Isavuconazole plasma concentrations in critically ill patients during extracorporeal membrane oxygenation-authors' response.

Abstract

We thank Mertens and colleagues not only for commending us for this first prospective study on isavuconazole exposure in critically ill extra-corporeal membrane oxygenation (ECMO) patients, but also for raising valuable points that need to be further discussed and investigated.1 First, Mertens et al. mentioned that distribution volumes of lipophilic substances such as isavuconazole are only minimally influenced by the ECMO priming solution and circuits and that the critical condition of the patients primarily contributes to the high distribution volumes regardless of the application of extracorporeal circuits. Nevertheless, in recent reviews addressing optimized antimicrobial dosing in patients receiving ECMO, an increased volume of distribution has also been mentioned for lipophilic drugs in patients receiving ECMO.2,3 Due to the fact that our measurements showed no evidence of extracorporeal clearance or sequestration we concluded therefore that isavuconazole concentrations might be influenced rather by the higher volume of distribution but not by drug sequestration during ECMO treatment, but agree that further research is needed to elucidate other factors that may contribute. Mertens et al.4 also mentioned that increasing the loading dose should not be narrowed to ECMO patients as the contribution of ECMO versus critical illness cannot be derived from our study. We fully acknowledge this important fact as we did not additionally collect data from matched critically ill patients without ECMO. Therefore, our data do not preclude that isavuconazole trough concentrations might be below 1 mg/L in critically ill patients without ECMO or in patients with ECMO and another extracorporeal treatment.4 In another mixed ICU cohort (as yet unpublished) comprising 34 patients with isavuconazole administration, we determined 74 isavuconazole concentrations (minimum 0.2, maximum 6.79, median 1.38 mg/L); a total of 53 measurements revealed isavuconazole trough concentrations >1 mg/l whereas 21 were below that threshold. One additional ECMO patient (BMI 27) treated with isavuconazole for invasive aspergillosis after thoracic surgery had eight isavuconazole trough concentrations with a median of 0.6 mg/L (range 0.45–0.78 mg/L). After cessation of ECMO, seven isavuconazole trough concentrations revealed a median of 0.73 mg/L (range 0.57–0.86). Isavuconazole dosage was subsequently increased from 200 mg of isavuconazole once to twice a day and trough concentrations were 0.96 mg/L on the next day and 1.78, 1.74 and 1.88 mg/L on the following days. Obviously, in this critically ill ECMO patient the underlying critical condition might have influenced isavuconazole concentrations and ECMO termination had no effect. Thus, even in the absence of ECMO an increase of isavuconazole dosage might be necessary to achieve concentrations above 1 mg/L. We performed our study as a pilot trail in a hypothesis-generating manner to plan further trials and show first insights into isavuconazole pharmacokinetics of ECMO patients. We agree that the implementation of multiple covariates optimally in a time-dependent approach or within mixed linear-effect models could better elucidate the impact of body composition or organ dysfunction on pharmacokinetics. But, due to the small number of patients and related difficulties in defining relevant outcomes for the efficacy of isavuconazole dosing, we demonstrated baseline variables at time of inclusion.