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

Author

Listed:
  • Marta Reyman

    (Wilhelmina Children’s Hospital and University Medical Center Utrecht
    Spaarne Gasthuis)

  • Marlies A. Houten

    (Spaarne Gasthuis)

  • Rebecca L. Watson

    (University of Edinburgh)

  • Mei Ling J. N. Chu

    (Wilhelmina Children’s Hospital and University Medical Center Utrecht)

  • Kayleigh Arp

    (Wilhelmina Children’s Hospital and University Medical Center Utrecht)

  • Wouter J. Waal

    (Diakonessenhuis)

  • Irene Schiering

    (Spaarne Gasthuis)

  • Frans B. Plötz

    (Tergooiziekenhuis)

  • Rob J. L. Willems

    (University Medical Centre Utrecht)

  • Willem Schaik

    (University of Birmingham)

  • Elisabeth A. M. Sanders

    (Wilhelmina Children’s Hospital and University Medical Center Utrecht
    National Institute for Public Health and the Environment)

  • Debby Bogaert

    (Wilhelmina Children’s Hospital and University Medical Center Utrecht
    University of Edinburgh)

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.

Suggested Citation

  • Marta Reyman & Marlies A. Houten & Rebecca L. Watson & Mei Ling J. N. Chu & Kayleigh Arp & Wouter J. Waal & Irene Schiering & Frans B. Plötz & Rob J. L. Willems & Willem Schaik & Elisabeth A. M. Sande, 2022. "Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28525-z
    DOI: 10.1038/s41467-022-28525-z
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    1. Sathish Subramanian & Sayeeda Huq & Tanya Yatsunenko & Rashidul Haque & Mustafa Mahfuz & Mohammed A. Alam & Amber Benezra & Joseph DeStefano & Martin F. Meier & Brian D. Muegge & Michael J. Barratt & , 2014. "Persistent gut microbiota immaturity in malnourished Bangladeshi children," Nature, Nature, vol. 510(7505), pages 417-421, June.
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    1. Achal Dhariwal & Polona Rajar & Gabriela Salvadori & Heidi Aarø Åmdal & Dag Berild & Ola Didrik Saugstad & Drude Fugelseth & Gorm Greisen & Ulf Dahle & Kirsti Haaland & Fernanda Cristina Petersen, 2024. "Prolonged hospitalization signature and early antibiotic effects on the nasopharyngeal resistome in preterm infants," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Xuanji Li & Asker Brejnrod & Jonathan Thorsen & Trine Zachariasen & Urvish Trivedi & Jakob Russel & Gisle Alberg Vestergaard & Jakob Stokholm & Morten Arendt Rasmussen & Søren Johannes Sørensen, 2023. "Differential responses of the gut microbiome and resistome to antibiotic exposures in infants and adults," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Victoria T. Chu & Alexandra Tsitsiklis & Eran Mick & Lilliam Ambroggio & Katrina L. Kalantar & Abigail Glascock & Christina M. Osborne & Brandie D. Wagner & Michael A. Matthay & Joseph L. DeRisi & Car, 2024. "The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Martin Stocker & Claus Klingenberg & Lars Navér & Viveka Nordberg & Alberto Berardi & Salhab el Helou & Gerhard Fusch & Joseph M. Bliss & Dirk Lehnick & Varvara Dimopoulou & Nicholas Guerina & Joanna , 2023. "Less is more: Antibiotics at the beginning of life," Nature Communications, Nature, vol. 14(1), pages 1-9, December.

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