Optimising empirical therapy for actinomycetoma in diagnostic-limited settings: Prioritising Amikacin and Linezolid via an Integrated Evidence-Concordance Framework.

Actinomycetoma is a chronic, destructive infection of the skin and subcutaneous tissues that is often treated empirically in endemic settings because species identification and antimicrobial susceptibility testing are unavailable or delayed. We developed an Evidence-Concordance Framework (ECF) integrating published clinical outcomes, phenotypic susceptibility data and CARD-RGI resistome predictions for major Nocardia, Actinomadura and Streptomyces pathogens. Amikacin and linezolid showed the strongest concordance across the three evidence domains. Trimethoprim-sulfamethoxazole (TMP-SMX) remained the therapeutic backbone despite variable in vitro susceptibility, particularly among Streptomyces. Genomic resistance determinants often showed limited agreement with phenotypic or clinical outcomes. The ECF therefore supports TMP-SMX-based therapy, with amikacin and linezolid as strongly supported adjunctive or alternative agents. Genomic prediction should complement, not replace, clinical judgement, species identification and phenotypic susceptibility testing.