IMPORTANCE: Appropriate use of antibiotics is life-saving in neonatal early-onset sepsis (EOS), but overuse of antibiotics is associated with antimicrobial resistance and long-term adverse outcomes. Large international studies quantifying early-life antibiotic exposure along with EOS incidence are needed to provide a basis for future interventions aimed at safely reducing neonatal antibiotic exposure. OBJECTIVE: To compare early postnatal exposure to antibiotics, incidence of EOS, and mortality among different networks in high-income countries. DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, cross-sectional study of late-preterm and full-term neonates born between January 1, 2014, and December 31, 2018, in 13 hospital-based or population-based networks from 11 countries in Europe and North America and Australia. The study included all infants born alive at a gestational age greater than or equal to 34 weeks in the participating networks. Data were analyzed from October 2021 to March 2022. EXPOSURES: Exposure to antibiotics started in the first postnatal week. MAIN OUTCOMES AND MEASURES: The main outcomes were the proportion of late-preterm and full-term neonates receiving intravenous antibiotics, the duration of antibiotic treatment, the incidence of culture-proven EOS, and all-cause and EOS-associated mortality. RESULTS: A total of 757 979 late-preterm and full-term neonates were born in the participating networks during the study period; 21 703 neonates (2.86%; 95% CI, 2.83%-2.90%), including 12 886 boys (59.4%) with a median (IQR) gestational age of 39 (36-40) weeks and median (IQR) birth weight of 3250 (2750-3750) g, received intravenous antibiotics during the first postnatal week. The proportion of neonates started on antibiotics ranged from 1.18% to 12.45% among networks. The median (IQR) duration of treatment was 9 (7-14) days for neonates with EOS and 4 (3-6) days for those without EOS. This led to an antibiotic exposure of 135 days per 1000 live births (range across networks, 54-491 days per 1000 live births). The incidence of EOS was 0.49 cases per 1000 live births (range, 0.18-1.45 cases per 1000 live births). EOS-associated mortality was 3.20% (12 of 375 neonates; range, 0.00%-12.00%). For each case of EOS, 58 neonates were started on antibiotics and 273 antibiotic days were administered. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that antibiotic exposure during the first postnatal week is disproportionate compared with the burden of EOS and that there are wide (up to 9-fold) variations internationally. This study defined a set of indicators reporting on both dimensions to facilitate benchmarking and future interventions aimed at safely reducing antibiotic exposure in early life.

Biostatistics and Methodology CTU CS Department 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 Pediatrics and Adolescence Medicine University Hospital of North Norway Tromsø Norway

Department of Pediatrics Children's Hospital Lucerne Lucerne Switzerland

Department of Pediatrics Inselspital Bern University Hospital University of Bern Bern Switzerland

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

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

Institute of Clinical Medicine University of Oslo and Oslo University Hospital Oslo Norway

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

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

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

Neonatologia e Terapia Intensiva Neonatale University of Bari Bari Italy

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

Paediatric Research Group Faculty of Health Sciences UiT The Arctic University of Norway Tromsø Norway

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

Service Néonatal Clinique CHC Montlegia Groupe Santé CHC Liège Belgium

JAMA Netw Open. 2022 Nov 1;5(11):e2243705. doi: 10.1001/jamanetworkopen.2022.43705. PubMed

Zobrazit více v PubMed

Versporten A, Zarb P, Caniaux I, et al. ; Global-PPS network . Antimicrobial consumption and resistance in adult hospital inpatients in 53 countries: results of an internet-based global point prevalence survey. Lancet Glob Health. 2018;6(6):e619-e629. doi:10.1016/S2214-109X(18)30186-4 PubMed DOI

Prusakov P, Goff DA, Wozniak PS, et al. ; Global NEO-ASP Study Group . A global point prevalence survey of antimicrobial use in neonatal intensive care units: the no-more-antibiotics and resistance (NO-MAS-R) study. EClinicalMedicine. 2021;32:100727. doi:10.1016/j.eclinm.2021.100727 PubMed DOI PMC

Hufnagel M, Versporten A, Bielicki J, Drapier N, Sharland M, Goossens H; ARPEC Project Group . High rates of prescribing antimicrobials for prophylaxis in children and neonates: results from the Antibiotic Resistance and Prescribing in European Children Point Prevalence Survey. J Pediatric Infect Dis Soc. 2019;8(2):143-151. doi:10.1093/jpids/piy019 PubMed DOI

World Health Organization . World Health Assembly 69. Global action plan on antimicrobial resistance: options for establishing a global development and stewardship framework to support the development, control, distribution and appropriate use of new antimicrobial medicines, diagnostic tools, vaccines and other interventions—report by the Secretariat. 2016. Accessed April 5, 2022. https://apps.who.int/iris/handle/10665/252682

Fjalstad JW, Esaiassen E, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic therapy in neonates and impact on gut microbiota and antibiotic resistance development: a systematic review. J Antimicrob Chemother. 2018;73(3):569-580. doi:10.1093/jac/dkx426 PubMed DOI

Antimicrobial Resistance Collaborators . Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655. doi:10.1016/S0140-6736(21)02724-0 PubMed DOI PMC

Stiemsma LT, Michels KB. The role of the microbiome in the developmental origins of health and disease. Pediatrics. 2018;141(4):e20172437. doi:10.1542/peds.2017-2437 PubMed DOI PMC

Sourour W, Sanchez V, Sourour M, et al. . The association between prolonged antibiotic use in culture negative infants and length of hospital stay and total hospital costs. Am J Perinatol. Published online May 11, 2021. doi:10.1055/s-0041-1729560 PubMed DOI

Stark A, Smith PB, Hornik CP, et al. . Medication use in the neonatal intensive care unit and changes from 2010 to 2018. J Pediatr. 2022;240:66-71.e4. doi:10.1016/j.jpeds.2021.08.075 PubMed DOI PMC

Benitz WE, Achten NB. Finding a role for the neonatal early-onset sepsis risk calculator. EClinicalMedicine. 2020;19:100255. doi:10.1016/j.eclinm.2019.100255 PubMed DOI PMC

Achten NB, Klingenberg C, Benitz WE, 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. 2019;173(11):1032-1040. doi:10.1001/jamapediatrics.2019.2825 PubMed DOI PMC

Klingenberg C, Kornelisse RF, Buonocore G, Maier RF, Stocker M. Culture-negative early-onset neonatal sepsis: at the crossroad between efficient sepsis care and antimicrobial stewardship. Front Pediatr. 2018;6:285. doi:10.3389/fped.2018.00285 PubMed DOI PMC

Cantey JB, Patel SJ. Antimicrobial stewardship in the NICU. Infect Dis Clin North Am. 2014;28(2):247-261. doi:10.1016/j.idc.2014.01.005 PubMed DOI

Araujo da Silva AR, Marques A, Di Biase C, et al. . Effectiveness of antimicrobial stewardship programmes in neonatology: a systematic review. Arch Dis Child. 2020;105(6):563-568. doi:10.1136/archdischild-2019-318026 PubMed DOI

Flannery DD, Horbar JD. Metrics of neonatal antibiotic use. Semin Perinatol. 2020;44(8):151329. doi:10.1016/j.semperi.2020.151329 PubMed DOI

Fitchett EJA, Seale AC, Vergnano S, et al. ; SPRING (Strengthening Publications Reporting Infection in Newborns Globally) Group . Strengthening the Reporting of Observational Studies in Epidemiology for Newborn Infection (STROBE-NI): an extension of the STROBE statement for neonatal infection research. Lancet Infect Dis. 2016;16(10):e202-e213. doi:10.1016/S1473-3099(16)30082-2 PubMed DOI

Kuzniewicz MW, Puopolo KM, Fischer A, et al. . A quantitative, risk-based approach to the management of neonatal early-onset sepsis. JAMA Pediatr. 2017;171(4):365-371. doi:10.1001/jamapediatrics.2016.4678 PubMed DOI

American Academy of Pediatrics Committee on Fetus And Newborn . Levels of neonatal care. Pediatrics. 2012;130(3):587-597. doi:10.1542/peds.2012-1999 PubMed DOI

Giannoni E, Agyeman PKA, Stocker M, et al. ; Swiss Pediatric Sepsis Study . Neonatal sepsis of early onset, and hospital-acquired and community-acquired late onset: a prospective population-based cohort study. J Pediatr. 2018;201:106-114.e4. doi:10.1016/j.jpeds.2018.05.048 PubMed DOI

Schrag SJ, Farley MM, Petit S, et al. . Epidemiology of invasive early-onset neonatal sepsis, 2005 to 2014. Pediatrics. 2016;138(6):e20162013. doi:10.1542/peds.2016-2013 PubMed DOI

Stoll BJ, Puopolo KM, Hansen NI, et al. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network . Early-onset neonatal sepsis 2015 to 2017, the rise of Escherichia coli, and the need for novel prevention strategies. JAMA Pediatr. 2020;174(7):e200593. doi:10.1001/jamapediatrics.2020.0593 PubMed DOI PMC

Cailes B, Kortsalioudaki C, Buttery J, et al. ; neonIN Network . Epidemiology of UK neonatal infections: the neonIN Infection Surveillance Network. Arch Dis Child Fetal Neonatal Ed. 2018;103(6):F547-F553. doi:10.1136/archdischild-2017-313203 PubMed DOI

Braye K, Foureur M, de Waal K, Jones M, Putt E, Ferguson J. Epidemiology of neonatal early-onset sepsis in a geographically diverse Australian health district 2006-2016. PLoS One. 2019;14(4):e0214298. doi:10.1371/journal.pone.0214298 PubMed DOI PMC

Schulman J, Benitz WE, Profit J, et al. . Newborn antibiotic exposures and association with proven bloodstream infection. Pediatrics. 2019;144(5):e20191105. doi:10.1542/peds.2019-1105 PubMed DOI

Escobar GJ, Puopolo KM, Wi S, et al. . Stratification of risk of early-onset sepsis in newborns ≥ 34 weeks’ gestation. Pediatrics. 2014;133(1):30-36. doi:10.1542/peds.2013-1689 PubMed DOI PMC

Mundal HS, Rønnestad A, Klingenberg C, Stensvold HJ, Størdal K. Antibiotic use in term and near-term newborns. Pediatrics. 2021;148(6):e2021051339. doi:10.1542/peds.2021-051339 PubMed DOI

Goel N, Cannell S, Davies G, 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. 2022;107(3):303-310. doi:10.1136/archdischild-2020-321489 PubMed DOI

Berardi A, Bedetti L, Spada C, Lucaccioni L, Frymoyer A. Serial clinical observation for management of newborns at risk of early-onset sepsis. Curr Opin Pediatr. 2020;32(2):245-251. doi:10.1097/MOP.0000000000000864 PubMed DOI

Vatne A, Klingenberg C, Øymar K, Rønnestad AE, Manzoni P, Rettedal S. Reduced antibiotic exposure by serial physical examinations in term neonates at risk of early-onset sepsis. Pediatr Infect Dis J. 2020;39(5):438-443. doi:10.1097/INF.0000000000002590 PubMed DOI

Duvoisin G, Fischer C, Maucort-Boulch D, Giannoni E. Reduction in the use of diagnostic tests in infants with risk factors for early-onset neonatal sepsis does not delay antibiotic treatment. Swiss Med Wkly. 2014;144:w13981. doi:10.4414/smw.2014.13981 PubMed DOI

Schulman J, Dimand RJ, Lee HC, Duenas GV, Bennett MV, Gould JB. Neonatal intensive care unit antibiotic use. Pediatrics. 2015;135(5):826-833. doi:10.1542/peds.2014-3409 PubMed DOI

van Herk W, el Helou S, Janota J, et al. . Variation in current management of term and late-preterm neonates at risk for early-onset sepsis: an international survey and review of guidelines. Pediatr Infect Dis J. 2016;35(5):494-500. doi:10.1097/INF.0000000000001063 PubMed DOI

Steinmann KE, Lehnick D, Buettcher M, et al. . Impact of empowering leadership on antimicrobial stewardship: a single center study in a neonatal and pediatric intensive care unit and a literature review. Front Pediatr. 2018;6:294. doi:10.3389/fped.2018.00294 PubMed DOI PMC

Satterfield J, Miesner AR, Percival KM. The role of education in antimicrobial stewardship. J Hosp Infect. 2020;105(2):130-141. doi:10.1016/j.jhin.2020.03.028 PubMed DOI

Grünebaum A, McCullough LB, Arabin B, Dudenhausen J, Orosz B, Chervenak FA. Underlying causes of neonatal deaths in term singleton pregnancies: home births versus hospital births in the United States. J Perinat Med. 2017;45(3):349-357. doi:10.1515/jpm-2016-0200 PubMed DOI

Stocker M, van Herk W, El Helou S, et al. ; NeoPInS Study Group . Procalcitonin-guided decision making for duration of antibiotic therapy in neonates with suspected early-onset sepsis: a multicentre, randomised controlled trial (NeoPIns). Lancet. 2017;390(10097):871-881. doi:10.1016/S0140-6736(17)31444-7 PubMed DOI

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

Less is more: Antibiotics at the beginning of life