Antibiotic Therapy for Neonatal Sepsis - Studies on epidemiology, gentamicin safety, and early adverse effects of antibiotics

• Main Author: Fjalstad, Jon Widding
• Format: Doctoral or Postdoctoral Thesis
• Language: English
• Published: UiT The Arctic University of Norway 2018
• Subjects: VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Pediatri: 760; VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Pediatrics: 760; VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Infeksjonsmedisin: 776; VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Communicable diseases: 776; DOKTOR-003; Klingenberg; Laukli; Norway; Salvesen; Tromsø
• Online Access: https://hdl.handle.net/10037/13362

Paper 1, 2, 3 & 4 are not available in Munin. Paper 1: Fjalstad, J.W., Stensvold, H.J., Bergseng, H., Simonsen, G.S., Salvesen, B., Rønnestad, A.E. & Klingenberg, C. (2016). Early-onset Sepsis and Antibiotic Exposure in Term Infants: A Nationwide Population-based Study in Norway. Available in The Pediatric Infectious Disease Journal, 35(1), 1-6. Paper 2: Fjalstad, J.W., Laukli, W., van den Anker, J.N. & Klingenberg, C.(2013). High-dose gentamicin in newborn infants: is it safe? Available in European journal of pediatrics (2014),173, 489-495. Paper 3: Esaiassen, E., Fjalstad, J.W., Juvet, L.K., van den Anker, J.N. & Klingenberg, C. (2017). Antibiotic exposure in neonates and early adverse outcomes: a systematic review and meta-analysis. Available in Journal of Antimicrobial Chemotherapy, 72(7), 1858-70. Paper 4: Fjalstad, J.W., Esaiassen, E., Juvet, L.K., van den Anker, J.N. & Klingenberg, C. (2017). Antibiotic therapy in neonates and impact on gut microbiota and antibiotic resistance development: a systematic review. Available in Journal of Antimicrobial Chemoterapy (2018), 73(3), 569-580. Objectives: The overall aim of this thesis was to investigate different aspects of antibiotic therapy for neonatal sepsis. Material and Methods: The epidemiology of early onset sepsis (EOS) and systemic antibiotic exposure in the first week of life was studied in a nationwide population-based study from the Norwegian Neonatal Network between 2009-2011. A high-dose extended-interval gentamicin regimen was studied in the neonatal unit in Tromsø from 2004-2012. Early adverse effects of antibiotic therapy were studied in a systematic review. We included observational studies and randomized controlled trials that provided data on different categories of antibiotic therapy and either the risk of necrotizing enterocolitis, invasive fungal infection, death, antibiotic resistance development, or changes in the gut microbiota. Results: There were 0.54 cases of culture-confirmed EOS per 1000 live-born term infants with a mortality rate of 1%. Intravenous antibiotics were administered to 2.3% of all live-born term infants in Norway, and half of them were not diagnosed with an infection. In the neonatal unit in Tromsø, gentamicin trough concentrations were above the threshold of 2 mg/L in 6% of cases. Only 1% of these infants suffered from permanent hearing loss. In our systematic reviews, prolonged antibiotic exposure was significantly associated with necrotizing enterocolitis and/or death in preterm infants and reduced gut microbial diversity in all infants. Broad-spectrum antibiotic treatment increased the risk of invasive fungal infection. All categories of antibiotic exposure were associated with an increased risk of antibiotic resistance development. Main Conclusions: The incidence of culture-confirmed EOS in Norway was in line with previous international reports, and the mortality was very low. A large proportion of infants were treated with antibiotics without an infection. The extended-interval high-dose gentamicin regimen studied in this thesis seems safe. Neonatal antibiotic treatment was associated with several adverse effects.