Pharmacoeconomics of Empirical Antifungal Use in Febrile Neutropenic Hematological Malignancy and Hematopoietic Stem Cell Transplant Patients

Stuart J Turner; Sharon CA Chen; Monica A Slavin; David CM Kong

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2013;13(2):227-235. 

In This Article

Antifungal Agents in Empiric Therapy

The primary antifungal agents used in empiric therapy are amphotericin B (AmB; a polyene), voriconazole (Vfend®, Pfizer, NY, USA; an azole) or caspofungin (Cancidas®, Merck and Co., NJ, USA; an echinocandin). These antifungals have good invitro and invivo activity against the two most common fungal pathogens (Candida and Aspergillus species).[8,18–23] Other agents that have been used empirically include anidulafungin, micafungin, itraconazole and posaconazole; however, none are approved for this indication.[17,24–27] This review is focused primarily on liposomal AmB (LAmB; AmBisome®, Gilead Sciences, CA, USA), voriconazole and caspofungin. While LAmB is the traditional gold standard according to European guidelines (European Conference on Infections in Leukaemia [ECIL]-3), the Infectious Diseases Society of America have no specific agent recommended above another.[15,28]

AmB is available as conventional AmB (or AmB deoxycholate), colloidal dispersion or lipid complex (LAmB), with all formulations of AmB demonstrating nearly equivalent effectiveness.[29] Clinically, AmB has been superseded by the newer 'lipid-based' formulations, partly due to lower incidence of renal toxicity.[30] LAmB, the most expensive antifungal agent, is administered intravenously and is approved for use empirically in febrile neutropenia in Europe, and is also used in Australia and the USA.[30] A review concluded that a lower dose of LAmB (3 mg/kg), which was generally better tolerated, was as efficacious as higher doses (10 mg/kg).[30] This review supports the notion that further pharmacoeconomic evaluations are required to determine the place of LAmB within the treatment algorithms for IFI. In the ECIL guidelines,[28] LAmB was given a significantly higher grading of evidence for effectiveness in empiric therapy (graded A1) compared with voriconazole (B1); along with caspofungin, it is considered the gold standard in the empiric treatment of IFI.

Voriconazole is available in intravenous (iv.) and oral formulations. It can induce altered liver function (10–32%), visual hallucinations (4–18%) and skin reactions (17%).[31–34] While the oral formulation may reduce hospital length of stay, existing data are mixed; with one study reporting comparable success and survival rate to that seen in others using iv. voriconazole.[35] Of note, voriconazole is not registered in Europe, Australia or the USA for the empiric treatment of febrile neutropenic patients, primarily due to its failure to meet the prespecified noninferiority test in comparison to LAmB.[8]

Caspofungin is available only as an iv. formulation.[11] It is generally well tolerated and safe. A previously published study has shown noninferiority in comparison to LAmB for empiric therapy of IFI.[18] It is approved in the USA, Europe and Australia for use as empiric therapy.

While many clinical studies have shown little difference in the effectiveness between LAmB, caspofungin and voriconazole in the empiric treatment of IFI,[8,18,30,34,36,37] this does not necessarily reflect cost–effectiveness, as other factors, such as hospitalization costs and costs associated with managing side effects from the antifungal agents, need to be considered.[7,38] Since there are relatively few studies that compare the effectiveness of the newer antifungal agents (i.e., LAmB, voriconazole, posaconazole, caspofungin, micafungin and anidulafungin) on a 'head-to-head' basis, well-designed prospective randomized controlled studies are urgently needed to guide the use of these agents in empirical treatment.[39]

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