Antifungal Dosing in Critically Ill Patients on Extracorporeal Membrane Oxygenation

Abstract

Extracorporeal membrane oxygenation (ECMO) is an established advanced life support system, providing temporary cardiac and/or respiratory support in critically ill patients. Fungal infections are associated with increased mortality in patients on ECMO. Antifungal drug dosing for critically ill patients is highly challenging because of altered pharmacokinetics (PK). PK changes during critical illness; in particular, the drug volume of distribution ( V d ) and clearance can be exacerbated by ECMO. This article discusses the available literature to inform adequate dosing of antifungals in this patient population. The number of antifungal PK studies in critically ill patients on ECMO is growing; currently available literature consists of case reports and studies with small sample sizes providing inconsistent findings, with scant or no data for some antifungals. Current data are insufficient to provide definitive empirical drug dosing guidance and use of dosing strategies derived from critically patients not on ECMO is reasonable. However, due to high PK variability, therapeutic drug monitoring should be considered where available in critically ill patients receiving ECMO to prevent subtherapeutic or toxic antifungal exposures. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01264-0.

Antifungals in Patients With Extracorporeal Membrane Oxygenation: Clinical Implications

“…We performed a structured literature review by searching PubMed from July 2022 to December 2023 to include recent papers in addition to the literature review truncated in July 2022 and published recently [ 15 ]. To put new data into context, some of the already reviewed data are nevertheless included here as deemed necessary by the authors.…”

“…Subtherapeutic concentrations of voriconazole and loss of voriconazole in the ECMO oxygenator have been reported in a recent review [ 15 ]. Based on the anticipated loss to the ECMO system, a dose escalation was applied in 2 patients, which surprisingly led to supratherapeutic concentrations (trough levels >10 mg/L, peak 15 mg/L), obviously due to saturation of the ECMO circuit [ 15 , 20 ]. In another ECMO case report, approximately twice as much as the routine dose was necessary to achieve the target concentration of voriconazole [ 21 ].…”

“…In addition to known pathophysiological changes in ICU patients such as peripheral vasodilation, hypoalbuminemia, and renal and/or liver failure, it is necessary to elucidate the influence of the ECMO system itself on altered concentrations of antifungals. Critically ill patients often already exhibit altered pharmacokinetics (PK), such as changes in volume of distribution and clearance (which tend to increase during the early stages of sepsis but to decrease in later stages), renal or liver failure, altered blood pH, hypoalbuminemia, and drug–drug interactions [ 15 ]. Application of ECMO and additional extracorporeal treatments (eg, RRT) can further influence these PK changes through factors related to the ECMO and/or the RRT system (eg, priming volumes, technical ECMO factors like material and flow rate, sequestration, removal of hydrophilic drugs by RRT, and others) [ 16 ].…”

“…In addition, PK parameters and potentially modified dosing regimens must be considered in patients with ECMO and certain indications for administration of antifungal agents. In a recent review, critical illness–related physiological changes and associated alterations of PK parameters, like volume of distribution and drug clearance as well as protein binding of lipophilic substances and potential sequestration of antifungal drugs within the ECMO circuit, were extensively discussed [ 15 ]. However, a comprehensive review of clinically applicable dosing regimens in patients with ECMO is lacking.…”

Pharmacokinetic Research in Pediatric Extracorporeal Therapies: Current State and Future Directions

“…Pharmacokinetics (PK) is defined as what the body does to a drug via absorption, distribution, metabolism, and elimination processes [3]. Drug PK in children receiving ECLS is altered due to drug-circuit interactions, physiologic changes associated with human-circuit interactions, and underlying critical illness [4]. Despite broadly known PK changes in this patient group, optimal dosing for most drugs is unknown in this population.…”