Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation

Abstract

Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4%) and three in the voriconazole group (6%). The percentage of patients with adverse events potentially related to clinical drugs were 14% in the voriconazole group, 12% in the itraconazole group, and 8% in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.

Fig. 1

Hepatotoxicity. Values of liver enzymes and cholestasis parameters are shown on the day before the start of oral antifungal prophylaxis (baseline), maximum values during (maximum) and end of itraconazole (white columns), voriconazole (gray columns), and posaconazole (dark gray columns) treatment (end). a Mean and standard deviation (SD) of serum alanine aminotransferase (ALT) (normal value ≤39 U/L). b Serum aspartate aminotransferase (AST) (normal value ≤39 U/L). c Total bilirubin (normal value ≤1.1 mg/dl). d Direct bilirubin (normal value ≤0.3 mg/dl). e Serum alkaline phosphatase (AP) (normal value ≤320 U/L). The horizontal line indicates the normal value. Statistical analysis of ALT and AST by the one-sample t-test showed a significant increase beyond the upper normal limit. A significant increase (by the Wilcoxon matched-pairs signed-ranks tests) of ALT between baseline and maximum in all three groups, itraconazole (p = 0.0007), voriconazole (p = 0.0151), posaconazole (p = 0.00066), and a significant increase of AST during itraconazole (p = 0.0013), voriconazole (p = 0.0032), and posaconazole (p = 0.0024) treatment was detected. Total bilirubin, direct bilirubin, and alkaline phosphatase during itraconazole, voriconazole, and posaconazole treatment remained within the age-corrected normal range. None of these changes was clinically relevant

Fig. 2

Electrolytes. Mean and standard deviation (SD) of electrolytes in peripheral blood. a Potassium (normal value >3.4 mmol/L). b Calcium (normal value >2.1 mmol/L). c Phosphate (normal value >0.8 mmol/L. d Bicarbonate (normal value >21 mmol/L) on the day before the start of oral antifungal prophylaxis (baseline), minimum values during (minimum) and end of itraconazole (white columns), voriconazole (gray columns), and posaconazole (dark gray columns) treatment (end). The horizontal line indicates the normal value. Statistical analysis by the one-sample t-test showed no significant decrease below the lower limit of the normal range during antifungal monoprophylaxis