Microbiome Signatures and Inflammatory Biomarkers in Culture-Negative Neonatal Sepsis

Overuse of antibiotics is a concern in ‘culture-negative sepsis’ but it is unclear whether this is due to infection with viruses, fungi or other microbes that are not easily cultured, or whether it results from inflammatory processes. In a prospective study, we enrolled 50 preterm neonates with culture-positive sepsis (CP), culture-negative sepsis (CN), and asymptomatic preterm controls (CO). The microbiome of stool, skin, and blood, including bacterial, viral and fungal components and serum cytokine profiles were evaluated. The microbiome alpha or beta diversity did not differ between CN and CO groups. A MaAsLin analysis revealed increased relative abundances of specific bacterial and fungal genera in stool and skin samples in the CN group compared to CO. The virome analysis identified 24 viruses from skin samples, but they were not statistically different among the three groups. The cytokine and chemokine biomarker profiles were elevated in the CP group but were not statistically different between the CN and CO groups. Although the CN group had a longer hospital stay and higher BPD rates than the controls in unadjusted analyses, these differences were not significant after adjusting for gestational age and birth weight. The CN infants demonstrated microbial shifts without systemic immune activation or significantly worse clinical outcomes, supporting the rationale for discontinuing antibiotics in the absence of positive cultures.