Ananda-Rajah, M.R., Grigg, A., Downey, M.T., Bajel, A., Spelman, T., Cheng, A., . . . Slavin, M.A. (2012). Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica, 97, 459–463.

The study analyzed the relative effectiveness and safety of azole antifungal prophylaxis with particular attention to the tri-azoles compared to fluconazole/itraconazole.

Patients at the Royal Melbourne Hospital with AML/MDS undergoing remission-induction chemotherapy from December 1998–January 2010 who received one day or more of azole prophylaxis were included.  Prophylaxis consisted of fluconazole 400 mg daily, itraconazole sodium 2.5 mg/kg twice daily, voriconazole 200 mg twice daily or posaconazole 200 mg three times daily with fatty food. These were started 1–2 days prior to chemotherapy and continued until neutrophil recovery (greater than 0.5 cells/L), occurrence of a confirmed or suspected invasive fungal infection, drug-related toxicity/intolerance, or the patient’s condition becoming palliative. Oral administration was preferred, fluconazole or voriconazole could be given via IV when a patient’s gastrointestinal absorption was considered inadequate.

216 patients were evaluated (57 in the fluconazole group, 59 in the itraconazole group, 82 in the voriconazole group, and 68 in the posaconazole group).

The median age per group was: fluconazole, 57 (range = 20–79); itraconazole, 55 (range = 20–79); voriconazole, 51 (range = 17–81); posaconazole, 51 (range = 19–78).

Regarding key disease characteristics, 197 patients had AML and 18 had transformed MDS. Median duration of neutropenia ranged from 13–16 days. 

Patient receiving TPN per group: fluconazole, 38%; itraconazole, 40%; voriconazole, 21%; posaconazole, 31%.

Fluconazole was used from December 1998 to September 2008, itraconazole was used from May 1999 to January 2003, voriconazole was used from November 2002 to August 2008, posaconazole was used from September 2006 to January 2010.
 

• Single site 
• Inpatient 
• Royal Melbourne Hospital

Active antitumor treatment

The study was a retrospective review.

• Receipt of total parenteral nutrition (TPN) was a marker of severe mucositis.
• Invasive fungal infection onset was defined as the first day of suspicious CT abnormality or positive microbiology or pathological test.  
• Breakthrough invasive fungal infections were defined as occurrence of invasive fungal infection in patients during \"-azole\" prophylaxis or within seven days of drug cessation.   
   

The majority of patients (213/216) underwent chemotherapy for remission-induction or re-induction or relapsed disease. The median duration of neutropenia for fluconazole/itraconazole was significantly longer than voriconazole/posaconazole (16 days versus 14 days, p = 0.003). TPN requirement was 39% versus 26% (p = 0.001), and median duration of prophylaxis was 18 days versus 22 days (p < 0.001).   
Breakthrough invasive fungal infection occurred in 27 patients comprising of probable/proven (11) and possible (16). The incidence of breakthrough invasive fungal infection was significantly lower in the voriconazole/posaconazole group (10 of 125; 8%) versus fluconazole/itraconazole (17 of 85; 20%) (p = 0.011). All probable/proven invasive fungal infections were molds, most commonly aspergillosis.  
Sub-therapeutic drug levels were common in itraconazole (42%), voriconazole (38%), and posaconazole (69%).  
 

In this institution, the use of voriconazole/posaconazole coincided with a significant decrease in the incidence of breakthrough invasive fungal infections.

Risk of bias:

• No control group
• No blinding
• No random assignment
• No appropriate attentional control conditions
• Sample characteristics*
• Findings not generalizable*

*Findings generalizable to only hematologic malignancies. The retrospective nature is not as strong in this study and, although some good information was shared, the results are not as useful to change practice.

This study compared different agents used for antifungal prophylaxis. There is always the need for education of patients and staff of the signs on infection while on prophylactic therapy and the education of taking the medication correctly and changing to an alternate therapy if the risk of impaired gastrointestinal function is greater for particular patients (i.e., severe mucositis).