COVID-19 associated pulmonary aspergillosis (CAPA) was recently reported as a potential infective complication affecting critically ill patients with acute respiratory distress syndrome following SARS-CoV-2 infection, with incidence rates varying from 8 to 33% depending on the study. However, definitive diagnosis of CAPA is challenging. Standardised diagnostic algorithms and definitions are lacking, clinicians are reticent to perform aerosol-generating bronchoalveolar lavages for galactomannan testing and microscopic and cultural examination, and questions surround the diagnostic sensitivity of different serum biomarkers. Between 11th March and 14th July 2020, the UK National Mycology Reference Laboratory received 1267 serum and respiratory samples from 719 critically ill UK patients with COVID-19 and suspected pulmonary aspergillosis. The laboratory also received 46 isolates of Aspergillus fumigatus from COVID-19 patients (including three that exhibited environmental triazole resistance). Diagnostic tests performed included 1000 (1-3)-β-d-glucan and 516 galactomannan tests on serum samples. The results of this extensive testing are presented here. For a subset of 61 patients, respiratory specimens (bronchoalveolar lavages, tracheal aspirates, sputum samples) in addition to serum samples were submitted and subjected to galactomannan testing, Aspergillus-specific PCR and microscopy and culture. The incidence of probable/proven and possible CAPA in this subset of patients was approximately 5% and 15%, respectively. Overall, our results highlight the challenges in biomarker-driven diagnosis of CAPA especially when only limited clinical samples are available for testing, and the importance of a multi-modal diagnostic approach involving regular and repeat testing of both serum and respiratory samples.

The multiple dose pharmacokinetics of a solution of itraconazole given orally were measured in an open study of 20 patients undergoing remission induction chemotherapy for acute myeloid leukaemia. Patients were given itraconazole 5 mg/kg od, 2.5 mg/kg bd, 2.5 mg/kg od or 1.25 mg/kg bd. The mean daily dose of itraconazole was 407 mg for patients receiving 5 mg/kg/day and 148 mg in patients receiving 2.5 mg/kg/day. Mean concentrations of 493 and 495 micrograms/L were achieved on day 8 in patients who received 5 mg/kg/d od or 2.5 mg/kg bd itraconazole respectively. However, mean concentrations were significantly lower for those who received 2.5 mg/kg od itraconazole being 110 micrograms/L on day 8. Mean areas under the serum-concentration time curves were also markedly higher in patients receiving 5 mg/kg/day than in those receiving 2.5 mg/kg/day itraconazole and were 22,382 and 5615 micrograms.h/L on day 15 respectively. These findings suggest that the serum concentrations attained with an oral solution of 5 mg/kg itraconazole either once daily or in two divided doses are suitable for antifungal prophylaxis in patients receiving chemotherapy for acute myeloid leukaemia.

The pharmacokinetics of itraconazole oral solution were measured in seven patients receiving chemotherapy followed by autologous bone marrow transplantation for leukaemia or lymphoma. Patients received 5 mg/kg/day itraconazole either as a once or twice daily dose. Drug concentrations reached steady state by day 15, in both groups. The mean pre-dose itraconazole serum concentration at hour 0, day 8 was 385 ng/mL in the od group and 394 ng/mL in the bd group, rising to 762 and 845 ng/mL by day 15, respectively. The mean AUCs for 0-24 h on day 8, 15 and 22 were 17,310 and 13,302 ng/mL/h, 24,476 and 25,154 and 22,621 and 21,423, for the od and bd groups, respectively. Thus serum concentrations of itraconazole suitable for antifungal prophylaxis can be attained in neutropenic patients, with the administration of an oral solution in a dosage of 5 mg/kg as either an od or bd schedule, following pre-autograft high-dose cytotoxic chemotherapy.

The aim of this study was to compare the concentrations of itraconazole in serum and saliva after treatment with itraconazole cyclodextrin solution or itraconazole capsules in Candida-associated denture stomatitis patients without evidence of immunodeficiency. Forty patients were randomly assigned to receive either itraconazole cyclodextrin solution or itraconazole capsules, both at a dosage of 100 mg bd for 15 days. On completion of treatment palatal erythema was assessed and an oral rinse and imprint cultures were collected. Serum and saliva samples were collected at the same time and itraconazole concentrations measured using reverse-phase high-performance liquid chromatography. Itraconazole susceptibilities of Candida albicans and Candida glabrata strains isolated at baseline were measured by a broth microdilution method. Serum itraconazole concentrations achieved did not differ significantly between the two preparations (P = 0.39) although a significantly higher number of patients in the itraconazole cyclodextrin group (P < 0.001) had detectable levels of itraconazole in their saliva compared with the capsule group. Mycologically cured patients had slightly, though not significantly (P = 0.28), higher serum itraconazole concentrations than those from whom yeasts were not eradicated. It was concluded that both formulations of itraconazole were equally effective in treatment of denture stomatitis. Among immunocompetent patients, the absorption of the liquid preparation is no greater than that of the capsules. Therapeutic success in this group was achieved with lower serum itraconazole concentrations than have been reported for immunocompromised groups.

We determined isavuconazole serum concentrations for 150 UK patients receiving standard isavuconazole dosing regimens, including serial therapeutic drug monitoring for several patients on prolonged therapy. Mean trough isavuconazole concentrations in these patients were virtually identical to those reported previously from clinical trials, although greater variability was seen in patients below 18 years of age. Serial monitoring in patients receiving prolonged therapy suggested gradual, near-linear accumulation of the drug over many weeks.