Unai Caballero (1), Elena Eraso (2), Guillermo Quindós (2), Valvanera Vozmediano (3), Stephan Schmidt (3) and Nerea Jauregizar (1)
(1) Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain, (2) Department of Immunology, Microbiology and Parasitology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain, (3) Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA
Objectives: Candida auris is a multi-drug resistant fungal pathogen responsible for several cases of invasive fungaemia since 2009. Echinocandins are the first line treatment to treat infections caused by C. auris, but resistance to these drugs can emerge rapidly and therapeutic failures have been reported. As treatment options are limited, the combination of echinocandins with other antifungal agents like isavuconazole may be a suitable alternative. Additionally, PK/PD models that characterize the activity of antifungal combination therapy against C. auris are still lacking. The aim of this work was to develop a model that characterized the in vitro activity of isavuconazole with echinocandins and perform simulations of different dosing regimens to evaluate the efficacy of this combination to treat C. auris infections.
Methods: Previously reported in vitro static time-kill curves against six C. auris clinical blood isolates [1] were analysed. The experimental concentrations of the drugs were 0.06, 0.125, 0.25, 2 and 4 mg/L for isavuconazole and 0.125, 0.5, 1, 2 and 4 mg/L for anidulafungin, caspofungin and micafungin. Logarithm of colony forming units (log CFU/mL) for each isolate and drug concentration were simultaneously analysed in NONMEM v.7.4.3. 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. First, each drug in monotherapy was analysed to determine the model for drug effects and to obtain initial estimates for combination data modelling. Different semi-mechanistic models for antimicrobial interactions were tested [2]. Precision of parameter estimates, goodness of fit plots and internal validation techniques (VPC and bootstrap) were evaluated for model performance. Once the final model was chosen, combination regimens with standard and alternative dosing of isavuconazole with echinocandins were simulated using in vivo pharmacokinetic parameters from literature. Additional simulations were performed testing different MIC scenarios, including lower than 0.06 mg/L for isavuconazole and 0.125 mg/L for the echinocandins.
Results: A single-population model, with an empirical interaction function to test for statistically significant differences from additivity [3] described the data well. The EC50 of isavuconazole was similar in the three combinations (0.0683, 0.0554 and 0.0584 mg/L for the combinations of isavuconazole with anidulafungin, caspofungin and micafungin respectively). The EC50 of anidulafungin and micafungin were also similar (0.176 and 0.171 mg/L) whereas caspofungin EC50 was almost 3 times higher (0.452 mg/L). The interaction parameter Int was positive for every combination, which alongside a positive 95% CI, allowed to classify the drug interactions as synergistic. Neither the inclusion of IIV nor IOV improved the model fit, so those variabilities were absent in the final model. Thus, variability was solely defined by the residual error. Model parameters in the three combinations were estimated with RSE < 20% and with relative bias under 2%. None of the simulated dosing scenarios for any combination showed successful activity against the studied C. auris isolates over a 1-week-treatment. Simulation outcomes for lower MICs showed that the combination of isavuconazole and micafungin was not successful for the evaluated doses and MIC scenarios. Conversely, combinations of isavuconazole with anidulafungin or caspofungin were able to inhibit fungal growth, depending on the dosing regimens tested for MICs up to 0.03 mg/L for isavuconazole and 0.06 mg/L for echinocandins.
Conclusions: A PK/PD model adapted for drug combinations characterized successfully the activity of the combinations of isavuconazole with anidulafungin, caspofungin or micafungin. Model-based simulations predicted that the studied C. auris isolates would be resistant to isavuconazole and echinocandin combination treatment.
References:
[1] Caballero, U., Kim, S., Eraso, E., Quindos, G., Vozmediano, V., Schmidt, S. and Jauregizar, N. (2021). In vitro synergistic interactions of isavuconazole and echinocandins against candida auris. Antibiotics (Basel). 4,
[2] Brill, M. J. E., Kristoffersson, A. N., Zhao, C., Nielsen, E. I. and Friberg, L. E. (2018). Semi-mechanistic pharmacokinetic-pharmacodynamic modelling of antibiotic drug combinations. Clin.Microbiol.Infect. 7, 697-706.
[3]Mohamed, A. F., Kristoffersson, A. N., Karvanen, M., Nielsen, E. I., Cars, O. and Friberg, L. E. (2016). Dynamic interaction of colistin and meropenem on a WT and a resistant strain of pseudomonas aeruginosa as quantified in a PK/PD model. J.Antimicrob.Chemother. 5, 1279-1290.
Reference: PAGE 29 (2021) Abstr 9858 [www.page-meeting.org/?abstract=9858]
Poster: Drug/Disease Modelling - Infection