Early attainment of isavuconazole target concentration using an increased loading dose in critically ill patients with extracorporeal membrane oxygenation.

BACKGROUND: In critically ill patients with extracorporeal membrane oxygenation (ECMO) attainment of target concentration of isavuconazole is delayed using the routine loading dose. OBJECTIVES: We investigated the influence of increasing the first loading dose of isavuconazole on plasma concentrations in critically ill patients treated with ECMO. METHODS: Fifteen patients were included in this study, and isavuconazole concentrations were measured at several timepoints starting 2 h after the first isavuconazole dose up to 168 h. By interim analysis of isavuconazole concentrations and meticulous screening for adverse events, the first loading dose was stepwise increased from 200 to 300 mg, and finally to 400 mg. RESULTS: Seven of 15 patients (47%) received standard isavuconazole loading dosage with 200 mg as the first dose, 3/15 (20%) received 300 mg, and 5/15 (33%) received 400 mg isavuconazole as the first dose, followed by subsequent standard dosing in all patients. In patients receiving 400 mg as the first dose all isavuconazole concentrations were significantly higher at timepoints up to the first 24 h, resulting in higher proportions of isavuconazole concentrations ≥1 mg/L compared with patients with other loading dosages. In timepoints ≥24 h after isavuconazole initiation all patient groups reached comparable plasma concentrations, regardless of the first loading dose regimen. We did not observe concentrations above ≥5 mg/L or any adverse events related to isavuconazole administration. CONCLUSIONS: In critically ill patients with ECMO the 400 mg loading dose of isavuconazole resulted in immediate median isavuconazole plasma concentrations ≥1 mg/L and remained constant above this threshold after the first loading dose.

Isavuconazole Treatment in a Mixed Patient Cohort with Invasive Fungal Infections: Outcome, Tolerability and Clinical Implications of Isavuconazole Plasma Concentrations.

Isavuconazole (ISA) is a triazole antifungal agent recommended for treatment of invasive aspergillosis or mucormycosis. The objective of this study was to evaluate ISA levels in a real world setting in a mixed patient cohort including patients with non-malignant diseases and extracorporeal treatments, and to correlate findings with efficacy and safety outcomes. We investigated 33 ISA treatment courses in 32 adult patients with hematological and other underlying diseases and assessed the clinical response, side effects and ISA trough plasma concentrations. ISA treatment led to complete and partial response in 87% of patients and was well tolerated. The median ISA plasma concentration was 3.05 µg/mL (range 1.38-9.1, IQR 1.93-4.35) in patients without renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) and significantly lower in patients with RRT including cases with additional ECMO or Cytosorb® adsorber therapy (0.88 µg/mL, range 0.57-2.44, IQR 0.71-1.21). After exclusion of values obtained from four patients with ECMO or Cytosorb® adsorber the median concentration was 0.91 µg/mL (range 0.75-2.44, IQR 0.90-1.36) in the RRT group. In addition to previous recommendations we propose to monitor ISA trough plasma concentrations in certain circumstances including RRT, other extracorporeal treatments and obesity.

Comparison of functional fibrinogen (FF/CFF) and FIBTEM in surgical patients - a retrospective study.

BACKGROUND: Fibrinogen-based clot firmness is reported as the maximum amplitude (MA) when using the citrated functional fibrinogen (CFF) assay in thrombelastography (TEG), and as the maximum clot firmness (MCF) together with several clot amplitude parameters when using the FIBTEM assay in thromboelastometry (ROTEM). Concern is currently being raised that these two tests have different platelet inhibiting performance and consequently provide different values. This is relevant for the clinical setting of fibrinogen replacement. We aim herein to compare the parameters of these two fibrinogen-based clot quality tests and their correlation with the plasma fibrinogen level as determined by the Clauss method. METHODS: In total 261 whole blood samples taken from 163 clinical routine surgical patients were analyzed with TEG 5000 and ROTEM tests, and correlation with Clauss fibrinogen level was assessed. RESULTS: Using TEG, the overall fibrin-based clot firmness measured in the CFF assay was significantly higher than the MCF measured by FIBTEM assay. Both assays showed significantly positive correlations with the fibrinogen levels measured using the Clauss method. However, individual values of Clauss fibrinogen concentration corresponded with different values for the two viscoelastometric tests; e.g. within the range of 1.9-2.1 g/L Clauss fibrinogen the median of CFF MA was 16.3 mm whereas FIBTEM MCF was 12.0 mm. CONCLUSIONS: We showed herein by measurements of citrated whole blood samples from surgical patients that CFF MA values were different from FIBTEM MCF values measured in the same sample. Awareness that these whole blood assays provide different clot amplitude results is mandatory, particularly if they are being considered as tools for guiding fibrinogen supplementation. Thromboembolic side effects caused by a potentially too high fibrinogen substitution must also kept in mind in this context.