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Isavuconazole plasma concentrations in critically ill patients during extracorporeal membrane oxygenation
Lisa Kriegl1, Stefan Hatzl2, Christoph Zurl3,4
1Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
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.
Insights
Isavuconazole plasma concentrations in critically ill patients on extracorporeal membrane oxygenation (ECMO) were assessed. The ECMO circuit did not alter drug levels, which reached therapeutic targets within 24 hours.
Area of Science:
- Pharmacokinetics
- Critical Care Medicine
- Infectious Diseases
Background:
- Isavuconazole is a key antifungal for invasive fungal infections.
- Critically ill COVID-19 and influenza patients on extracorporeal membrane oxygenation (ECMO) are at risk for invasive pulmonary aspergillosis.
- Limited data exists on isavuconazole plasma concentrations during ECMO therapy.
Purpose of the Study:
- To determine isavuconazole plasma concentrations in patients receiving intravenous isavuconazole during ECMO.
- To evaluate the influence of the ECMO circuit on isavuconazole concentrations post-initial dose.
Main Methods:
- Seven critically ill patients on ECMO receiving standard intravenous isavuconazole doses were studied.
- Sixty-four blood samples were collected over 168 hours to measure isavuconazole levels.
- Twenty-seven additional samples from ECMO inflow and outflow lines assessed drug clearance by the device.
Main Results:
- Median isavuconazole trough levels exceeded 1 μg/mL by 24 hours and 2 μg/mL by 96 hours post-dose.
- Isavuconazole concentrations were highly correlated between ECMO inflow and outflow lines (ρ=0.987).
- Post-oxygenator concentrations strongly correlated with arterial line samples (ρ=0.942).
Conclusions:
- Isavuconazole plasma concentrations were not reduced by the ECMO oxygenator.
- Therapeutic isavuconazole levels (>1 μg/mL) were achieved within 24 hours of the loading dose.
- ECMO therapy may influence drug distribution, but does not appear to clear isavuconazole.
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