Thomas H Dierikx1,2, Nancy Deianova3,4, Jip Groen3,4, Daniel C Vijlbrief5, Christian Hulzebos6, Willem P de Boode7, Esther J d'Haens8, Veerle Cossey9, Boris W Kramer10, Mirjam M van Weissenbruch11,12, Wouter J de Jonge13, Marc A Benninga4,14, Chris H van den Akker11,12, Anton H van Kaam11,12, Nanne K H de Boer4,15, Douwe H Visser11,12, Hendrik J Niemarkt16, Tim G J de Meij3,4. 1. Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, location Vrije Universiteit Amsterdam, De Boelelaan 1117, room PK-1 Z 050, Amsterdam, 1081 HZ, The Netherlands. t.dierikx@amsterdamumc.nl. 2. Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, the Netherlands. t.dierikx@amsterdamumc.nl. 3. Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, location Vrije Universiteit Amsterdam, De Boelelaan 1117, room PK-1 Z 050, Amsterdam, 1081 HZ, The Netherlands. 4. Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam, the Netherlands. 5. Department of Neonatology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands. 6. Division of Neonatology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 7. Department of Neonatology, Amalia Children's Hospital, Radboud UMC, Radboud Institute for Health Sciences, Nijmegen, The Netherlands. 8. Neonatal Intensive Care Unit, Amalia Children's Center, Isala, Zwolle, the Netherlands. 9. Department of Neonatology, University Hospitals Leuven, Leuven, Belgium. 10. Neonatal Intensive Care Unit, Department of Pediatrics, Maastricht UMC, University Maastricht, Maastricht, the Netherlands. 11. Department of Neonatology, Amsterdam UMC, Location University of Amsterdam, Amsterdam, the Netherlands. 12. Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands. 13. Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism Research Institute, Amsterdam UMC, location University of Amsterdam, Amsterdam, the Netherlands. 14. Department of Pediatric Gastroenterology, Amsterdam UMC, location University of Amsterdam, Amsterdam, the Netherlands. 15. Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 16. Department of Neonatology, Máxima Medical Center, Veldhoven, the Netherlands.
Abstract
The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003). CONCLUSION: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. WHAT IS KNOWN: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. WHAT IS NEW: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.
The threshold to initiate empiric antibiotics for suspicion of early-onset sepsis (EOS) is low in preterm infants. Antibiotics' effects on short-term outcomes have recently been debated. We aimed at exploring the extent of early empiric antibiotic exposure (EEAE) in preterm infants and the association between the duration of EEAE with necrotizing enterocolitis (NEC) and late-onset sepsis (LOS) within different EEAE groups. EEAE practice for suspicion of EOS was evaluated in all included infants (gestational age < 30 weeks) born in 9 centers in the Netherlands and Belgium between Oct. 2014 and Jan. 2019. EEAE association with NEC and LOS development was analyzed by multivariate regression. After excluding 56 EOS cases, 1259 infants were included. A total of 1122 infants (89.1%) were exposed to empirical antibiotics for the suspicion of EOS of whom 802 (63.7%) had short (≤ 72 h) and 320 (25.4%) prolonged EEAE (> 72 h). Infants with EEAE ≤ 72 h had a lower incidence of NEC compared to both infants without EEAE (adjusted odds ratio (aOR) 0.39; 95% confidence interval (CI) [0.19-0.80]; p = 0.01) and with prolonged EEAE (> 72 h) (aOR [95%CI]: 0.58 [0.35-0.96]; p = 0.03). With every additional day of EEAE, LOS incidence decreased (aOR [95%CI]: 0.90 [0.85-0.97]; p = 0.003). CONCLUSION: Almost 90% of preterm infants who have negative blood culture results in the first 72 h of life are exposed to EEAE under suspicion of EOS. One-fourth has prolonged EEAE. Duration of EEAE was differently associated with NEC and LOS incidence. The effects of antibiotics, and potentially induced microbial dysbiosis related to development of NEC and LOS, should further be explored. WHAT IS KNOWN: • Preterm infants often receive antibiotics empirically directly after birth for suspicion of early-onset sepsis. • The effects of the duration of early empirical antibiotic exposure on the risk for necrotizing enterocolitis and late-onset sepsis are debated. WHAT IS NEW: • Almost 90% of preterm infants with a gestational age below 30 weeks are exposed to antibiotics empirically after birth despite negative culture results. In a quarter of these culture-negative infants, empirical antibiotics are prolonged. • A short course of empirical antibiotics (≤72h) is associated with decreased odds for necrotizing enterocolitis compared to both prolonged (>72h) or no empirical antibiotics after birth. Furthermore, every additional day of empirical antibiotic exposure is associated with decreased risk for late-onset sepsis in the first month of life.
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