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

Author:

Beredaki Maria-Ioanna1,Arendrup Maiken C.234ORCID,Pournaras Spyros1,Meletiadis Joseph1ORCID

Affiliation:

1. Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, NKUA, Athens, Greece

2. Unit of Mycology, Department of Microbiological Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark

3. Department of Clinical Microbiology, University Hospital Rigshospitalet, Copenhagen, Denmark

4. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

Abstract

ABSTRACT As comparative pharmacokinetic/pharmacodynamic (PK/PD) studies of liposomal amphotericin B (L-AMB) against Candida spp. are lacking, we explored L-AMB pharmacodynamics against different Candida species in an in vitro PK/PD dilution model. Eight Candida glabrata , Candida parapsilosis , and Candida krusei isolates (EUCAST/CLSI AMB MIC 0.125–1 mg/L) were studied in the in vitro PK/PD model simulating L-AMB C max = 0.25–64 mg/L and t 1/2 = 9 h. The model was validated with one susceptible and one resistant Candida albicans isolate. The C max /MIC-log 10 CFU/mL reduction from the initial inoculum was analyzed with the E max model, and Monte Carlo analysis was performed for the standard (3 mg/kg with C max = 21.87 ± 12.47 mg/L) and higher (5 mg/kg with C max = 83 ± 35.2 mg/L) L-AMB dose. A ≥1.5 log 10 CFU/mL reduction was found at L-AMB C max = 8 mg/L against C. albicans , C. parapsilosis , and C. krusei isolates (MIC 0.25–0.5 mg/L) whereas L-AMB C max ≥ 32 mg/L was required for C. glabrata isolates. The in vitro PK/PD relationship followed a sigmoidal pattern ( R 2 ≥ 0.85) with a mean C max /MIC required for stasis of 2.1 for C. albicans (close to the in vivo stasis), 24/17 (EUCAST/CLSI) for C. glabrata , 8 for C. parapsilosis , and 10 for C. krusei . The probability of target attainment was ≥99% for C. albicans 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- C . albicans species than C. albicans . A standard 3-mg/kg dose is pharmacodynamically sufficient for C. albicans whereas our data suggest that 5 mg/kg may be recommendable for the included non- C . albicans species.

Funder

Gilead Sciences

Publisher

American Society for Microbiology

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