Citation: Mertens, B.; Elkayal, O.; Dreesen, E.; Wauters, J.; Meersseman, P.; Debaveye, Y.; Degezelle, K.; Vermeersch, P.; Gijsen, M.; Spriet, I. Isavuconazole Exposure in Critically Ill Patients Treated with Extracorporeal Membrane Oxygenation: Two Case Reports and a Narrative Literature Review. Antibiotics 2023, 12, 1085. https://doi.org/10.3390/ antibiotics12071085 Academic Editors: Romain Guilhaumou and Amélie Marsot Received: 28 March 2023 Revised: 17 May 2023 Accepted: 19 June 2023 Published: 21 June 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antibiotics Article Isavuconazole Exposure in Critically Ill Patients Treated with Extracorporeal Membrane Oxygenation: Two Case Reports and a Narrative Literature Review Beatrijs Mertens 1, * , Omar Elkayal 2 , Erwin Dreesen 2 , Joost Wauters 3 , Philippe Meersseman 3 , Yves Debaveye 4 , Karlien Degezelle 5 , Pieter Vermeersch 6 , Matthias Gijsen 1,† and Isabel Spriet 1,† 1 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven and Pharmacy Department, University Hospitals Leuven, 3000 Leuven, Belgium 2 Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium 3 Department of Microbiology, Immunology and Transplantation, KU Leuven and Medical Intensive Care Unit, University Hospitals Leuven, 3000 Leuven, Belgium 4 Department of Cellular and Molecular Medicine, KU Leuven and Intensive Care Unit, University Hospitals Leuven, 3000 Leuven, Belgium 5 Department of Perfusion Technology, University Hospitals Leuven, 3000 Leuven, Belgium 6 Clinical Department of Laboratory Medicine, University Hospitals Leuven, 3000 Leuven, Belgium * Correspondence: beatrijs.1.mertens@uzleuven.be; Tel.: +0032-16-34-69-57 † These authors contributed equally to this work. Abstract: Effective dosing of isavuconazole in patients supported by extracorporeal membrane oxy- genation (ECMO) is important due to the role of isavuconazole as a first-line treatment in patients with influenza- and COVID-19-associated pulmonary aspergillosis. To date, robust pharmacoki- netic data in patients supported by ECMO are limited. Therefore, it is unknown whether ECMO independently impacts isavuconazole exposure. We measured isavuconazole plasma concentrations in two patients supported by ECMO and estimated individual pharmacokinetic parameters using non-compartmental analysis and two previously published population pharmacokinetic models. Furthermore, a narrative literature review on isavuconazole exposure in adult patients receiving ECMO was performed. The 24 h areas under the concentration–time curve and trough concentrations of isavuconazole were lower in both patients compared with exposure values published before. In the literature, highly variable isavuconazole concentrations have been documented in patients with ECMO support. The independent effect of ECMO versus critical illness itself on isavuconazole expo- sure cannot be deduced from our and previously published (case) reports. Pending additional data, therapeutic drug monitoring is recommended in critically ill patients, regardless of ECMO support. Keywords: extracorporeal membrane oxygenation; invasive fungal infections; critical care; isavuconazole; pharmacokinetics; therapeutic drug monitoring 1. Introduction The mold-active triazoles voriconazole and isavuconazole are recommended as first- line therapies for invasive aspergillosis, including influenza-associated and coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (IAPA and CAPA, respec- tively) [1–4]. Antifungal treatment with voriconazole poses challenges in clinical practice due to its nonlinear pharmacokinetic (PK) profile, the risk for concentration-dependent toxicity (i.e., neuro- and hepatotoxicity) and its involvement in drug–drug interactions as a substrate and inhibitor of CYP2C19, CYP2C9 and CYP3A4 [5,6]. The newest triazole, isavu- conazole, is characterized by high plasma protein binding (98–99%), high lipophilicity and a long elimination half-life (110–115 h) [7]. It undergoes hepatic metabolization via CYP3A4 and CYP3A5 iso-enzymes and—subsequently—via uridine diphosphate glucuronosyltrans- ferases [5,7]. Compared with voriconazole, isavuconazole is a more favorable triazole in Antibiotics 2023, 12, 1085. https://doi.org/10.3390/antibiotics12071085 https://www.mdpi.com/journal/antibiotics