Weissella Confusa Infections and Strain-Level Biosafety: Clinical Evidence and Intrinsic Vancomycin Resistance

Abstract: Weissella confusa is an emerging opportunistic pathogen increasingly implicated in invasive infection among immunocompromised individuals, while selected strains continue to be investigated for probiotic applications-creating an inherent tension between beneficial use and infection risk. This is the first systematic synthesis of 39 published cases of invasive W. confusa infection. In this review, we analyzed these cases and summarized current evidence regarding epidemiology, diagnostic approaches, antimicrobial susceptibility, therapeutic management, and biosafety implications. Bacteremia (74.4%) and infective endocarditis (10.3%) were the predominant clinical manifestations and occurred mainly in patients with malignancy, prolonged hospitalization, indwelling medical devices, gastrointestinal barrier disruption, or immunosuppression. Accurate identification remains difficult because W. confusa shares phenotypic characteristics with other lactic acid bacteria and exhibits intrinsic resistance to vancomycin, frequently leading to misidentification and delayed effective therapy. Advanced diagnostic methods including MALDI-TOF MS, 16S rRNA sequencing, and whole-genome sequencing are therefore important for definitive identification. Available evidence suggests that pathogenicity is largely host-dependent, although definitive functional genomic evidence remains limited. Clinically effective antimicrobial agents generally include beta-lactams, daptomycin, and linezolid, whereas glycopeptides should be avoided because of predictable intrinsic resistance. The overall mortality rate in this cohort was 33.3% (13/39). Beyond its clinical relevance, W. confusa highlights limitations of traditional species-level probiotic safety evaluation. We propose a strain-specific biosafety assessment framework integrating genomic screening, antimicrobial resistance profiling, virulence assessment, and phenotypic validation to support safer probiotic development and regulatory evaluation. This framework may provide a useful model for assessing other microorganisms with dual probiotic and opportunistic pathogenic potential. Keywords: Weissella confusa , antimicrobial resistance, vancomycin resistance, opportunistic pathogen, strain-specific assessment, probiotic safety