Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID-19.

Background: The broad-spectrum antifungal isavuconazole is administered to treat invasive aspergillosis and mucormycosis.Objectives: Isavuconazole plasma concentrations in critically ill ICU patients with or without COVID-19 and invasive fungal infection were determined, and factors for sub-therapeutic drug levels (<1 mu g/mL) were evaluated.Patients and Methods: Isavuconazole plasma levels were measured as part of therapeutic drug monitoring (TDM) in ICUs of a tertiary hospital. Concentrations determined 20-28 h after previous dosing were defined as trough (Cmin) levels. A total of 160 Cmin levels from 62 patients with invasive fungal infections were analysed, 30 of which suffering from COVID-19. Patient characteristics included into univariable and multivariable analyses were gender, age, COVID-19 status, body mass index (BMI), sepsis-related organ failure (SOFA) score, renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) requirement.Results: The mean Cmin of isavuconazole in all patients was 1.64 mu g/mL (interquartile range 0.83-2.24 mu g/mL, total range 0.24-5.67 mu g/mL). In total, 34.4% of the Cmin values (corresponding to 46.8% of patients) were below a threshold concentration of 1 mu g/mL. Drug concentrations between patients with or without COVID-19 did notdiffer (p =.43). In contrast, levels were significantly lower in patients with female sex (p =.0007), age = 65 years (p =.002), BMI > 25 (p =.006), SOFA score > 12 (p =.026), RRT (p =.017) and ECMO requirement (p =.001).Conclusions: Isavuconazole plasma levels can be negatively affected by patients' risk factors, supportive renal replacement and ECMO therapy. Future prospective studies analysing the relevance of isavuconazole drug levels in ICU patient outcome are urgently needed.