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.ObjectiveTo 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 participantsThe 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.InterventionsEnrolled 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 measuresPrimary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment.ResultsA 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 group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged.Trial registrationClinicalTrials.gov Identifier: NCT03130114.

Dataset Information

Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.

Background

Methods

Results

Conclusions

Publications

Indirect effect of oral azithromycin on the gut resistome of untreated children: a randomized controlled trial.

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