Döring, M., Blume, O., Haufe, S., Hartmann, U., Kimmig, A., Schwarze, C. P., . . . Muller, I. (2014). Comparison of itraconazole, voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation. European Journal of Clinical Microbiology & Infectious Diseases, 33, 629–638. 

To explore the efficacy of itraconazole, voriconazole, and posaconazole for breakthrough fungal infections with a secondary objective of analyzing the safety and feasibility of these three different regimens in a pediatric hematopoietic stem cell transplantation (HSCT) population

This study consisted of the observation of 150 pediatric patients split into three groups between the ages of 0.6–17.7 years with hematologic malignancies undergoing allogeneic HSCT. All patients received one of the azoles as primary oral antifungal prophylaxis following HSCT. Fifty consecutive patients from 2006 to 2007 were in the itraconazole group, 50 consecutive patients from 2006 and 2010 in the voriconazole group, and 50 consecutive patients from 2010 to 2011 were in the posaconazole group when the center switched to posaconazole for prophylaxis. The observation period lasted from the start of oral prophylactic treatment till two weeks after the withdrawal of therapy.

• N = 150  
• AGE: All patients were aged less than 18 years
• MALES: 54%, FEMALES: 46%
• KEY DISEASE CHARACTERISTICS: Majority were hematological malignancies, but also included some solid tumors, neurometabolic disease, and immunodeficiency syndromes; all underwent HSCT 
• OTHER KEY SAMPLE CHARACTERISTICS: Conditioning regimens and transplant type (MUD, MMUD, MMFD, and MFD)

• SITE: Single site  
• SETTING TYPE: Inpatient    
• LOCATION: University Children’s Hospital Tübingen

• PHASE OF CARE: Active antitumor treatment
• APPLICATIONS: Pediatrics

Retrospective, single-center survey; one sample t-test used the Wilcoxon matched-pairs signed-rank test

• Proven probable and possible invasive fungal infections classified according to the National Institute of Allergy and Infectious Disease Mycoses Study Group
• Galactomannan antigen testing

Possible invasive fungal infections occurred in 4% of the itraconazole group, 6% of the voriconazole group, and 0% of the posaconazole group. There were no significant differences comparing all three. Adverse events occurred in 12% of the itraconazole group, 14% of the voriconazole group and 8% of the posaconazole group (no significant difference). All three groups showed a significant increase in ALT and AST as well as a significant difference between baseline and maximum levels of ALT and AST without clinical symptoms. Bilirubin also was increased during all three drug regimens but remained within the upper limits of normal. The kidney parameters (BUN/Cr) also showed an increase in all three groups but were not above reference values. Other adverse effects included hyponatremia. Cyclosporine (CsA) levels were evaluated in select patients in all three groups requiring dosage adjustments with a 12% dose reduction of CsA in the itraconazole and voriconazole group and as much as a 25% dose reduction in the posaconazole group.

Current guidelines for the use of oral antifungal prophylaxis in pediatric patients after HSCT are based on insufficient data. Despite the positive results, showing efficacy of all three drugs, it was comparable with no proven or probable fungal invasive infections. The analysis of a larger number of patients is required.

• Risk of bias (no control group)
• Risk of bias (no blinding)
• Other limitations/explanation: The majority of patient’s received IV liposomal amphotericin or IV caspofungin prior to the switch to oral monoprophylaxis, and this may have been a positive contributing factor to prevent invasive fungal infections. The interpretation that there was no significant difference in side effects – due to a few occurrences in the posaconazole arm the power was low at 16.2% – urges caution when interpreting the difference.

Because of the small number of current trials, larger trials are needed to compare each of the azoles as monoprophylaxis. Additional studies are needed to better understand the side effect profiles of the azoles and their interactions with antibiotics or immunosuppressants.