Background and Importance Extracorporeal membrane oxygenation (ECMO) may lead to pharmacokinetic alterations of antimicrobials. Isavuconazole is not approved in paediatric patients (PedP) (off-label use) and data on paediatric ECMO are non-existent.

Aim and Objectives To describe two case reports using therapeutic drug monitoring (TDM) to optimise isavuconazole dosage in PedP during ECMO.

Material and Methods Prospective study in critically ill PedP treated with intravenous isavuconazole receiving ECMO (January 2021to August 2022). Biodemographic, clinical and pharmacokinetic data were collected. Initial proposed dose of isavuconazole base was 5.4 mg/kg (first 48h q8h, followed by q24h; maximum 200 mg/dose). Isavuconazole trough serum concentration (IsaCmin) of 2.5-5 μg/mL was considered as therapeutic range (internal protocol). Continuous variables were expressed as median (range).

Results 1) A 2-year-old boy (11.5kg, 90cm) lung transplant recipient (pulmonary capillary hemangiomatosis) diagnosed with tracheobronchitis caused by Aspergillus flavus (9 months after transplant). Isavuconazole was started at a proposed dose and IsaCmin remained in therapeutic range: 5.1(2.5-5.5) μg/mL. Secondary prophylaxis with isavuconazole was maintained (same dose), requiring ECMO due to severe acute respiratory failure (multifactorial). During ECMO (165 days), it was necessary to increase the dose to 16.5 (8.7-19.1) mg/kg/24h to achieve target concentration of median IsaCmin 2.82 (1.3-6.5) μg/mL (24 blood samples). No new fungal infections were observed but sadly the patient died due to intracranial haemorrhage.

2) A 11-year-old girl (70kg, 158cm) admitted for influenza A infection and necrotising pneumonia (Staphylococcus aureus), requiring ECMO. Invasive fungal infection was probable (EORTC criteria; positive galactomannan and tracheal aspirate for Aspergillus niger) and isavuconazole was started: loading dose of 300mg/6h (suspected interaction with pentobarbital during first 48h) and TDM-guided maintenance therapy. During ECMO (30 days) median maintenance dose was 900mg (12.9mg/kg)/24h (varied widely ranging from 200mg/12h to 250mg/4h) and median IsaCmin remained in the therapeutic range: 4.0 (1.1-8.4) μg/mL (9 blood samples). After ECMO decannulation, isavuconazole dose was reduced to 200mg/12-24h and median IsaCmin remained in range: 3.9 (2.8-11.4) μg/mL. She continues isavuconazole maintenance treatment with a partial response.

Conclusion and Relevance

• PedP on ECMO may require higher doses of isavuconazole to achieve therapeutic concentrations, suggesting that TDM may be clinically useful.

• Further studies in critically ill PedP, especially those on ECMO, are necessary to confirm the optimal isavuconazole dosage.

Conflict of Interest No conflict of interest.