Differentiating Tuberculous and Pyogenic Spondylodiscitis: Part I-Epidemiology, Clinical Features, Laboratory Markers, and Tissue-Based Diagnosis.

Distinguishing tuberculous spondylodiscitis (TS) from pyogenic spondylodiscitis (PS) remains difficult when presentation is non-specific, blood cultures are negative, or initial biopsy is non-diagnostic. The two entities differ substantially in antimicrobial strategies, resistance testing requirements, public health interventions, and surgical thresholds, yet diagnostic delay is associated with neurological deficits, spinal instability, and permanent deformity. This narrative review maps the non-imaging evidence most useful for frontline differentiation between TS and PS across five domains: epidemiology and risk stratification, clinical presentation, laboratory markers, tissue acquisition and histopathology, and molecular diagnostics. PubMed/MEDLINE was searched from inception to 31 March 2026 using pre-specified Boolean search terms; a secondary Scopus search identified no additional eligible records. Following screening, approximately 90 records were included in this synthesis. Priority was given to comparative TS-versus-PS cohorts, biopsy-yield and culture-negative studies, pathology series, pediatric data, and recent molecular diagnostics literature. Epidemiological TB (tuberculosis) risk, longer symptom duration, constitutional symptoms, deformity, and a less intense acute-phase response increase the probability of TS, whereas healthcare exposure, bacteraemia, recent spinal procedures, and brisk neutrophilic inflammation favor PS. In stable patients, the highest-yield strategy is early blood cultures followed by image-guided biopsy with parallel tissue allocation for bacterial culture, mycobacterial studies, histopathology, and selected molecular assays. No single laboratory marker reliably distinguishes TS from PS without tissue confirmation. Per a 2023 systematic review and meta-analysis, image-guided percutaneous biopsy achieves microbiological confirmation in approximately one-third of cases. Histopathology demonstrating caseating granulomatous inflammation supports TS, although a substantial minority of confirmed cases lack classic features. Supported by cohort prospective data, Xpert MTB/RIF Ultra has the clearest first-line molecular role when TS is plausible and should be requested at the time of first biopsy rather than reserved for salvage testing; broader or targeted next-generation sequencing is best reserved for selected unresolved cases. Imaging differentiation is addressed in the companion manuscript, Part II.