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

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Macrolide resistance in the gut microbiome may influence the efficacy of azithromycin in children discharged from the hospital. Clinical Trials Registration. NCT02414399.

Keywords: azithromycin; gut microbiome; hospital; macrolide resistance; mortality; postdischarge.

Figure 1.

Study profile and reasons for exclusion at each stage. Abbreviation: AMR, antimicrobial resistance.

Figure 2.

Distribution of macrolide resistance gene carriage at baseline by randomization arm (defined by cycle threshold <30). A and B, Antimicrobial resistance genes detected in fecal DNA (A) and Escherichia coli isolates (B).

Figure 3.

Effect of azithromycin (AZM) for preventing rehospitalization or death (composite outcome) among children discharged from hospital with and without the specified antimicrobial resistance gene in fecal DNA (defined by cycle threshold <30). The black square dots and the error bars represent the hazard ratio (HR) and 95% confidence interval (CI).

Figure 4.

Effect of azithromycin on change in length-for-age/height-for-age z-score (HAZ, A) and mid-upper arm circumference (MUAC, B) between enrollment and 6-month follow-up among children discharged from hospital with and without the specified antimicrobial resistance gene detected in fecal DNA (defined by cycle threshold <30). Data represent the monthly change in HAZ and MUAC (cm), respectively. The black square dots and the error bars represent the net monthly change in growth between the azithromycin group and the placebo group, with 95% confidence intervals (CIs).