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

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.

Neonatal Early Onset Sepsis (EOS) Calculator plus Universal Serial Physical Examination (SPE): A Prospective Two-Step Implementation of a Neonatal EOS Prevention Protocol for Reduction of Sepsis Workup and Antibiotic Treatment

“…Unnecessary laboratory tests and unneeded antibiotic administration show short- and long-term consequences: infant discomfort and parental stress, admissions to NICU and, therefore, the interruption of parental bonding and breastfeeding, prolonged length of hospital stay, and increased health care costs [ 19 , 29 , 30 ]. Early neonatal antibiotic exposure has been recently demonstrated to be correlated to asthma, allergic and autoimmune disease, microbiome alteration, and obesity [ 31 , 32 , 33 , 34 , 35 , 36 ]. Strategies avoiding unnecessary pre- and postnatal antibiotics and favoring mother-newborn bonding and breastfeeding should be implemented [ 34 ].…”

A complete guide to human microbiomes: Body niches, transmission, development, dysbiosis, and restoration

“…Although the microbiota in neonates is established at birth, it will shape throughout the next 3 years of life due to environmental factors such as diet, antibiotics, hygiene, and the built environment (Indiani et al, 2018). Antibiotics are known to decrease the overall diversity of the infant's microbiota and aid in the selection of drug-resistant organisms (Reyman et al, 2022). Infants treated with antibiotics tend to have lower bacterial diversity as well as an increase of Enterobacteriaceae and Enterococcus (Reyman et al, 2022).…”

“…Antibiotics are known to decrease the overall diversity of the infant's microbiota and aid in the selection of drug-resistant organisms (Reyman et al, 2022). Infants treated with antibiotics tend to have lower bacterial diversity as well as an increase of Enterobacteriaceae and Enterococcus (Reyman et al, 2022). The early use of this treatment has been associated with higher risks of allergic diseases (Zwittink et al, 2018), eczema (Kim et al, 2019a), and obesity (Schulfer and Blaser, 2015), and type 1 diabetes (Langdon et al, 2016).…”

How does age determine the development of human immune-mediated arthritis?

“…Microbiota are heritable from the mother, and this vertical transmission is influenced by the birth mode 141 . Other factors that affect microbiota transmission include maternal health status and lifestyle during pregnancy, antibiotic use around birth, geographical location, family environment, type of feeding, duration of lactation and use of antibiotics in infancy 142 . Microbiota composition varies according to infant body sites and age 143 .…”