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Acute respiratory viral-bacterial co-infections complicate antimicrobial decisions because pathogen detection may not establish whether both organisms are clinically contributing to disease. We synthesized evidence from adult and pediatric acute respiratory infection cohorts, including influenza, SARS-CoV-2, respiratory syncytial virus, adenovirus, and selected mixed-detection febrile illness studies, to evaluate host-response biomarkers for distinguishing co-infection from mono-infection. Conventional C-reactive protein and procalcitonin were most useful as supportive or rule-out markers of bacterial involvement, but lacked sufficient specificity when used alone. Dual-axis strategies that combine antiviral and bacterial-response signals, including MxA/CRP, TRAIL/IP-10/CRP, CD169/CD64, IFI44L/FAM89A, and targeted transcriptomic or proteomic signatures, provided more biologically coherent discrimination of mixed infection states. These findings support prospective validation of integrated host-response panels as rapid decision-support tools for antimicrobial stewardship and clinically meaningful co-infection diagnosis.