Martin Stocker1, Wendy van Herk2, Salhab El Helou3, Sourabh Dutta3, Matteo S Fontana1, Frank A B A Schuerman4, Rita K van den Tooren-de Groot5, Jantien W Wieringa6, Jan Janota7, Laura H van der Meer-Kappelle8, Rob Moonen9, Sintha D Sie10, Esther de Vries11, Albertine E Donker12, Urs Zimmerman13, Luregn J Schlapbach14, Amerik C de Mol15, Angelique Hoffman-Haringsma16, Madan Roy17, Maren Tomaske18, René F Kornelisse19, Juliette van Gijsel20, Eline G Visser21, Sten P Willemsen22, Annemarie M C van Rossum21. 1. Department of Paediatrics, Neonatal and Paediatric Intensive Care Unit, Children's Hospital Lucerne, Lucerne, Switzerland. 2. Department of Paediatrics, Division of Paediatric Infectious Diseases & Immunology, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands. Electronic address: w.vanherk@erasmusmc.nl. 3. Division of Neonatology, McMaster University Children's Hospital, Hamilton Health Sciences, Hamilton, ON, Canada. 4. Department of Paediatrics, Flevo Hospital, Almere, Netherlands. 5. Department of Paediatrics, Bronovo Hospital, 's Gravenhage, Netherlands. 6. Department of Paediatrics, MC Haaglanden, 's Gravenhage, Netherlands. 7. Department of Neonatology, Thomayer Hospital, Prague, Czech Republic; Institute of Pathological Physiology, First Medical Faculty, Charles University in Prague, Czech Republic. 8. Department of Neonatology, Reinier de Graaf Gasthuis, Delft, Netherlands. 9. Department of Neonatology, Atrium Medical Centre, Heerlen, Netherlands. 10. Department of Neonatology, VU University Medical Centre, Amsterdam, Netherlands. 11. Department of Paediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch, Netherlands. 12. Department of Paediatrics, Maxima Medical Centre, Veldhoven, Netherlands. 13. Department of Paediatrics, Kantonsspital Winterthur, Winterthur, Switzerland. 14. Department of Paediatrics, Bern University Hospital, Inselspital, University of Bern, Bern, Switzerland; Paediatric Critical Care Research Group, Mater Research Institute, University of Queensland, Brisbane, QLD, Australia; Paediatric Intensive Care Unit, Lady Cilento Children's Hospital, Brisbane, QLD, Australia. 15. Department of Neonatology, Albert Schweitzer Hospital, Dordrecht, Netherlands. 16. Department of Neonatology, Sint Franciscus Gasthuis, Rotterdam, Netherlands. 17. Department of Neonatology, St. Josephs Healthcare, Hamilton Health Sciences, Hamilton, ON, Canada. 18. Department of Paediatrics, Stadtspital Triemli, Zürich, Switzerland. 19. Division of Neonatology, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands. 20. Julius Training General Practitioner, University Medical Centre Utrecht, Netherlands. 21. Department of Paediatrics, Division of Paediatric Infectious Diseases & Immunology, Erasmus MC University Medical Centre-Sophia Children's Hospital, Rotterdam, Netherlands. 22. Department of Biostatistics, Erasmus MC University Medical Centre, Rotterdam, Netherlands.
Abstract
BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION:Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.
RCT Entities:
BACKGROUND: Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment. METHODS: We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned [1:1] using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932. FINDINGS: Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI -4·6 to 4·8) in the intention-to-treat analysis (5 [0·6%] of 866 neonates in the procalcitonin group vs 4 [0·5%] of 844 neonates in the standard group) and 0·1% (-5·2 to 5·3) in the per-protocol analysis (5 [0·7%] of 745 neonates in the procalcitonin group vs 4 [0·6%] of 663 neonates in the standard group). INTERPRETATION: Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death. FUNDING: The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.
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