Isavuconazole for COVID-19-Associated Invasive Mold Infections

Abstract

Isavuconazole is a broad-spectrum antifungal drug recently approved as a first-line treatment for invasive aspergillosis and as a first or alternative treatment for mucormycosis. The purpose of this review was to report and discuss the use of isavuconazole for the treatment of COVID-19-associated aspergillosis (CAPA), and COVID-19-associated mucormycosis (CAM). Among all studies which reported treatment of CAPA, approximately 10% of patients were reportedly treated with isavuconazole. Considering 14 identified studies that reported the use of isavuconazole for CAPA, isavuconazole was used in 40% of patients (95 of 235 treated patients), being first-line monotherapy in over half of them. We identified six studies that reported isavuconazole use in CAM, either alone or in combination therapy. Overall, isavuconazole was used as therapy in 13% of treated CAM patients, frequently as combination or sequential therapy. The use of isavuconazole in CAPA and CAM is complicated by the challenge of achieving adequate exposure in COVID-19 patients who are frequently obese and hospitalized in the ICU with concomitant renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO). The presence of data on high efficacy in the treatment of aspergillosis, lower potential for drug–drug interactions (DDIs) and for subtherapeutic levels, and no risk of QT prolongation compared to other mold-active azoles, better safety profile than voriconazole, and the possibility of using an intravenous formulation in the case of renal failure are the advantages of using isavuconazole in this setting.

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

“…In addition, the authors emphasized the negative impact of plasma on the antifungal activity, which may overestimate the efficacy found in vitro for isavuconazole in this study, as similar results were found in studies on posaconazole [ 46 ]. Furthermore, isavuconazole appears to have significant inter-individual variability [ 23 , 47 ]. Microbiologically, the EUCAST threshold in 01/2022 was set at 2 mg/L for isavuconazole [ 28 ].…”

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

“…Obesity increases the volume of distribution, 20,21 and it was shown that the clearance of other related azole antifungals like voriconazole is higher 22,23 . It was previously concluded that the BMI might influence the exposure to isavuconazole, suggesting that patients with severe obesity might have lower therapeutic drug levels 13 . Another possible reason for lower C min levels in critically ill patients could be an increased volume of distribution in the early phase of sepsis.…”

“…CARDS‐patients commonly suffer from fungal superinfections, 10–12 such as COVID‐19‐associated pulmonary aspergillosis (CAPA) and COVID‐19‐associated mucormycosis (CAM). Such patients are frequently obese and hospitalised with concomitant renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) requirement which can affect isavuconazole levels 13 …”

“…Such patients are frequently obese and hospitalised with concomitant renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) requirement which can affect isavuconazole levels. 13 In this study, we evaluated 160 C min levels from 62 critically ill patients and tested seven demographic and clinical characteristics for correlations with sub-threshold plasma concentrations of isavuconazole, according to EUCAST. To the best of our knowledge, this is the first study to analyse COVID-19 versus non-COVID-19 cohorts and to conduct a multivariable analysis of seven clinically relevant patient characteristics in search for risk factors associated with isavuconazole plasma levels.…”

Managing the Next Wave of Influenza and/or SARS-CoV-2 in the ICU—Practical Recommendations from an Expert Group for CAPA/IAPA Patients

“…Initially, Troutine monitoring of isavuconazole levels was not considered, based on data from a pivotal study that found no association between blood levels and drug efficacy and/or toxicity. An analysis of eight studies in which isavuconazole levels were monitored in a total of 368 patients produced no conclusive findings in this regard [ 38 ]. However, suboptimal isavuconazole concentrations have been reported in critically ill patients, and are more frequent in obese patients and those undergoing renal replacement techniques [ 19 ].…”