Can fluconazole be used to treat non-resistant Candida (Candidozyma) auris infections? Preclinical PK/PD data from a Galleria mellonella infection model.

Abstract

Azole therapy is currently not used against Candida auris infections. Although fluconazole resistance is prevalent, 10-45% of isolates among clades remain non-resistant (MICs ≤32 mg/L). We evaluated fluconazole pharmacokinetics/pharmacodynamics (PK/PD) against these isolates using a Galleria mellonella model. Nine C. auris isolates representing five clades and MICs 1-128 mg/L were studied, and four Candida albicans isolates were included for model validation. Larvae were infected with lethal inocula and treated for four days with human-equivalent fluconazole doses. Efficacy endpoints were 24-hour change in fungal burden and 7-day survival. Free-drug 24-hour area under the concentration-time curve divided by the MIC (fAUC0-24/MIC) targets were derived using a sigmoidal Emax model, and Monte Carlo simulations estimated probability of target attainment (PTA). For C. albicans, the fAUC0-24/Clinical and Laboratory Standards Institute (CLSI) MIC corresponding to EI50 for 24-hour fungal burden reduction was 35.5, consistent with murine models. EI90 survival targets were 76.5 (CLSI) and 68.9 (European Committee on Antimicrobial Susceptibility Testing, EUCAST), supporting the clinical breakpoints and validating the model. For C. auris, EI90 targets for survival were 93.2 (CLSI) and 63.2 (EUCAST) and PTA >95% were found for isolates with MICs up to 2, 4, and 8 mg/L with fluconazole doses of 400, 800, and 1,200 mg/day, respectively. Fluconazole demonstrated similar in vivo activity against C. auris and C. albicans. Putative WT isolates with MICs ≤8 mg/L may be treatable with 1,200 mg/day. Clinical studies are needed to verify the efficacy of fluconazole against C. auris.