Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial
Reyman, Marta; van Houten, Marlies A.; Watson, Rebecca L.; Chu, Mei Ling J.N.; Arp, Kayleigh; de Waal, Wouter J.; Schiering, Irene; Plötz, Frans B.; Willems, Rob J.L.; van Schaik, Willem; Sanders, Elisabeth A.M.; Bogaert, Debby
(2022) Nature Communications, volume 13, issue 1, pp. 1 - 12
(Article)
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
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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.
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Keywords: Amoxicillin-Potassium Clavulanate Combination/pharmacology, Anti-Bacterial Agents/adverse effects, Bacteria/classification, Bifidobacterium/isolation & purification, Cefotaxime/pharmacology, Enterococcus/isolation & purification, Gastrointestinal Microbiome/drug effects, Gentamicins/pharmacology, Humans, Infant, Newborn, Klebsiella/isolation & purification, Microbial Sensitivity Tests, Neonatal Sepsis/drug therapy, Penicillins/pharmacology, RNA, Ribosomal, 16S/genetics, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: The authors are grateful for the participation of all the children and their families. We wish to acknowledge all the members of the research team of the Spaarne Gasthuis Academy and the Neonatology Departments of the Spaarne Gasthuis Hoofddorp and Haarlem, Diakonessenhuis Utrecht and Tergooiziekenhuis Blaricum for the help in participant recruitment, and the laboratory staff, with special thanks to Raiza Hasrat of the University Medical Center Utrecht. We would also like to acknowledge Edinburgh Genomics for executing the MGS sequencing and Katherine Emelianova for the bioinformatic processing of the MGS sequences. This research was funded by the Netherlands Organisation for Health Research and Development (ZonMw Priority Medicines Antimicrobiële Resistentie project number 205300001, MR/MAvH), Chief Scientist Office (SCAF/16/03, DB) and the Spaarne Gasthuis (MR/MAvH). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Funding Information: The authors are grateful for the participation of all the children and their families. We wish to acknowledge all the members of the research team of the Spaarne Gasthuis Academy and the Neonatology Departments of the Spaarne Gasthuis Hoofddorp and Haarlem, Diakonessenhuis Utrecht and Tergooiziekenhuis Blaricum for the help in participant recruitment, and the laboratory staff, with special thanks to Raiza Hasrat of the University Medical Center Utrecht. We would also like to acknowledge Edinburgh Genomics for executing the MGS sequencing and Katherine Emelianova for the bioinformatic processing of the MGS sequences. This research was funded by the Netherlands Organisation for Health Research and Development (ZonMw Priority Medicines Antimicrobi?le Resistentie project number 205300001, MR/MAvH), Chief Scientist Office (SCAF/16/03, DB) and the Spaarne Gasthuis (MR/MAvH). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: © 2022, The Author(s).
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