Can Fluconazole Be Used to Treat Non-Resistant Candida (Candidozyma) auris Infections? Preclinical Pharmacokinetic/Pharmacodynamic Data From a Galleria mellonella Infection Model.

BACKGROUND

Azole therapy is currently not used against Candida auris infections. Although fluconazole resistance is prevalent, 10% to 45% of isolates among clades remain non-resistant (minimum inhibitory concentrations [MICs] <32 mg/L). We evaluated fluconazole pharmacokinetics/pharmacodynamics against these isolates using a Galleria mellonella model.

METHODS

Nine C. auris isolates representing 5 clades and MICs of 1 to 128 mg/L were studied, and 4 Candida albicans isolates were included for model validation. Larvae were infected with lethal inocula and treated for 4 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) target was derived by a sigmoidal Emax model, and Monte Carlo simulations estimated the probability of target attainment.

RESULTS

For C. albicans, the Clinical and Laboratory Standards Institute (CLSI) fAUC0-24/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) fAUC0-24/MIC, supporting the clinical breakpoints and validating the model. For C. auris, EI90 targets for survival were 93.2 (CLSI) and 63.2 (European Committee on Antimicrobial Susceptibility Testing) fAUC0-24/MIC, and probabilities of target attainment >95% were found for isolates with MICs up to 2, 4, and 8 mg/L with fluconazole doses of 400, 800, and 1200 mg/d, respectively.

CONCLUSIONS

Fluconazole demonstrated similar in vivo activity against C. auris and C. albicans. Putative wild type isolates with MICs ≤8 mg/L may be treatable with 1200 mg/d. Clinical studies are needed to verify the efficacy of fluconazole against C. auris.