Background: Bacteroides fragilis is the most clinically important anaerobic bacterium and has shown increasing carbapenem resistance mediated by the cfiA metallo-β-lactamase. Although insertion sequence (IS)-mediated activation of cfiA is a well-recognized mechanism, the contribution of IS-independent genomic mechanisms remains incompletely characterized. This study investigated the phenotypic and genomic mechanisms of cfiA-associated carbapenem resistance in clinical B. fragilis isolates from Korea. Methods: Twenty-six non-duplicate carbapenem-nonsusceptible B. fragilis isolates were collected from three Korean institutions between 2022 and 2023. Antimicrobial susceptibility was tested by disk diffusion and agar dilution methods, and carbapenemase activity was assessed using the anaerobic carbapenem inactivation method (Ana-CIM) and the meropenem double-ended Etest. Whole-genome sequencing was performed to identify resistance determinants, insertion sequences, promoter structures, and multilocus sequence types. Results: Among 26 isolates, 12 (46.2%) were cfiA-positive and 14 (53.8%) were cfiA-negative. High-level resistance (imipenem MIC ≥ 32 mg/L; meropenem MIC ≥ 128 mg/L) was observed in four cfiA-positive isolates carrying activating IS elements (IS1187 or IS942) upstream of cfiA. Notably, three additional highly resistant cfiA-positive isolates lacked upstream IS elements and showed distinct genomic features, including tandem duplication of cfiA2 (SEV23_101), duplicated promoter architecture upstream of cfiA14 (SEV23_15), and high-level resistance associated with cfiA18 (SCL22_40). Ana-CIM yielded positive results only among isolates with meropenem MIC ≥ 128 mg/L, whereas the meropenem double-ended Etest failed to discriminate cfiA-associated carbapenemase activity. Conclusions: These findings indicate that high-level carbapenem resistance in B. fragilis may be associated with several genomic features, including IS-mediated activation, increased cfiA gene dosage, and promoter amplification. Molecular characterization is therefore essential for accurate interpretation of carbapenem resistance in B. fragilis.

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