Use of Isavuconazole MIC to guide dosing in the management of Aspergillosis in patients with pulmonary disease

Introduction: The burden of fungal infection is rising in patients with pulmonary disease. Options for antifungal therapy are limited compared to antibiotics, with some of the orally active triazoles demonstrating inter-patient variability, non-linear kinetics, toxicity, drug interactions and resistance. Therapeutic Monitoring (TDM) of Itraconazole, Voriconazole and Posaconazole has been necessary to ensure their safety and efficacy, but was considered unecessary for the newest triazole Isavuconazole, use of which is increasing. Aims: To determine in a single-centre study the use of Isavuconazole MIC to guide dosing in the management of Aspergillosis in patients with pulmonary disease. Methods: A retrospective observational analysis of adult patients with respiratory disease between 2016 and 2019. Cultures, sensitivities, azole MIC and serological response (Aspergillus IgG and IgE) were collected. Results: 56 fungal isolates were obtained from 48 patients. 29% of aspergillus isolates had Isavuconazole MIC upto the EUCAST cut-off of 2mg/l. 91.5% had Isavuconazole TDM of >1mg/l, and 64% achieved levels >2mg/l. Toxicity was not observed until levels of >5mg/l which necessitated dose reduction for one patient. There was good correlation between Isavuconazole MIC and Voriconazole MIC (r =0.7, p=0.0002). Conclusion: With the greater likelihood of Isavuconazole being used in a setting of azole resistance, we recommend dosing titrated to TDM (aim:2-5 mg/l) to maximise efficiency and avoid toxicity. Isavuconazole MIC demonstrated good correlation with voriconazole MIC and thus the latter can be used as a surrogate marker for Isavuconazole susceptibility.