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.

Abstract and Introduction

Abstract

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.

Introduction

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).

(Enlarge Image)

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.

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Next Section

Abstract and Introduction
Antifungal Agents in Empiric Therapy
Pharmacoeconomics of Empiric Antifungal Treatment
Considerations, Challenges & Gaps for Future Research
Conclusion
Expert Commentary
Five-year View
References
Sidebar

Table 1. Summary of pharmacoeconomic studies of empiric antifungal treatment of invasive fungal infection.
Study (year)	Country	Alternatives evaluated	Type of economic analysis	Patient population studied	Outcome measures	Cost categories included	Conclusions	Ref.
Al-Badriyeh et al. (2009)	Australia	Voriconazole and LAmB	CEA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure^†	Drug acquisition, per diem costs, monitoring tests	LAmB net cost saving AU$1422 per patient treated	[40]
Al-Badriyeh et al. (2009)	Australia	Caspofungin and LAmB	CMA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure	Drug acquisition, per diem costs, monitoring tests	Caspofungin net cost saving AU$7245 per patient treated	[41]
Al-Badriyeh et al. (2012)	Australia	Caspofungin and voriconazole	CMA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure	Drug acquisition, per diem costs, monitoring tests	Caspofungin net cost saving AU$798 per patient treated	[42]
Bruynesteyn et al. (2007)	UK	Caspofungin and LAmB	CUA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure and QALY	Drug acquisition, per diem costs, mild toxicity costs (e.g., chills, nausea)	Caspofungin net cost saving GBP£2033 per patient treated, caspofungin 0.40 additional QALYs saved	[43]
Collins et al. (2007)	USA	Voriconazole and LAmB	CMA	Adult hematology patients receiving study drug and had chemotherapy for leukemia, lymphoma or other hematological cancers	Retrospective chart review of response rates and development of adverse effects	Drug acquisition, nephrotoxicity treatment cost, per diem costs	27% reduced treatment cost associated with voriconazole (US$14950 vs US$20591)	[44]
Kaskel et al. (2008)	Germany	Caspofungin and LAmB	CMA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	NNT for harm from nephrotoxicity and bed days reduced	Staff costs, all medication costs, infrastructure, microbiology	8.9 fewer patients (of 100 randomized) experienced worsening renal function. NNT for harm by LAmB of 12, 0.48 extra bed days per patient treated with LAmB worth €298 extra per patient receiving LAmB compared with caspofungin	[45]
Stam et al. (2008)	Italy	Caspofungin and LAmB	CUA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure and QALY	Drug acquisition, per diem costs, mild toxicity costs (e.g., chills, nausea)	Caspofungin net cost saving €3470 per patient treated, caspofungin 0.25 additional QALYs saved	[46]
Wingard et al. (2007)	USA	Caspofungin and LAmB	CMA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	Rate of impaired renal function	Drug acquisition, nephrotoxicity treatment cost	Overall treatment cost US$5326 less with caspofungin	[47]
Naik et al. (2011)	Sweden	Caspofungin and LAmB	CUA	Hematology–oncology patients predominantly with AML as the underlying condition who have undergone chemotherapy or HSCT	5-point composite outcome measure and QALY	Drug acquisition, per diem costs, mild toxicity costs (e.g., chills, nausea)	Caspofungin net cost saving SEK38,080, caspofungin 0.25 additional QALYs saved	[48]
Romá-Sánchez et al. (2008)	Spain	Voriconazole, caspofungin, LAmB and amphotericin B Lipid complex	CEA	Oncohematological patients at high risk of IFI and received empiric antifungal therapy	Partial or complete response with or without adverse drug reaction	Drug acquisition, per diem costs, diagnostic tests, monitoring tests	Voriconazole dominant over other alternatives (€144,794 net cost saving compared with caspofungin as next best alternative)	[49]
Shehab et al. (2007)	USA	Voriconazole and LAmB	CEA	Adult patients who received chemotherapy for leukemia, lymphoma or other hematologic cancers. Excluded baseline fungal infections within 24 h.	4-point composite outcome measure^‡	Drug acquisition, per diem costs	Voriconazole net cost saving of US$2551 per episode	[50]

†Included absence of a breakthrough fungal infection, survival for 7 days beyond end of therapy, no premature discontinuation of therapy, resolution of fever during the period of neutropenia and successfully treated for any baseline fungal infection.
‡Included resolution of fever during the period of neutropenia, absence of a breakthrough IFI within 7 days of the end of therapy, no discontinuation due to efficacy or safety concerns and survival within 7 days of the end of therapy.
AML: Acute myeloid leukemia; CEA: Cost–effectiveness analysis; CMA: Cost-minimization analysis; CUA: Cost–utility analysis; HSCT: Hematopoietic stem cell transplant; IFI: Invasive fungal infections; LAmB: Liposomal amphotericin B; NNT: Number needed to treat; QALY: Quality-adjusted life year; SEK: Swedish Krona.