Impact of Macrolide Resistance on Azithromycin for Prevention of Rehospitalization or Death Among Children Discharged From Hospitals in Western Kenya

TL;DR

A study in Kenya found that gut bacteria resistance to azithromycin may affect its ability to prevent rehospitalization or death in children after hospital discharge.

Contribution

The study identifies the mef(A) gene as a modifier of azithromycin's effect in children.

Findings

94.7% of children had at least one macrolide resistance gene in their gut microbiome.

The mef(A) gene significantly modified azithromycin's effect on rehospitalization or death.

Azithromycin reduced risk in children without mef(A), but increased risk in those with mef(A).

Abstract

The Toto Bora trial tested whether a 5-day course of azithromycin reduced the risk of rehospitalization or death in the 6 months following hospitalization among Kenyan children and found no overall benefit. We hypothesized that macrolide resistance in gut microbes could modify azithromycin's effect.

From June 2016 to November 2019, Kenyan children aged 1–59 months were enrolled at hospital discharge and randomized to azithromycin or placebo. DNA from fecal samples and Escherichia coli isolates was analyzed for common macrolide resistance genes. Cox proportional hazards regression models, including interaction terms between randomization arm and individual macrolide resistance genes, were used to analyze time to rehospitalization or death, with Bonferroni correction applied to account for multiple comparisons.

Among 1393 children tested, 94.7% had at least 1 macrolide resistance gene in their fecal DNA at hospital discharge, most commonly mph(A) (68.6% [955/1393]), followed by msr(D) (67.3% [937/1393]) and erm(B) (60.7% [846/1393]). Mef(A) (23.7% [330/1393]) was the only macrolide resistance gene that modified azithromycin's effect on rehospitalization or death (interaction P = .008). In children without the mef(A) gene, azithromycin reduced the hazard of rehospitalization or death by a third (hazard ratio [HR], 0.66 [95% confidence interval {CI}, .45–.99]) whereas among children with the mef(A) gene, there was a higher risk in those randomized to azithromycin (HR, 2.72 [95% CI, 1.21–6.09]). The effect size of azithromycin's impact on mortality and rehospitalization as separate outcomes in children with and without mef(A) were consistent but underpowered.

Macrolide resistance in the gut microbiome may influence the efficacy of azithromycin in children discharged from the hospital.

Clinical Trials Registration. NCT02414399.

The Toto Bora trial showed no overall benefit of azithromycin posthospitalization in Kenyan children. High prevalence of gut macrolide resistance was found. The mef(A) gene significantly modified azithromycin's effect. Gut microbiome resistance may influence azithromycin efficacy following hospital discharge.

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