Procalcitonin- and Presepsin-Guided Antibiotics for Early-Onset Sepsis in Preterm Infants: A Randomized Clinical Trial

Importance Early administration of antibiotics in the absence of proven sepsis, such as for treatment of early-onset sepsis (EOS), has been associated with adverse outcomes in very preterm infants. Reference values for procalcitonin (PCT) and presepsin (P-SEP) have been established in preterm infants. Objective To determine whether PCT- and P-SEP–guided antibiotic treatment for EOS was noninferior to universal antibiotic treatment with respect to survival without major morbidity. Design, Setting, and Participants This randomized multicenter noninferiority clinical trial was conducted in 17 Italian neonatal intensive care units between June 1, 2023, and January 31, 2025, among preterm infants born at 25 weeks and 0 days to 31 weeks and 6 days of gestation. Interventions Enrolled infants were randomly allocated to receive either PCT- and P-SEP–guided antibiotic treatment, administered if PCT and P-SEP levels exceeded prespecified thresholds, or universal antibiotic treatment for EOS. Main Outcomes and Measures The composite primary outcome was defined as survival without late-onset sepsis (LOS), bronchopulmonary dysplasia, grade 3 or 4 intraventricular hemorrhage (IVH), grade 2 or higher necrotizing enterocolitis (NEC), periventricular leukomalacia (PVL), or stage 3 or higher retinopathy of prematurity (ROP). The prespecified noninferiority margin was −5 percentage points. Both a primary intention-to-treat analysis and a secondary per-protocol analysis were performed, as recommended for noninferiority trials. Results The study enrolled and randomized 283 very preterm infants (mean [SD] gestational age, 30.2 [2.2] weeks; 161 girls [57%]); 143 received procalcitonin- and presepsin-guided treatment and 140 received universal antibiotic treatment. The primary outcome did not differ between the PCT- and P-SEP–guided treatment group and the universal antibiotic treatment groups (76 of 143 [53%] vs 77 of 140 [55%]; risk difference, −1.8 percentage points; 90% CI, −11.9 to 8.3 percentage points; P = .32). Noninferiority of PCT- and P-SEP–guided treatment compared with universal treatment was not demonstrated, because the lower bound of the 2-sided 90% CI crossed the prespecified noninferiority margin. The risk differences for LOS, IVH, NEC, PVL, ROP, and death were not significantly different between the groups. PCT and P-SEP values were not different between the groups. No patient developed EOS. Conclusions and Relevance In this randomized clinical trial conducted among neonates born between 25 weeks and 0 days and 31 weeks and 6 days of gestation, a PCT- and P-SEP–guided strategy for the treatment of EOS did not demonstrate noninferiority to universal antibiotic treatment with respect to survival without major morbidity. Within the limits of this study, these findings do not support the routine use of a biomarker-guided approach as an alternative to universal treatment for this high-risk population. Trial Registration Clinicaltrials.gov identifier: NCT05796115