Unai Caballero (1), Sandra Gil-Alonso (1,2), Elena Eraso (2), Javier Pemán (3), Guillermo Quindós (2) and Nerea Jaureguizar (1)
(1) Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Spain. (2) Department of Immunology, Microbiology and Parasitology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Spain. (3) Servicio de MicrobiologÃa, Hospital Univeristario y Politécnico La Fe, Valencia, Spain
Objectives: Candida auris is an emerging multidrug-resistant yeast that causes invasive candidiasis. It is associated with high mortality rates, up to 40%, and the control and treatment of hospital outbreaks are challenging due to difficulties in identification, persistence in the environment and reduced sensitivity to first-line antifungal agents. Most isolates show resistance to azoles and echinochandins, whereas with amphotericin B variable results have been reported [1]. Despite the importance of a complete characterization of the antifungal susceptibility of C. auris, there is a lack of studies regarding PK/PD modelling. The aim of this study was to develop a PK/PD model that characterized the in vitro activity of amphotericin B against C. auris.
Methods: In vitro static time-kill curves experiments were performed in microtitre plates in RPMI-1640 medium with six C. auris clinical blood isolates (Hospital La Fe, Valencia, Spain). Inoculum size ranged from 1 to 5 x 105 CFU/mL, amphotericin B concentrations ranged from 0.25 to 4 mg/L and samples for viable counts were taken at 0, 2, 4, 6, 8, 24 and 48 hours [2]. Colony forming units (CFU) counts over time for each drug concentration and isolate were simultaneously modelled in NONMEM v7.4 with first order conditional estimation method. Residual variability was modelled with an additive model and an exponential model was used to describe inter-individual variability in model parameters. The first-rate order constant for growth (kgrowth) and natural death rate (kdeath) of the fungal system were estimated in the absence of drug. The estimated values were later fixed when analysing drug-exposure data. Due to the multiresistant profile of C. auris, several models that tried to explain reduced drug sensitivity were tested [3]. Precision of parameter estimates, goodness of fit plots, changes in objective function value and performance of visual predicted checks were evaluated to assess model performance.
Results: A mixture model that included a sensitive (S) subpopulation and a non-growing drug-resistant (R) fungal subpopulation with a first- order transfer rate constant from S to R (kSR) best described the experimental data. The effect of amphotericin B, which increased the killing rate of the sensitive subpopulation, was described by an Emax sigmoidal function. The typical values and relative standard errors were Emax=1,43 h-1 (1,03%), EC50= 2,94 mg/L (%2,87%), Hill Factor=2,7 (3,87%) . Amphotericin B showed concentration-dependent fungicidal activity.
Conclusions: The model successfully described the activity of amphotericin B against C. auris in vitro and provides more information about the antifungal susceptibility of a newly discovered multiresistant species. To date, this is the first study that has modelled amphotericin time-kill data against C. auris with a semi-mechanistic approach. PK/PD modelling of in vitro data might help in the design of dosing regimens that optimize fungal killing and minimize antifungal resistance.
References:
[1] Ruiz-Gaitán et al., IJAA 2019 doi: https://doi.org/10.1016/j.ijantimicag.2019.02.005
[2] Caballero U et al., XIV Congreso Nacional de Micología (2018) Abstract book
[3] Nielsen EI, Friberg L. Pharmacol Rev 2013; 65:1053-90
Reference: PAGE 28 (2019) Abstr 9009 [www.page-meeting.org/?abstract=9009]
Poster: Drug/Disease Modelling - Infection