Heteroresistance to Fluconazol in Clinical and Environmental Brazilian Strains of Cryptococcus neoformans/C. gattii Species Complex

To review the literature on heteroresistance to fluconazole (FLC) and investigate the level of heteroresistance to FLC (LHF), we analyzed 100 clinical and environmental Brazilian Cryptococcus strains. Heteroresistance is a phenomenon described as the emergence of resistant subpopulation cells within a single susceptible strain that can tolerate higher concentrations of fluconazole above the minimal inhibitory concentration (MIC) level. We found lower FLC-MICs (0.12–64 mg/L) than LHF (8–128 mg/L). Highly heteroresistant adapted subpopulations (256 mg/L) was found in minority (9%) strains, but importantly, 33% showed low FLC-MIC (8 mg/L). We concluded for similar LHF in both species, but higher LHF in clinical strains in comparison to environmental ones. Our findings stressed that the LHF is not correlated to species and pretty is strain-dependent and alert about high heteroresistant subpopulations that hardly reverts to the original LHF even upon the removal of drug pressure.