Low isavuconazole trough levels in critically ill patients with and without extracorporeal membrane oxygenation

Abstract

Data on isavuconazole exposure in critically ill patients and particularly during extracorporeal membrane oxygenation (ECMO) are scarce, and therapeutic drug monitoring is not routinely performed. Critically ill patients admitted to a tertiary ECMO referral center from October 2017 to August 2024 with documented isavuconazole trough levels were retrospectively analyzed. First, measured isavuconazole trough blood levels and the occurrence of dose adjustments were analyzed in patients with and without ECMO support. Fifty-three adult patients were included, of whom 11 (21%) patients were on ECMO support at the first isavuconazole trough level measurement. Median isavuconazole trough level was overall 1.4 (interquartile range [IQR] 0.9-2.5) mg/L and did not differ between ECMO (1.3 [IQR 0.9-1.5] mg/L) and non-ECMO patients (1.6 [IQR 0.9-2.8] mg/L, P = 0.423). During the entire intensive care unit stay, individual doses were increased in 12 (23%) patients, of whom 5 were on ECMO support, whereas dosage was reduced or interrupted in 2 (4%) patients (both without ECMO support). Dose adjustments occurred irregularly and inconsistently after therapeutic drug monitoring, i.e., only in 6 (11%) patients after the initial therapeutic drug monitoring despite 37 (70%) drug levels being outside the target range of 2-4 mg/L. In conclusion, below targeted isavuconazole trough levels were common in critically ill patients investigated, but ECMO did not seem to have an additional negative influence. Dose adjustments appeared more frequently than previously reported, albeit irregularly performed. Regular therapeutic drug monitoring and protocolized dose adjustments should be investigated in future studies.

Keywords: antifungals; aspergillosis; drug dosing; pharmacokinetics; therapeutic drug monitoring.

Fig 1

Horizontal boxplot chart of IVZ C_trough (first measurement per patient) grouped by subgroups. Outliers are not displayed for better visualization. Numerical results of the number of observations, central tendency (median [IQR]), and P-value for the Wilcoxon rank sum test are displayed on the right side of the plot. KRT, kidney replacement therapy; Obesity, body mass index >30 kg/m².

Fig 2

Flow chart of dose adjustment between TDM measurements. Each flow represents one patient. Colors represent dose adjustments made between measurements (increased, stopped/reduced, or unchanged). Patients who did not have a subsequent TDM are colored in light gray (“Not applicable”). Strata represent categories of IVZ C_trough measurements (<1.0, 1.0–1.9, 2.0–4.0, or >4.0 mg/L) or “Not applicable” if no subsequent measurement was performed.