isavuconazole and Critical-Illness

Infections caused by filamentous fungi represent a major burden in the ICU. Invasive aspergillosis is emerging in non-neutropenic individuals with predisposing conditions, e.g. corticosteroid treatment, chronic obstructive pulmonary disease, liver cirrhosis, solid organ cancer, HIV infection and transplantation. Diagnosis is challenging because the signs and symptoms are non-specific, and initiation of additional diagnostic examinations is often delayed because clinical suspicion is low. Isolation of an Aspergillus species from the respiratory tract in critically ill patients, and tests such as serum galactomannan, bronchoalveolar lavage 1-3-β-d-glucan and specific PCR should be interpreted with caution. ICU patients should start adequate antifungal therapy upon suspicion of invasive aspergillosis, without awaiting definitive proof. Voriconazole, and now isavuconazole, are the drugs of choice. Mucormycosis is a rare, but increasingly prevalent disease that occurs mainly in patients with uncontrolled diabetes mellitus, immunocompromised individuals or previously healthy patients with open wounds contaminated with Mucorales. A high proportion of cases are diagnosed in the ICU. Rapidly progressing necrotizing lesions in the rhino-sinusal area, the lungs or skin and soft tissues are the characteristic presentation. Confirmation of diagnosis is based on demonstration of tissue invasion by non-septate hyphae, and by new promising molecular techniques. Control of underlying predisposing conditions, rapid surgical resection and administration of liposomal amphotericin B are the main therapeutic actions, but new agents such as isavuconazole are a promising alternative. Patients with mucormycosis receive a substantial part of their care in ICUs and, despite advances in diagnosis and treatment, mortality remains very high.

Topics: Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Critical Illness; Galactose; Humans; Immunocompromised Host; Intensive Care Units; Invasive Fungal Infections; Lung Diseases, Fungal; Mannans; Mucor; Mucormycosis; Nitriles; Opportunistic Infections; Pyridines; Respiratory System; Triazoles; Voriconazole

Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy.. A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach.. Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure.. In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population.. ClinicalTrials.gov identifier: NCT04777058.

Topics: Adult; Anti-Bacterial Agents; Critical Illness; Humans; Prospective Studies; Triazoles

In critically ill patients with extracorporeal membrane oxygenation (ECMO) attainment of target concentration of isavuconazole is delayed using the routine loading dose.. We investigated the influence of increasing the first loading dose of isavuconazole on plasma concentrations in critically ill patients treated with ECMO.. 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.. 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.. 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.

Topics: Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Nitriles; Pyridines

Isavuconazole is an antifungal drug used for treatment of invasive fungal infections. Critically ill COVID-19 and influenza patients require extracorporeal membrane oxygenation (ECMO) in cases with severe acute respiratory distress syndrome and have risk factors for invasive pulmonary aspergillosis. Little is known about isavuconazole plasma concentrations during ECMO.. To determine isavuconazole plasma concentrations in seven patients treated with intravenous isavuconazole under ECMO and the influence of the ECMO circuit immediately after the first isavuconazole dose.. Critically ill patients treated with isavuconazole (standard doses) and ECMO were included in this study. Sixty-four blood samples used for measurement of isavuconazole concentrations were collected at several timepoints starting 2 h after the first isavuconazole dose up to 168 h. An additional 27 blood samples were drawn from the inflow and outflow line of the membrane oxygenator to assess any potential isavuconazole clearance effect of the ECMO oxygenation device and the lines.. Median isavuconazole trough levels above 1 μg/mL (min. 0.83, max. 1.73) or 2 μg/mL (min. 0.84, max. 2.97) were achieved 24 h or 96 h after the first dose of isavuconazole. The isavuconazole plasma concentrations pre (inflow line) and post (outflow line) the membrane oxygenator were directly correlated (ρ = 0.987, R2 = 0.994, P < 0.001). Post membrane oxygenator isavuconazole concentrations were directly correlated to contemporaneous samples obtained from the arterial lines of patients (ρ = 0.942, R2 = 0.945, P < 0.001).. Isavuconazole concentrations might be influenced by the higher volume of distribution due to ECMO therapy, but were not altered by the ECMO oxygenator and achieved median plasma concentrations >1 μg/mL 24 h after the first loading dose.

Topics: COVID-19; Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Nitriles; Pyridines; Triazoles

Topics: Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Nitriles; Triazoles

Topics: Critical Illness; Extracorporeal Membrane Oxygenation; Humans; Nitriles; Triazoles

Isavuconazole plasma concentrations were measured before and after sustained low-efficiency dialysis (SLED) treatment in 22 critically ill adult patients with probable invasive aspergillosis and underlying hematological malignancies. Isavuconazole levels were significantly lower after SLED treatment (5.73 versus 3.36 μg/ml;

Topics: Adult; Antifungal Agents; Aspergillosis; Aspergillus; Critical Illness; Female; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Nitriles; Pyridines; Triazoles