PK/PD modeling and simulation of the in vitro activity of the combinations of isavuconazole with echinocandins against Candida auris

Abstract

In vitro combination of echinocandins and isavuconazole against the emerging species Candida auris is mainly synergistic. However, this combination has not been evaluated in clinical settings. A pharmacokinetic/pharmacodynamic modeling and simulation approach based on in vitro data may be helpful to further study the therapeutic potential of these combinations. Therefore, the aims of this study were to characterize the time course of growth and killing of C. auris in response to the combination of the three approved echinocandins and isavuconazole using a semimechanistic model and to perform model-based simulations in order to predict the in vivo response to combination therapy. In vitro static time-kill curve data for isavuconazole and echinocandins combinations against six blood isolates of C. auris were best modeled considering the total killing of the fungal population as dependent on the additive effects of both drugs. Once assessed, the predictive performance of the model using simulations of different dosing and fungal susceptibility scenarios were conducted. Model-based simulations revealed that none of the combinations at standard or higher dosages would be effective against the studied isolates of C. auris and it was predicted that the combinations of isavuconazole with anidulafungin or caspofungin would be effective for minimum inhibitory concentrations up to 0.03 and 0.06 mg/L respectively, whereas the combination with micafungin would lead to treatment failure.The current approach highlights the importance of bridging the in vitro results to the clinic. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?In previous in vitro studies, synergism was demonstrated for the combination of isavuconazole with echinocandins against Candida auris.

Efficacy of the combination of amphotericin B and echinocandins against Candida auris in vitro and in the Caenorhabditis elegans host model

“…A synergistic effect was also obtained with the combination of AND plus voriconazole and AND plus isavuconazole against 14% and 31%, respectively, of the C. auris isolates analyzed ( 37 ). In other studies, the combination of isavuconazole with echinocandins, analyzed with different in vitro approaches, also achieved synergism and fungistatic activity against C. auris ( 24 , 52 , 55 ). In addition, the interaction of echinocandins (AND and CAS) with flucytosine or with the non-antifungal drug colistin presented synergistic effects, while in combination with MCF, these two compounds showed indifferent effects against C. auris ( 48 – 50 ).…”