Decreased isavuconazole trough concentrations in the treatment of invasive aspergillosis in an adult patient receiving extracorporeal membrane oxygenation support

Abstract

Purpose We present the case of a 56-year-old man with stage IV sarcoidosis on veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for the management of respiratory failure receiving treatment with isavuconazole for invasive aspergillosis. Summary VV-ECMO is an increasingly utilized life support therapy for patients with cardiac and/or respiratory failure, but its impact on medication dosing is poorly understood. In our patient with invasive Aspergillus infection receiving VV-ECMO, because of difficulty achieving therapeutic serum concentrations of voriconazole, we administered isavuconazole 372 mg intravenously (IV) every 8 hours for 6 doses followed by 372 mg IV once daily. Isavuconazole has a favorable pharmacokinetic and safety profile compared to other azole antifungal agents, but its high protein binding and lipophilicity raise concerns about drug sequestration in the VV-ECMO circuit. To optimize the efficacy and safety of this treatment, the isavuconazole trough concentration was measured at days 5 and 17, at which time it was 1.7 and 0.7 μg/mL, respectively. The dose was subsequently increased to 744 mg IV once daily, and serum trough concentrations were measured 5 and 8 days after dose adjustment, corresponding to 3.7 and 2.9 μg/mL, respectively. To our knowledge, this is the third report to describe inadequate isavuconazole trough concentrations during VV-ECMO support when utilizing standard doses. Conclusion In the case described here, standard-dose isavuconazole (372 mg every 8 hours for 6 doses followed by 372 mg daily) did not achieve target trough concentrations in a patient receiving concomitant ECMO support.

The impact of extracorporeal membrane oxygenation on the exposure to isavuconazole: a plea for thorough pharmacokinetic evaluation

“…In contrast, the isavuconazole C min in cases C and D did not exceed the target of 1 mg/L when correcting for the standard maintenance dose of 200 mg q24h. The latter results are in line with the previous reports by Zhao et al [ 3 ] and Miller et al [ 1 ], in which subtherapeutic exposure following a standard dosing regimen was documented and ascribed to ECMO as such .…”

“…Unfortunately, based on the previously published reports [ 1 – 3 ] and our case series, the independent impact of ECMO on isavuconazole exposure in critically ill patients cannot be assessed. Therefore, the key question whether subtherapeutic isavuconazole exposure in ECMO patients is caused by ECMO or by critical illness itself remains unanswered.…”

“…Based on the high lipophilicity and extensive plasma protein binding of isavuconazole, the triazole is theoretically prone to adsorption to ECMO circuits and subsequent reduction in plasma concentrations. To date, isavuconazole exposure in ECMO patients has only been documented in two case reports and a case series ( n = 3) in which reduced plasma concentrations during ECMO have been suggested [ 1 – 3 ]. In this correspondence, we would like to emphasize that the suggestion of reduced isavuconazole exposure due to ECMO as such should be interpreted cautiously and that additional studies are needed to evaluate the independent impact of ECMO on the PK of isavuconazole.…”

Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID‐19

“…The nine ECMO patients included in our study exhibited lower isavuconazole drug levels, which is in line with other reports, 16,28–30 in which a sum of nine ECMO patients had been included. In contrast, one study reported sufficient levels of this drug in seven ECMO patients with prophylactic administration 31 .…”

Isavuconazole for COVID-19-Associated Invasive Mold Infections

“…In another case of a patient with pulmonary blastomycosis, for which therapeutic target concentration of isavuconazole was set at 3 mg/L, these concentrations could be only achieved by increasing the dose of isavuconazole (200 mg bid), while the standard dose resulted in a concentration of 1.9 mg/L [ 85 ]. In an additional case of a patient treated with ECMO but no RRT, treatment with voriconazole did not result in adequate plasma levels, while standard dose of isavuconazole resulted in initial adequate plasma level (1.7 mg/L), which nevertheless decreased to 0.7 mg/L over the following 12 days [ 86 ]. The ECMO circuit exchange (which was done approximately every 7 days) was cited as the most probable cause of the decrease in plasma levels.…”