Evaluation of the Synergistic Activity of Anidulafungin with Isavuconazole, Voriconazole, Posaconazole, and Amphotericin B in Candida auris (Candidozyma auris) Isolates

Abstract

Introduction: Candida auris poses a global public health threat due to its multidrug resistance and association with severe invasive infections. With limited treatment options, combination therapies are being explored to enhance antifungal efficacy. This study aimed to evaluate the in vitro synergistic activity of anidulafungin combined with isavuconazole, voriconazole, posaconazole, and amphotericin B against clinical C. auris isolates. Methods: Fifty clinical C. auris isolates were identified via MALDI-TOF MS. Antifungal susceptibility testing was performed using the EUCAST broth microdilution method to determine Minimum Inhibitory Concentrations (MICs). Subsequently, the in vitro interactions of anidulafungin with four other antifungals were assessed using a checkerboard assay. Drug interactions were classified by calculating the Fractional Inhibitory Concentration Index (FICI). Results: High resistance rates were observed for fluconazole (72%) and amphotericin B (48%), whereas no isolates were resistant to echinocandins. In combination tests, interactions were predominantly indifferent (56–84%), followed by partial synergy (12–40%). A single instance of true synergy (FICI = 0.49) was noted with the anidulafungin-posaconazole combination in one isolate. Synergy rates (synergy + partial synergy) varied significantly across combinations (Fisher’s exact test, p = 0.0044), with anidulafungin-azole combinations showing the highest rates (36–40%) compared to anidulafungin-amphotericin B (12%). No antagonism (FICI ≥ 4) was detected in any combination. Discussion: The predominance of indifferent interactions, with some partial synergy, suggests that combination therapy may not consistently offer a strong synergistic benefit for these isolates. This exploratory study characterizes the in vitro interaction landscape in our isolate collection, providing foundational data to guide future research and inform clinical decisions where treatment options are scarce.