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.

Biostatistics and Methodology CTU CS Faculty of Health Sciences and Medicine University of Lucerne Lucerne Switzerland

Clinic of Neonatology Department Mother Woman Child Lausanne University Hospital and University of Lausanne Lausanne Switzerland

Department of Neonatology and Neonatal Intensive Care Medical University of Warsaw Warsaw Poland

Department of Neonatology Karolinska University Hospital and Department of Clinical Science Intervention and Technology Karolinska Institutet Stockholm Sweden

Department of Neonatology Thomayer University Hospital Prague Prague Czech Republic

Department of Paediatrics University of Szeged Szeged Hungary

Department of Pathological Physiology 1st Medical School Charles University Prague Prague Czech Republic

Department of Pediatric Research Institute of Clinical Medicine University of Oslo and Oslo University Hospital Oslo Norway

Department of Pediatrics and Adolescence Medicine University Hospital of North Norway Tromsø Norway

Department of Pediatrics Children's Hospital Lucerne Lucerne Switzerland

Department of Pediatrics Women and Infants Hospital of Rhode Island Warren Alpert Medical School of Brown University Providence RI USA

Division of Neonatology Department of Pediatrics McMaster Children's Hospital McMaster University Hamilton Health Sciences Hamilton Ontario ON Canada

Division of Neonatology Department of Pediatrics University of Rochester Medical Center Rochester NY USA

Division of Pediatric Infectious Disease Department of Pediatrics Inselspital Bern University Hospital University of Bern Bern Switzerland

Neonatal Directorate Child and Adolescent Health Service King Edward Memorial Hospital Perth WA Australia

Neonatal Intensive Care Unit Mother and Child Department Policlinico University Hospital Modena Italy

Neonatal Service CHC Montlegia Clinic CHC Health Group Liège Belgium

Neonatal Unit Department of Obstetrics and Gynecology Motol University Hospital Prague Prague Czech Republic

Neonatology and Neonatal Intensive Care Unit CHIREC Delta Hospital Brussels Belgium

Neonatology and Neonatal Intensive Care Unit Ecclesiastical General Hospital F Miulli Acquaviva delle Fonti Italy

Neonatology and Neonatal Intensive Care Unit Policlinico Riuniti Foggia Foggia Italy

Neonatology and Neonatal Intensive Care Unit University of Bari Bari Italy

Neonatology and Paediatric Intensive Care Unit Geneva University Hospitals and Geneva University Geneva Switzerland

Perinatal Intensive Care Unit Department of Obstetrics and Gynaecology Semmelweis University Budapest Hungary

Research Group for Child and Adolescent Health Faculty of Health Sciences UiT The Arctic University of Norway Tromsø Norway

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