Antifungal Susceptibility and Genotypic Analysis of cyp51A Mutations in Aspergillus fumigatus Isolates in Malaysia

Abstract

Azole resistance in Aspergillus fumigatus poses a significant challenge in the management of invasive aspergillosis. This study aimed to investigate the antifungal susceptibility and cyp51A mutation profiles of A. fumigatus isolates in Malaysia. Patients and Methods: Sixty clinical A. fumigatus isolates were collected and subjected to antifungal susceptibility testing (AFST) and molecular analysis. The antifungal susceptibility testing was performed according to CLSI M38 guideline. The geometric mean (GM) minimum inhibitory concentration (MIC), MIC 50 /MIC 90 for voriconazole, itraconazole, posaconazole, amphotericin B, and isavuconazole against A. fumigatus in non-invasive cases and invasive cases were calculated. In addition, the presence of cyp51A mutations was also identified. Results:The present study revealed an overall resistance rate of 6.7% among the isolates. In non-invasive cases, isavuconazole and posaconazole demonstrated the lowest GM MIC of 0.08 µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.15µg/mL, 0.16µg/mL and 0.90µg/mL, respectively. Similarly, in invasive cases, isavuconazole and posaconazole exhibited the lowest GM MIC of 0.09µg/mL. Following them were itraconazole, voriconazole, and amphotericin B with concentrations of 0.14µg/mL, 0.17µg/mL and 0.80µg/mL, respectively. Genotypic analysis revealed various cyp51A mutations, including F46Y, M172V, N248K, R34L, V244A, V244S, and E427K. However, not all mutations corresponded to antifungal resistance. Conclusion:The majority of clinical Aspergillus fumigatus isolates demonstrated susceptibility to the antifungal agents tested, with isavuconazole and posaconazole demonstrating the lowest MIC values. However, cyp51A mutations were discovered without a consistent correlation to antifungal resistance, emphasising the need for additional research.