Global patterns and temporal evolution of fusidic acid resistance in Staphylococcus aureus: A genomic analysis of 2701 resistant isolates spanning six decades.

OBJECTIVES

Fusidic acid resistance in Staphylococcus aureus is a growing clinical concern, but its temporal dynamics and mechanism evolution at a global scale are poorly characterised.

METHODS

We combined 2512 fusidic acid-resistant S. aureus isolates from Pathogenwatch (1964-2021) with 189 resistant isolates identified from 5051 NCBI GenBank genomes deposited January 2022-April 2026, yielding 2701 isolates across 72 countries (2549 with collection years, 1964-2025). AMR determinants were identified using AMRFinderPlus v4.2.7 and sequence types using mlst v2.23.0. Temporal mechanism shifts were tested by chi-squared across six eras.

RESULTS

fusC (52.0%), fusA (35.1%), and fusB (12.8%) were the primary mechanisms. A highly significant temporal shift was observed (chi-squared = 283.7, P = 4.4 × 10⁻⁵⁵): fusB rose from 15% (pre-2000) to 61.5% (2021-2025), overtaking both fusC and fusA. The earliest chromosomal events were fusA P404L in ST250 (1964) and P404Q in ST247 (1965). 93.9% of isolates were MDR; fusA independently predicted quinolone co-resistance (adjusted OR = 12.47). PVL positivity was 13.3%, driven by clonal background. ST121 (EEFIC) showed late emergence (92% in 2011-2025).

CONCLUSION

Fusidic acid resistance is shifting from chromosomal fusA towards plasmid-mediated fusB, supporting integrated molecular surveillance to guide therapy and stewardship.