Defining optimal doses of Liposomal Amphotericin B against Candida auris: Data from an in vitro pharmacokinetic-pharmacodynamic model.

BACKGROUND

C. auris isolates exhibit elevated amphotericin B MICs. As liposomal AMB (L-AMB) can be safely administered at high doses, we explored L-AMB pharmacodynamics against C. auris isolates in an in vitro PK/PD dilution model.

METHODS

Four C. auris isolates (AMB MIC 0.5-2 mg/L) were tested in an in vitro PK/PD model simulating L-AMB pharmacokinetics. The in vitro model was validated using a C. albicans isolate tested in animals. The Cmax/MIC vs log10CFU/mL reduction from the initial inoculum was analyzed with Emax model. Monte Carlo analysis was performed for the standard (3 mg/kg) and higher (5 mg/kg) L-AMB doses.

RESULTS

The in vitro PK/PD relationship Cmax/MIC vs log10CFU/mL reduction followed a sigmoidal pattern (R2 ≥ 0.91 for C. albicans, R2 ≥ 0.86 for C. auris). The Cmax/MIC associated with stasis was 2.1 for C. albicans and 9 for C. auris. The probability of target attainment was >95% with 3 mg/kg for wild-type C. albicans isolates with MIC ≤ 2 mg/L and C. auris isolates with MIC ≤ 1 mg/L whereas 5 mg/kg L-AMB is needed for C. auris isolates with MIC 2 mg/L.

CONCLUSIONS

L-AMB was 4-fold less active against C. auris than C. albicans. C. auris isolates with CLSI MIC 2 mg/L would require a higher L-AMB dose.

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.