Differential Response of Candida Species Morphologies and Isolates to Fluconazole and Boric Acid

Candida albicans is the most prevalent cause of vulvovaginal candidiasis ("yeast infection" or VVC) and recurrent vulvovaginal candidiasis (RVVC), although the incidence of non-albicans yeast species is increasing. The azole fluconazole is the primary antifungal drug used to treat RVVC, yet isolates from some species have intrinsic resistance to fluconazole, and recurrent infection can occur even with fluconazole-susceptible populations. The second-line broad-spectrum antimicrobial drug, boric acid, is an alternative treatment that has been found to successfully treat complicated VVC infections. Far less is known about how boric acid inhibits growth of yeast isolates in different morphologies compared to fluconazole. We found significant differences in drug resistance and drug tolerance (the ability of a subpopulation to grow slowly in high levels of drug) between C. albicans, Candida glabrata, and Candida parapsilosis isolates, with the specific relationships dependent on both drug and phenotype. Population-level variation for both susceptibility and tolerance was broader for fluconazole than boric acid in all species. Unlike fluconazole, which neither prevented hyphal formation nor disrupted mature biofilms, boric acid inhibited C. albicans hyphal formation and reduced mature biofilm biomass and metabolic activity in all isolates in a dose-dependent manner. Variation in planktonic response did not generally predict biofilm phenotypes for either drug. Overall, our findings illustrate that boric acid is broadly effective at inhibiting growth across many isolates and morphologies, which could explain why it is an effective treatment for RVVC.