Isavuconazole plasma concentrations in critically ill patients during extracorporeal membrane oxygenation

Abstract

Background Isavuconazole is an antifungal drug used for treatment of invasive fungal infections. Critically ill COVID-19 and influenza patients require extracorporeal membrane oxygenation (ECMO) in cases with severe acute respiratory distress syndrome and have risk factors for invasive pulmonary aspergillosis. Little is known about isavuconazole plasma concentrations during ECMO. Objectives To determine isavuconazole plasma concentrations in seven patients treated with intravenous isavuconazole under ECMO and the influence of the ECMO circuit immediately after the first isavuconazole dose. Methods Critically ill patients treated with isavuconazole (standard doses) and ECMO were included in this study. Sixty-four blood samples used for measurement of isavuconazole concentrations were collected at several timepoints starting 2 h after the first isavuconazole dose up to 168 h. An additional 27 blood samples were drawn from the inflow and outflow line of the membrane oxygenator to assess any potential isavuconazole clearance effect of the ECMO oxygenation device and the lines. Results Median isavuconazole trough levels above 1 μg/mL (min. 0.83, max. 1.73) or 2 μg/mL (min. 0.84, max. 2.97) were achieved 24 h or 96 h after the first dose of isavuconazole. The isavuconazole plasma concentrations pre (inflow line) and post (outflow line) the membrane oxygenator were directly correlated (ρ = 0.987, R2 = 0.994, P < 0.001). Post membrane oxygenator isavuconazole concentrations were directly correlated to contemporaneous samples obtained from the arterial lines of patients (ρ = 0.942, R2 = 0.945, P < 0.001). Conclusions Isavuconazole concentrations might be influenced by the higher volume of distribution due to ECMO therapy, but were not altered by the ECMO oxygenator and achieved median plasma concentrations >1 μg/mL 24 h after the first loading dose.

Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses

“…The use of ECMO in the ICU has been described as possibly playing a role in pharmacokinetic changes in some patients and, particularly with lipophilic and highly protein-bound therapies, that may be captured by the ECMO system [ 59 ]. In the study by Kriegl et al, no difference was found between pre- and post-membrane concentrations, therefore excluding adsorption on the membrane [ 60 ]. The data in the literature are limited concerning isavuconazole and ECMO.…”

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

“…The nine ECMO patients included in our study exhibited lower isavuconazole drug levels, which is in line with other reports, 16,28–30 in which a sum of nine ECMO patients had been included. In contrast, one study reported sufficient levels of this drug in seven ECMO patients with prophylactic administration 31 . A mean isavuconazole C min level of 1.09 μg/mL was measured after 24 h. It was discussed that ECMO therapy also increases the volume of distribution which can lower the drug's levels 32,33 …”

“…In contrast, one study reported sufficient levels of this drug in seven ECMO patients with prophylactic administration. 31 A mean isavuconazole C min level of 1.09 μg/mL was measured after 24 h. It was discussed that ECMO therapy also increases the volume of distribution which can lower the drug's levels. 32,33 Regarding the influence of RRT on isavuconazole levels, a study with seven solid-organ transplant patients reported no rapid removal by RRT, 34 while others found an association between RRT and sub-therapeutic levels of the drug.…”

Salvage Treatment for Invasive Aspergillosis and Mucormycosis: Challenges, Recommendations and Future Considerations

“…[1][2][3][4] Invasive aspergillosis (IA) and mucormycosis are the two most common IMIs in humans and, even when treated appropriately, associated with mortality rates of 30% and above. [5][6][7][8][9][10] Failure of first line treatment, which consists of antifungal treatment and often -especially in the case of mucormycosis -also of surgical debridement, 2,6,11 may occur due to (i) absence of clinical response resulting in refractory or breakthrough fungal infection, [12][13][14] (ii) intolerance/adverse events to first line antifungals, 15 or (iii) insufficient antifungal plasma levels [16][17][18] remaining below defined thresholds for clinical efficacy. [19][20][21] As a consequence, failure of first line antifungal treatment necessitating salvage treatment is quite common.…”