Comparative pharmacodynamics and dose optimization of liposomal amphotericin B against Candida species in an in vitro pharmacokinetic/pharmacodynamic model

As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against spp. are lacking, we explored L-AMB pharmacodynamics against different species in an PK/PD dilution model. Eight , , and isolates (EUCAST/CLSI AMB MIC 0.125-1 mg/L) were studied in the PK/PD model simulating L-AMB = 0.25-64 mg/L and = 9 h. The model was validated with one susceptible and one resistant isolate. The /MIC-log CFU/mL reduction from the initial inoculum was analyzed with the model, and Monte Carlo analysis was performed for the standard (3 mg/kg with = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 log CFU/mL reduction was found at L-AMB = 8 mg/L against , , and isolates (MIC 0.25-0.5 mg/L) whereas L-AMB ≥ 32 mg/L was required for isolates. The PK/PD relationship followed a sigmoidal pattern ( ≥ 0.85) with a mean /MIC required for stasis of 2.1 for (close to the stasis), 24/17 (EUCAST/CLSI) for , 8 for , and 10 for . The probability of target attainment was ≥99% for wild-type (WT) isolates with 3 mg/kg and for wild-type isolates of the other species with 5 mg/kg. L-AMB was four- to eightfold less active against the included non- . species than . A standard 3-mg/kg dose is pharmacodynamically sufficient for whereas our data suggest that 5 mg/kg may be recommendable for the included non- . species.