Study population
Inclusion criteria
Pediatric patients requiring antifungal prophylaxis after allogeneic HSCT and bone marrow engraftment.
Patients with toxicity to azoles or amphotericin B requiring a change of therapy.
Age between 2 months and 18 years.
Informed consent from parents or guardians for all patients and informed assent for mature minors (over 12 years) following current regulations (Declaration of Helsinki, Law 14/2007 of July 3 on Biomedical Research).
Exclusion criteria
Severe allergic reaction to micafungin.
Grade 4 toxicity attributable to previous use of micafungin.
Breakthrough IFI during previous use of micafungin.
No informed consent from the patient and/or legal guardian.
Protocol (Figure 1)
1. Micafungin was administered at a dose of 1 mg/kg/day as an antifungal prophylaxis starting at the onset of the transplant conditioning regimen and continuing as long as prolonged neutropenia is anticipated.
2. The alternating prophylaxis protocol was initiated after bone marrow engraftment, that is, when patients present sustained neutrophil counts ≥500 according to the following guidelines: - In patients weighing <33 kg: 3 mg/kg/dose on Mondays, Wednesdays and Fridays, with a maximum dose of 100 mg.
-In patients weighing between 33 and 60 kg: 50 mg/dose on Mondays, Wednesdays and Fridays. -In patients weighing >60 kg: 100 mg/dose on Mondays, Wednesdays and Fridays.
The doses were agreed upon with the hospital pharmacy based on existing data in the literature and the available presentation of the drug. In children weighing ≤33 kg, agreement was based on existing publications in pediatrics that suggest maintaining a dose of 3 mg/kg/48 h to minimize the risks of greater clearance and greater volume of distribution described in patients with lower weight (22-24). In patients with a higher weight and older age, the doses were adjusted to those used in the Adult Hematology Unit of the center and reported in studies, that is, an alternating dose of 300 mg/weekly in adults (26).
Administration is performed on Mondays, Wednesdays and Fridays on an outpatient basis.
Drug administration schedule
Micafungin (diluted in 0.9% saline solution to a 1 mg/mL standardized concentration in a horizontal laminar flow booth of the pharmacy department to garantee its adequate sterility (27)) was administered as an intravenous infusion for 1 hour, preferably using an infusion pump. The medication was administered through a Port-a-Cath central line by expert nurses in the department. The solution should be adequately protected from light to prevent its degradation.
Alternating prophylaxis was maintained at least until 75 days after transplantation and was suspended if the patient did not require immunosuppressants and the CD4 count was >400.
In children with GVHD and/or CD4 ≤400, prophylaxis was maintained until the resolution of GVHD, the withdrawal of immunosuppression and/or an increase in the CD4 count.
Serum micafungin levels
Determinations of the valley levels of micafungin were performed in an alternating schedule. Blood was collected into a 5-mL vacutainer tube with heparin as an anticoagulant and was protected from light. The samples were transported under refrigeration to the microbiology laboratory. The plasma was frozen at -80ºC until analysis. The concentration of micafungin in human plasma samples was determined by a high-performance liquid chromatography (HPLC) technique with a linearity coefficient >0.99 for the entire concentration range studied, an accuracy of 85-115% and a precision (coefficient of variation) <20% for the intraday and interday variability, respectively, and a limit of quantification of 0.5 mg/L (28).