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


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

In This Article

Abstract and Introduction


Invasive fungal infections incur considerable costs to healthcare and are associated with high mortality. These infections are increasing, due in part to more intensive immunosuppressive regimens with longer periods of neutropenia for patients treated for conditions such as cancer and hematopoietic stem cell transplantation. Therapeutic strategies in treating invasive fungal infections include the initiation of empiric antifungal therapy. This early treatment is triggered by fever that is unresponsive to 48–72 h of broad-spectrum antibiotic therapy in high-risk patients, prior to diagnosis. Several antifungal agents are available for this purpose. Informed decisions with respect to the choice of antifungal drug require clinicians to consider both efficacy data of a particular drug and the economic consequences of using the drug. This enables a treatment decision to be based not only on drug acquisition cost, but also expenses associated with hospitalization, monitoring and managing adverse effects to the treatment(s) chosen.


Invasive fungal infections (IFIs) are a significant contributor to mortality in patients with hematological malignancy, ranging from approximately 30 to 50 and 30 to 55%, for Candida and Aspergillus infections, respectively.[1–6] IFIs can result in a large burden on hospital systems through high management cost and hospitalizations in excess of a 2-week duration.[7,8] These infections most commonly involve immunocompromised hosts, such as those exposed to chemotherapy for cancer, or in those that undergo hematopoietic stem cell transplantation.[9] The incidence of IFI has been steadily increasing.[10] It is estimated that up to a third of febrile neutropenic patients who fail to respond to a 1-week course of broad-spectrum antibiotics have an IFI.[11,12]

Importantly, recent evidence has suggested that early treatment with antifungal agents will reduce mortality-associated IFIs, such as candidemia and invasive aspergillosis. Thus, it is not surprising that there are four main therapeutic strategies in managing IFIs; prophylactic, empirical, pre-emptive and targeted antifungal therapy (Figure 1).[13] The differences between these strategies relate to 'time of commencing antifungal therapy and certainty of the diagnosis of IFI', with the first two strategies relating to the use of antifungal agents in the absence of a positive fungal culture.[9] Pre-emptive therapy, however, is more directed towards a probable IFI (i.e., positive sputum culture with diagnostic imaging and erological verification, without a definitive sterile site culture).

Figure 1.

Strategies in managing invasive fungal infection. IFI: Invasive fungal infection.Adapted with permission from [13] © Dove Medical Press (2008).

Empiric treatment, which is the focus of this manuscript, is defined as treatment with systemic antifungal agent(s) for a single oral temperature measurement of ≥38.3°C or a temperature of ≥38.0°C sustained over a 1-h period despite broad-spectrum antibiotics (usually for 4–7 days) in the setting of neutropenia (<0.5 × 109/l) and where thorough clinical, radiological and microbiological diagnostic evaluation has excluded other etiologies but has also failed to document a proven or probable IFI.[14,15] It is an attractive option in reducing the time to start treatment for a possible IFI, but this strategy risks overprescribing of an antifungal treatment to many patients that would otherwise have not developed IFI and may be associated with unnecessary side effects.[16]

To date, the optimal time to commence antifungal treatment remains uncertain.[17,18] Importantly, the selection of antifungal strategies should consider not just the clinical outcomes but the economic consequences (see below), which are often neglected during decision-making processes owing to a lack of available data.

The current review will examine one of the four strategies employed in antifungal therapy; empiric therapy. An overview of the major antifungal agents used in empirical antifungal therapy and supporting clinical evidence will be provided. This work will focus primarily on the pharmacoeconomics of empiric treatment of IFI, as well as the challenges and gaps that can be exploited for future research into the pharmacoeconomics of empirical antifungal therapy.