Introduction
In patients with underlying chronic lung disease, the prevalence of fungal infection is rising. The environmental mould Aspergillus fumigatus, as well as other filamentous fungi, are primarily responsible for this. Despite the significant burden of chronic respiratory fungal disease, antifungal agents are limited to only five classes (polyenes, triazoles, echinocandins, pyrimidines, and allyamines). TDM was required to ensure the safety and efficacy of itraconazole, voriconazole, and posaconazole, but it is now considered unnecessary for the newest triazole, isavuconazole, whose use is increasing. Resistant fungal infection is becoming more common in pulmonary disease, and there are few treatment options.
Therapeutic drug monitoring of azole antifungals was previously required to ensure safety and efficacy, but this is no longer required for the newest triazole, isavuconazole. There have been no studies of isavuconazole TDM in a chronic pulmonary fungal setting with increased antifungal resistance, drug–drug interactions, or cohorts with known reduced bioavailability to date. We examine the isavuconazole susceptibility of Aspergillus fumigatus isolates in a tertiary respiratory referral centre in this retrospective observational cohort study to better understand the prevalence of isavuconazole antimicrobial resistance. We also looked at the tolerability of isavuconazole and the therapeutic drug levels. We propose therapeutic drug monitoring for isavuconazole use in a chronic respiratory fungal disease setting based on our findings.
Methods
A retrospective observational analysis (2016–2021) of adult respiratory patients analyzing fungal culture, therapeutic drug monitoring, and outcome post-isavuconazole therapy. Patients who had either received isavuconazole treatment and/or had isavuconazole drug susceptibility testing on filamentous pathogenic mould isolates were included. Data was obtained from trust electronic prescribing management administration systems following data integration and consequential data mining using SAS Enterprise Guide software.
Fungal culture results, isolate antifungal sensitivities, and azole minimum inhibitory concentration (MIC) were recorded, in addition to trough isavuconazole serum levels Clinical demographics, including age, sex, disease-specific information, and co-morbidities, were collected. Case records were reviewed to analyse drug toxicities (attributed to the drug by the clinical team) and reasons for discontinuation or change of azole therapy.
Results
During the study period, isavuconazole susceptibility testing was performed on 26 Aspergillus spp. isolates. A total of 80.8% of A. fumigatus isolates had isavuconazole (MIC > 1 mg/L, and 73.0% > 2 mg/L) with a good correlation to
voriconazole MIC (r = 0.7, p = 0.0002).
A total of 54 patients underwent isavuconazole therapy during the study period (median duration 234 days (IQR:
24–499)). A total of 67% of patients tolerated isavuconazole, despite prior azole toxicity in 61.8%, with increased age
(rpb = 0.31; p = 0.021) and male sex ( c = 0.30; p = 0.027) being associated with toxicity.
Within the study period, 44 (81%) patients treated with isavuconazole had therapeutic trough drug levels performed, with a total of 132 drug levels measured. Of these, 86% (36 patients) attained TDM levels greater than 2 mg/L. Figure 3 shows the distribution of isavuconazole trough levels attained during the study period with a median isavuconazole level of 2.77 mg/L (IQR 2.35–3.10). Intra-individual variation was 2.03 mg/L (IQR 0.56–2.83). A total of 94.8% of isavuconazole trough TDM samples were >1 mg/L, and 72% of levels >2 mg/L.
Conclusion
We describe the use of isavuconazole as a salvage therapy in a chronic pulmonary fungal disease setting with a high
prevalence of azole resistance. Therapeutic concentrations at standard dosing were high; however, results reinforce
antifungal stewardship for optimization.
Source: Nwankwo, L.; Gilmartin, D.; Matharu, S.; Nuh, A.; Donovan, J.; Armstrong-James, D.; Shah, A. Experience of Isavuconazole as a Salvage Therapy in Chronic Pulmonary Fungal Disease. J. Fungi 2022, 8, 362. https://doi.org/10.3390/jof8040362
