Chaftari, A. M., Hachem, R. Y., Ramos, E., Kassis, C., Campo, M., Jiang, Y., . . . Raad, I. I. (2012). Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation. Transplantation, 94, 302–308.

To evaluate once weekly intravenous (IV) amphotericin B lipid complex (ABLC) given at a dose of 7.5 mg/kg as an alternative to posaconazole oral suspension (200 mg three times per day with food) for antifungal prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients.

Patients were randomized to either the ABLC arm (N = 22) or posaconazole arm (N = 24).  All patients were at risk for invasive fungal infection due to intensive chemotherapy for treatment of acute leukemia or lymphoma with a prolonged period of neutropenia expected or they were in the early phase after allogeneic HSCT.  Patients were given ABLC 7.5 mg/kg once weekly over four to six hours or posaconazole oral suspension 200 mg three times daily with a high fat content meal for the duration of neutropenia.  The study evaluated adverse events through the end of prophylaxis and up to two weeks thereafter. Study endpoints were the incidence of invasive fungal infections and drug-related toxicities.  ABLC was discontinued if the creatinine level increased to two times the baseline or greater.  

• Forty patients were included.
• Median age was 56 years (range 21–69) in the ABLC arm and 55 years (range 20–66) in the posaconazole arm.
• All patients in both arms had hematologic malignancies; 100% of those in the ABLC arm and 90% of those in the posaconazole arm received an allogeneic HSCT.  In the ABLC arm, 58% were human leukocyte antigen (HLA)-matched related donors and 42% were matched unrelated donors.  In the posaconazole arm, 63% were HLA-matched related donors and 37% were matched unrelated donors.  
• Duration of prophylaxis was a median of 20 days (range 7–42) in the ABLC arm and 42 days (range 6–42) in the posaconazole arm.

• Single site 
• Inpatient 
• The location was presumed to be MD Anderson Cancer Center (not stated in the article).

Patients were undergoing the active antitumor treatment phase of care.

 This was a prospective, randomized, open-label, single-institution study.

Toxicities were measured using grades 1–4 based on Common Terminology Criteria for Adverse Events (CTCAE) v3.0.  Patient tolerability of the drug was also measured.  Compliance to oral posaconazole and fatty meal intake were measured based on patient diary entries.  Infusion-related toxicity (ABLC) was reported and recorded by the infusion nurse.  Creatinine clearance for ABLC administration was calculated using Cockcroft-Gault formula.  All patients were evaluated for clinical signs and symptoms and radiologic and mycological findings suggestive of invasive fungal infection during the study period (the duration of neutropenia).

Both groups were comparable for the rate of occurrence of neutropenia and its duration, steroid usage, tacrolimus therapy, and tacrolimus blood levels during prophylaxis.  Both groups were comparable for the development of graft-versus-host disease.  Nineteen patients in the ABLC arm and 20 patients in the posaconazole arm developed adverse events, including 18 drug-related events in the ABLC arm (nephrotoxicity, hypokalemia, hypomagnesemia, fever, chills, and headache) and 17 in the posaconazole arm (increase in liver function tests, hypokalemia, hypomagnesemia, nausea, vomiting, and diarrhea).  The discontinuation rate from adverse events was 15 of 19 in the ABLC arm versus 8 of 20 in the posaconazole arm (p = 0.009).  Lower creatinine clearance was noted in the ABLC arm (p = 0.006).  Patients receiving ABLC experienced more chills (p = 0.04).  Median duration of prophylaxis was significantly longer in the posaconazole arm (p = 0.04).  One patient in the ABLC arm developed an invasive fungal infection compared to none in the posaconazole arm.  The study was stopped early because the interim data analysis suggested that there was more than a 70% chance that the nephrotoxicity rate of the ABLC group was greater than 50%.

High weekly doses of IV ABLC may not be appropriate antifungal prophylaxis in allogeneic HSCT recipients due to potential nephrotoxicity, although it could be useful in less complex patients, such as those receiving therapy for leukemia (non-HSCT).  Oral posaconazole can have erratic absorption, but it was shown to be safer than weekly ABLC in this study.  Better prophylaxis is needed in patients who cannot tolerate oral medications.

• Small sample (<100)
• Risk of bias (no control group, no blinding, no appropriate attentional control condition, and sample characteristics*)
• Findings not generalizable*

* The findings are generalizable only to HSCT/hematologic malignancy patients, and only those with hematologic malignancies were included in the sample.

Because posaconazole is such an effective antifungal agent for prophylaxis (reinforced here), nurses must be vigilant in patient education.  Patients must be given instructions to take the drug during or within 20 minutes of a full meal (preferably with high fat content) or liquid nutritional supplement or with an acidic carbonated beverage (i.e., ginger ale).  There are many restrictions, and patient education is key to taking this drug and ensuring its efficacy.