Population Pharmacokinetics of Isavuconazole in Critical Care Patients with COVID-19-Associated Pulmonary Aspergillosis and Monte Carlo Simulations of High Off-Label Doses.

Isavuconazole is a triazole antifungal agent recently recommended as first-line therapy for invasive pulmonary aspergillosis. With the COVID-19 pandemic, cases of COVID-19-associated pulmonary aspergillosis (CAPA) have been described with a prevalence ranging from 5 to 30%. We developed and validated a population pharmacokinetic (PKpop) model of isavuconazole plasma concentrations in intensive care unit patients with CAPA. Nonlinear mixed-effect modeling Monolix software were used for PK analysis of 65 plasma trough concentrations from 18 patients. PK parameters were best estimated with a one-compartment model. The mean of ISA plasma concentrations was 1.87 [1.29-2.25] mg/L despite prolonged loading dose (72 h for one-third) and a mean maintenance dose of 300 mg per day. Pharmacokinetics (PK) modeling showed that renal replacement therapy (RRT) was significantly associated with under exposure, explaining a part of clearance variability. The Monte Carlo simulations suggested that the recommended dosing regimen did not achieve the trough target of 2 mg/L in a timely manner (72 h). This is the first isavuconazole PKpop model developed for CAPA critical care patients underlying the need of therapeutic drug monitoring, especially for patients under RRT.

Admission High-Sensitive Cardiac Troponin T Level Increase Is Independently Associated with Higher Mortality in Critically Ill Patients with COVID-19: A Multicenter Study.

BACKGROUND: In coronavirus disease 2019 (COVID-19) patients, increases in high-sensitive cardiac troponin T (hs-cTnT) have been reported to be associated with worse outcomes. In the critically ill, the prognostic value of hs-cTnT, however, remains to be assessed given that most previous studies have involved a case mix of non- and severely ill COVID-19 patients. METHODS: We conducted, from March to May 2020, in three French intensive care units (ICUs), a multicenter retrospective cohort study to assess in-hospital mortality predictability of hs-cTnT levels in COVID-19 patients. RESULTS: 111 laboratory-confirmed COVID-19 patients (68% of male, median age 67 (58-75) years old) were included. At ICU admission, the median Charlson Index, Simplified Acute Physiology Score II, and PaO2/FiO2 were at 3 (2-5), 37 (27-48), and 140 (98-154), respectively, and the median hs-cTnT serum levels were at 16.0 (10.1-31.9) ng/L. Seventy-five patients (68%) were mechanically ventilated, 41 (37%) were treated with norepinephrine, and 17 (15%) underwent renal replacement therapy. In-hospital mortality was 29% (32/111) and was independently associated with lower PaO2/FiO2 and higher hs-cTnT serum levels. CONCLUSIONS: At ICU admission, besides PaO2/FiO2, hs-cTnT levels may allow early risk stratification and triage in critically ill COVID-19 patients.