Genotypes, Fluconazole Tolerance and Virulence Phenotypes of Candida albicans Bloodstream Isolates: A Multilocus...

Fluconazole tolerance is an emerging phenotype in Candida albicans bloodstream infections, but its relationship to multilocus sequence typing (MLST) lineages and virulence traits is unclear.

To investigate the relationships among MLST genotypes, fluconazole tolerance, and virulence phenotypes in C. albicans bloodstream isolates.

179 C. albicans bloodstream isolates collected from three hospitals in southern Taiwan (2013-2020) were evaluated. Fluconazole tolerance was quantified as the fraction of growth within the inhibition zone (FoG₂₀) using the diskImageR pipeline. Phenotypic profiling included quantification of biofilm biomass and extracellular hydrolytic enzymes. Genetic relatedness was determined via MLST.

The cohort exhibited significant fluconazole tolerance with a mean FoG₂₀ of 0.29 ± 0.19. FoG₂₀ weakly correlated with biofilm biomass (r = 0.218, p = 0.003). MLST identified 169 unique diploid sequence types with 14 clades and 25 clonal complexes (CCs). The high fluconazole tolerance phenotype was broadly distributed across genetically diverse lineages, although clade 16 showed higher mean FoG₂₀ (0.39) (p = 0.003) and biofilm biomass (0.83) (p = 0.039). In multivariable analysis, clade 16 (aOR 2.86; 95% CI 1.08-7.56; p = 0.034) and protease activity (aOR 2.65; 95% CI 1.24-5.64; p = 0.012), but not biofilm biomass (p = 0.142), were independently associated with high tolerance. High tolerance showed a borderline association with 14-day mortality (aOR 2.56; 95% CI 0.99-6.62; p = 0.052).

Fluconazole tolerance in C. albicans was distributed across diverse lineages, suggesting convergent adaptation. Clade 16 and protease activity were independently associated with tolerance. Given the observed trend toward an association between high tolerance and 14-day mortality, future mechanistic studies and larger clinical outcome studies are warranted.