Pharmacometric analysis of the in vitro activity of echinocandins, amphotericin B and isavuconazole against Candida Auris

Abstract

C. auris is a multidrug-resistant fungal pathogen that has recently emerged globally as a cause of life-threatening invasive infections. Despite the increasing concern on the reduced treatment options of C. auris infections, very few studies have investigated the in vitro time-kill activity of antifungal drugs against this species. Furthermore, PK/PD models, valuable tools to better characterise the activity of antimicrobial agents, are still lacking for this species.The overall aim of this Doctoral Thesis was to evaluate the in vitro activity of antifungal drugs belonging to the three main classes against C. auris, in monotherapy and in combinations, and to develop pharmacometric models for describing and predicting the activity of the drugs.In this work, Amphotericin B showed concentration-dependent fungicidal activity against C. auris in time-kill assays. Conversely, neither isavuconazole nor the echinocandins showed fungicidal or fungistatic against C. auris. The combination of amphotericin B with anidulafungin or caspofungin significantly enhanced the activity of the drugs compared to monotherapy. The interaction of isavuconazole and anidulafungin, caspofungin or micafungin was also deemed synergistic. The developed PK/PD models successfully characterised both monotherapy and isavuconazole plusechinocandin activity. Model-based simulations pointed out that amphotericin B susceptibility breakpoint for C. auris may be lower than the currently suggested one and that high dosing combination therapy of isavuconazole plus caspofungin or anidulafungin would be effective for the treatment of C. auris fungaemia.