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

Varvara Dimopoulou; Claus Klingenberg; Lars Navér; Viveka Nordberg; Alberto Berardi; Salhab El Helou; Gerhard Fusch; Joseph M Bliss; Dirk Lehnick; Nicholas Guerina; Joanna Seliga-Siwecka; Pierre Maton; Donatienne Lagae; Judit Mari; Jan Janota; Philipp K A Agyeman; Riccardo Pfister; Giuseppe Latorre; Gianfranco Maffei; Nicola Laforgia; Enikő Mózes; Ketil Størdal; Tobias Strunk; Martin Stocker; Eric Giannoni; AENEAS Study Group

doi:10.1038/s41390-024-03532-6

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

Pediatr Res. 2024 Sep 17. doi: 10.1038/s41390-024-03532-6. Online ahead of print.

Authors

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

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
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.