Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial

Marta Reyman,Irene Schiering,Frans B Plötz,Kayleigh Arp,Marlies A Van Houten,Debby Bogaert,Rob J L Willems,Willem Van Schaik,Wouter J De Waal,Rebecca L Watson,Mei Ling J N Chu,Elisabeth A M Sanders

doi:10.1038/s41467-022-28525-z

Abstract

Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R2 = 9.5%, adjusted p-value = 0.001 and R2 = 7.5%, adjusted p-value = 0.001, respectively) and normalize over 12 months (R2 = 1.1%, adjusted p-value = 0.03 and R2 = 0.6%, adjusted p-value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects.

Highlights

1234567890():,; Broad-spectrum antibiotics for suspected early-onset neonatal sepsis may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome
To identify the antibiotic regimen with the least ecological and antimicrobial resistance (AMR) gene selection effects, we performed the ZEBRA study in which we enrolled 147 infants born at term, either by natural delivery or by secondary caesarean section (CS) (SCS), for whom broad-spectrum antibiotics were indicated in the first week of life because of suspected early-onset neonatal sepsis (sEONS), and randomized them over three most commonly prescribed intravenous antibiotic combinations for this indication in the Netherlands, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime[16]
Neonates were randomized over the following antibiotic regimens (49 per group): penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime

Summary

Introduction

1234567890():,; Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects. To identify the antibiotic regimen with the least ecological and AMR gene selection effects, we performed the ZEBRA study in which we enrolled 147 infants born at term, either by natural delivery or by secondary CS (SCS), for whom broad-spectrum antibiotics were indicated in the first week of life because of sEONS, and randomized them over three most commonly prescribed intravenous antibiotic combinations for this indication in the Netherlands, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime[16]. We find marked differences in ecological perturbation between the three different antimicrobial regimens, suggesting that, next to adequate treatment, the choice of empirical antibiotics is relevant for adverse ecological side-effects

Methods

Results

Conclusion