Background 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. Objectives 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. Methods 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. Results 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). Conclusions 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.

Background Febrile neutropenia (FN) following chemotherapy is a major cause of morbidity during cancer treatment. The performance of metagenomic next-generation sequencing (mNGS) of circulating cell-free DNA from plasma may be superior to blood culture (BC) diagnostics for identification of causative pathogens. The aim of this study was to validate mNGS (DISQVER test) for the detection of pathogens in hematologic patients with FN. Methods We collected paired whole blood specimens from central venous catheter and peripheral vein during FN for BC and mNGS testing. We repeated paired sampling at the earliest after 3 days of fever, which was defined as one FN episode. All clinical data were retrospectively reviewed by an infectious disease expert panel. We calculated percent positive agreement (PPA), percent negative agreement (PNA), percent overall agreement (POA), and sensitivity and specificity. Results We analyzed a total of 98 unselected FN episodes in 61 patients who developed predominantly FN after conditioning therapy for allogeneic (n = 22) or autologous (n = 21) hematopoietic stem cell transplantation. Success rate of mNGS was 99% (97/98). Positivity rate of mNGS was 43% (42/97) overall and 32% (31/97) excluding viruses compared to 14% (14/98) in BC. PPA, PNA and POA between mNGS and BC were 84.6% (95% CI, 54.6% to 98.1%), 63.1% (51.9% to 73.4%) and 66% (55.7% to 75.3%), respectively. Sensitivity for bacteria or fungi was 40% (28.0% to 52.9%) and 18.5% (9.9% to 30.0%), respectively. Conclusion Pathogen detection by mNGS (DISQVER) during unselected FN episodes shows twofold higher sensitivity and a broader pathogen spectrum than BC.

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Background: Antifungal stewardship (AFS) has emerged as an important component of quality in managing invasive fungal infections (IFIs), and cost-benefit calculations suggest regular training in AFS is well worth the effort. Methods: This review will discuss the most common IFIs in solid organ transplantation (SOT)-recipients, how to diagnose them, and current recommendations for antifungal treatment and prophylaxis before demonstrating key takeaway points of AFS in this high-risk population. Results: Effective AFS starts before a patient is admitted for SOT, through education and regular interactions of the interdisciplinary clinical team involved in patient management, considering local factors such as epidemiological data and knowledge of diagnostic options including local turnaround times. Understanding the spectrum of antifungal agents, their efficacy and safety profiles, and pharmacokinetics, as well as duration of therapy is hereby essential. The most frequent IFIs in SOT recipients are caused by Candida species, followed by Aspergillus species, both with increasing resistance rates. Diagnosis of IFI can be challenging due to unspecific clinical presentation and difficult interpretation of microbiological findings and biomarkers. Prophylactic strategies, such as those for invasive aspergillosis in lung transplantation or invasive candidiasis (IC) in certain liver transplant settings, as well as the selection of the appropriate therapeutic agents require detailed knowledge on the pharmacokinetics and drug-drug interactions of antifungals.

Purpose of reviewInvasive fungal diseases (IFDs) such as invasive aspergillosis continue to be associated with high morbidity and mortality while presenting significant diagnostic challenges. Siderophores are high-affinity Fe 3þ chelators produced by Aspergillus spp. and other fungi capable of causing IFD. Previously evaluated as a treatment target in mucormycosis, siderophores have recently emerged as new diagnostic targets for invasive aspergillosis and scedosporiosis. Here, we review the diagnostic potential of siderophores for diagnosing IFD, with a particular focus on invasive aspergillosis. Recent findingsThe major secreted siderophore of A. fumigatus, triacetylfusarinine C (TAFC), has been successfully detected by mass spectrometry in serum, BALF and urine of patients with invasive aspergillosis, with promising sensitivities and specificities in single-centre studies. Intracellular uptake of siderophores has also been utilized for imaging, wherein fungal siderophores have been conjugated with the easy-to-produce radioactive isotope gallium-68 ( 68 Ga) to visualize infected body sites in PET. For the Scedosporium apiospermum complex, another siderophore N(a)-methyl coprogen B has been shown promising as a marker for airway colonization in early studies. SummarySiderophores and particular TAFC have the potential to revolutionize diagnostic pathways for invasive aspergillosis and other mould infections. However, larger multicentre studies are needed to confirm these promising performances. Methods that allow rapid and cost-effective measurements in routine clinical practice need to be developed, particularly when TAFC is used as a biomarker in patient specimens.