Multicenter Study

. 2025 Apr;97(5):1629-1635.

doi: 10.1038/s41390-024-03532-6. Epub 2024 Sep 17.

Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study

Varvara Dimopoulou¹, Claus Klingenberg^{2

3}, Lars Navér⁴, Viveka Nordberg⁴, Alberto Berardi⁵, Salhab El Helou⁶, Gerhard Fusch⁶, Joseph M Bliss⁷, Dirk Lehnick⁸, Nicholas Guerina⁹, Joanna Seliga-Siwecka¹⁰, Pierre Maton¹¹, Donatienne Lagae¹², Judit Mari¹³, Jan Janota^{14

15

16}, Philipp K A Agyeman¹⁷, Riccardo Pfister¹⁸, Giuseppe Latorre¹⁹, Gianfranco Maffei²⁰, Nicola Laforgia²¹, Enikő Mózes²², Ketil Størdal²³, Tobias Strunk²⁴, Martin Stocker²⁵, Eric Giannoni²⁶; AENEAS Study Group

Collaborators, Affiliations

Affiliations

¹ Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. varvara.dimopoulou@chuv.ch.
² Research Group for Child and Adolescent Health, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
³ Department of Pediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway.
⁴ Department of Neonatology, Karolinska University Hospital and Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
⁵ Neonatal Intensive Care Unit, Mother and Child Department, Policlinico University Hospital, Modena, Italy.
⁶ Division of Neonatology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, ON, Canada.
⁷ Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
⁸ Biostatistics and Methodology, CTU-CS, Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland.
⁹ Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland.
¹¹ Neonatal Service, CHC-Montlegia Clinic, CHC Health Group, Liège, Belgium.
¹² Neonatology and Neonatal Intensive Care Unit, CHIREC-Delta Hospital, Brussels, Belgium.
¹³ Department of Paediatrics, University of Szeged, Szeged, Hungary.
¹⁴ Neonatal Unit, Department of Obstetrics and Gynecology, Motol University Hospital Prague, Prague, Czech Republic.
¹⁵ Department of Pathological Physiology, 1st Medical School, Charles University Prague, Prague, Czech Republic.
¹⁶ Department of Neonatology, Thomayer University Hospital Prague, Prague, Czech Republic.
¹⁷ Division of Pediatric Infectious Disease, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁸ Neonatology and Paediatric Intensive Care Unit, Geneva University Hospitals and Geneva University, Geneva, Switzerland.
¹⁹ Neonatology and Neonatal Intensive Care Unit, Ecclesiastical General Hospital F. Miulli, Acquaviva delle Fonti, Italy.
²⁰ Neonatology and Neonatal Intensive Care Unit, Policlinico Riuniti Foggia, Foggia, Italy.
²¹ Neonatology and Neonatal Intensive Care Unit, University of Bari, Bari, Italy.
²² Perinatal Intensive Care Unit, Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary.
²³ Department of Pediatric Research, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
²⁴ Neonatal Directorate, Child and Adolescent Health Service, King Edward Memorial Hospital, Perth, WA, Australia.
²⁵ Department of Pediatrics, Children's Hospital Lucerne, Lucerne, Switzerland.
²⁶ Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. eric.giannoni@chuv.ch.

PMID: 39289592
PMCID: PMC12119336
DOI: 10.1038/s41390-024-03532-6

Multicenter Study

Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study

Varvara Dimopoulou et al. Pediatr Res. 2025 Apr.

. 2025 Apr;97(5):1629-1635.

doi: 10.1038/s41390-024-03532-6. Epub 2024 Sep 17.

Authors

Affiliations

¹ Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. varvara.dimopoulou@chuv.ch.
² Research Group for Child and Adolescent Health, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
³ Department of Pediatrics and Adolescence Medicine, University Hospital of North Norway, Tromsø, Norway.
⁴ Department of Neonatology, Karolinska University Hospital and Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
⁵ Neonatal Intensive Care Unit, Mother and Child Department, Policlinico University Hospital, Modena, Italy.
⁶ Division of Neonatology, Department of Pediatrics, McMaster Children's Hospital, McMaster University, Hamilton Health Sciences, Hamilton, Ontario, ON, Canada.
⁷ Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY, USA.
⁸ Biostatistics and Methodology, CTU-CS, Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland.
⁹ Department of Pediatrics, Women & Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, USA.
¹⁰ Department of Neonatology and Neonatal Intensive Care, Medical University of Warsaw, Warsaw, Poland.
¹¹ Neonatal Service, CHC-Montlegia Clinic, CHC Health Group, Liège, Belgium.
¹² Neonatology and Neonatal Intensive Care Unit, CHIREC-Delta Hospital, Brussels, Belgium.
¹³ Department of Paediatrics, University of Szeged, Szeged, Hungary.
¹⁴ Neonatal Unit, Department of Obstetrics and Gynecology, Motol University Hospital Prague, Prague, Czech Republic.
¹⁵ Department of Pathological Physiology, 1st Medical School, Charles University Prague, Prague, Czech Republic.
¹⁶ Department of Neonatology, Thomayer University Hospital Prague, Prague, Czech Republic.
¹⁷ Division of Pediatric Infectious Disease, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁸ Neonatology and Paediatric Intensive Care Unit, Geneva University Hospitals and Geneva University, Geneva, Switzerland.
¹⁹ Neonatology and Neonatal Intensive Care Unit, Ecclesiastical General Hospital F. Miulli, Acquaviva delle Fonti, Italy.
²⁰ Neonatology and Neonatal Intensive Care Unit, Policlinico Riuniti Foggia, Foggia, Italy.
²¹ Neonatology and Neonatal Intensive Care Unit, University of Bari, Bari, Italy.
²² Perinatal Intensive Care Unit, Department of Obstetrics and Gynaecology, Semmelweis University, Budapest, Hungary.
²³ Department of Pediatric Research, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
²⁴ Neonatal Directorate, Child and Adolescent Health Service, King Edward Memorial Hospital, Perth, WA, Australia.
²⁵ Department of Pediatrics, Children's Hospital Lucerne, Lucerne, Switzerland.
²⁶ Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. eric.giannoni@chuv.ch.

PMID: 39289592
PMCID: PMC12119336
DOI: 10.1038/s41390-024-03532-6

Abstract

Background: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week.

Methods: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases.

Results: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths.

Conclusions: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases.

Impact: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs.

PubMed Disclaimer

Conflict of interest statement

Competing interests: Alberto Berardi reported receiving personal fees from Atheneum Partners, GmbH outside the submitted work. Joseph M. Bliss reported receiving personal fees from Mead Johnson Nutrition outside the submitted work. No other disclosures were reported.

Figures

**Fig. 1. Duration of antibiotic treatment in infants with negative cultures and in infants with culture-proven early-onset sepsis.**
Histogram and density plot of the duration of antibiotic treatment for infants with negative cultures (No CP-EOS) and for infants with culture-proven early-onset sepsis (CP-EOS) in the whole cohort. Data is presented as the proportion of infants with No CP-EOS and with CP-EOS.

**Fig. 2. Relationship between the incidence of culture-negative cases with an antibiotic treatment of at least 5 days and the incidence culture-proven early-onset sepsis.**
Relationship between the incidence of culture-negative cases with an antibiotic treatment of at least five days (CN ≥ 5d) and the incidence of culture-proven early-onset sepsis (CP-EOS) cases in each network. The size of the bubbles represents the number of births. The dashed lines represent the median of the 13 networks.

Fig. 3. Antibiotic exposure for culture-negative cases with antibiotic treatment for at least 5 days, culture-negative cases with antibiotic treatment for less than 5 days and for culture-proven early-onset sepsis.
Number of antibiotic days per 1000 livebirths in each network for culture-negative cases treated for at least 5 days (CN ≥ 5d), culture-negative cases treated shorter than 5 days (CN < 5d), and culture-proven early-onset sepsis (CP-EOS) cases.

See this image and copyright information in PMC

References

1. Schulman, J. et al. Newborn antibiotic exposures and association with proven bloodstream infection. Pediatrics144, e20191105 (2019). - PubMed
1. Goel, N. et al. Implementation of an adapted Sepsis Risk Calculator algorithm to reduce antibiotic usage in the management of early onset neonatal sepsis: a multicentre initiative in Wales, UK. Arch. Dis. Child. Fetal Neonatal Ed.107, 303–310 (2022). - PubMed
1. Achten, N. B. et al. Association of use of the neonatal early-onset sepsis calculator with reduction in antibiotic therapy and safety: a systematic review and meta-analysis. JAMA Pediatr.173, 1032–1040 (2019). - PMC - PubMed
1. Kuzniewicz, M. W. et al. A quantitative, risk-based approach to the management of neonatal early-onset sepsis. JAMA Pediatr.171, 365–371 (2017). - PubMed
1. Agyeman, P. K. A. et al. Epidemiology of blood culture-proven bacterial sepsis in children in Switzerland: a population-based cohort study. Lancet Child Adolesc. Health1, 124–133 (2017). - PubMed

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Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study

Collaborators

Affiliations

Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous