Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study
Varvara Dimopoulou, Claus Klingenberg, Lars Navér, Viveka Nordberg, Alberto Berardi, Salhab el Helou, Gerhard Fusch, Joseph M. Bliss, Dirk Lehnick, Nicholas Guerina, Joanna Seliga‐Siwecka, Pierre Maton, Donatienne Lagae, Judit Mari, Jan Janota, Philipp Agyeman, Riccardo Pfister, Giuseppe Latorre, G Maffei, Nicola Laforgia, Enikő Mózes, Ketil Størdal, Tobias Strunk, Martin Stocker, Éric Giannoni, the AENEAS Study Group, Capretti Maria Grazia, Ceccoli Martina, De Angelis Morena, Drimaco Pietro, Eap Khalyane, el Helou Zoe, Esmaeilizand Rana, Foglianese Alessandra, Geraci Carmelo, Grochowski Bartłomiej, Håkansson Stellan, Kaur Sharandeep, Kollegger Anne-Louise, Oldendorff Frida, Rizzo Vittoria, Arild E. Rønnestad, Shrestha Damber, Stensvold Hans Jørgen, Trefny Martin, Zilinska Kristyna, Zwijacz Aleksandra
Abstract
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.