Background: Accurately distinguishing bacterial from non-bacterial infections is essential to guide antibiotic use but remains clinically challenging. Current biomarkers such as C-reactive protein and procalcitonin have limited diagnostic accuracy. Objective: To identify novel blood protein biomarkers with clinically acceptable performance for differentiating bacterial from non-bacterial infections. Methods: Following PRISMA guidelines, we systematically searched Medline and prior reviews (2010-2024) for studies evaluating the diagnostic accuracy of protein biomarkers in serum or plasma for bacterial infection. Biomarkers were considered clinically useful if sensitivity >90%, specificity >80%, or AUC >0.9, was reported in studies with low risk of bias (assessed via modified QUADAS-2). Results: From 2,236 records, 47 studies were included, assessing 50 individual biomarkers and 12 signatures. Two individual biomarkers (LCN2, IFN-y) and three multi-marker signatures (TRAIL+IP-10+CRP, E-selectin+IL-18+NCAM1+LCN2+IFN-y, and E-selectin+IL-18+NCAM1+LG3BP+LCN2+IFN-y) met pre-defined performance thresholds. TRAIL+IP-10+CRP showed consistent performance across six studies. Conclusions: TRAIL+IP-10+CRP and LCN2 are promising host-response biomarkers for bacterial infection. Multi-marker panels may enhance diagnostic accuracy but require further validation. These tools have the potential to improve clinical decision-making and reduce unnecessary antibiotic use.

The authors have declared no competing interest.

This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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