Azoles therapeutic drug monitoring and fungal antimicrobial resistance in adults with Cystic Fibrosis

Introduction: Fungal disease is a complication of Cystic Fibrosis (CF) and is associated with poor outcomes. The mainstay of treatment is azoles, which require antimicrobial sensitivity testing for drug choice and therapeutic drug monitoring (TDM) to optimise dose. Due to variable pharmacokinetics, achieving therapeutic concentrations in CF is problematic, potentially leading to poor clinical outcome and antimicrobial resistance (AMR). Aims: To determine in a single-centre study the use of antifungal therapy, frequency of TDM over a 12 month period and its relation to AMR. Methods: A retrospective analysis of CF adults on azole therapy between 2016-17. Indication of use, duration, TDM frequency and microbiology including AMR were collected. Results: 98 adults were treated with an azole (itraconazole 63.3%, posaconazole 26.5%, voriconazole 7.1%, isavuconazole 3.1%). Main indications of use were ABPA (51%), persistently positive fungal culture (28.6%) and Aspergillus bronchitis (11.2%). 165 samples for TDM were taken, median per patient was 2 (range 0 – 4). Azole levels were sub-therapeutic in 50.3%. 196 of 831 (23.6%) sputum samples were positive for fungi ( A. fumigatus 44.9%, S. apiospermum 24%, E. dermatitidis 20.4%). Azole resistance was reported in 18.6% (15.7% to itraconazole). AMR prevalence in those with sub-therapeutic azole levels was significantly higher compared to those with therapeutic levels (52.4% vs 13.3%, p = 0.045). Conclusion: There is high variability in azole TDM in CF adults associated with frequent sub-therapeutic levels and poor drug optimisation. There is a high prevalence of fungal AMR in CF adults with a significant association with sub-therapeutic azole levels.