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Empiric Antifungal Therapy for the Neutropenic Patient

Empiric Antifungal Therapy for the Neutropenic Patient

The article written by Drs. Wingard and Leather presents a thoughtful review of the current approaches to empiric antifungal therapy in neutropenic patients. Empiric antifungal therapy has evolved as a standard of care for the prevention of invasive fungal infections in neutropenic patients who remain persistently febrile despite the use of broad-spectrum antibacterial antibiotics.[1-3] Empiric antifungal therapy in this setting provides early treatment for clinically occult invasive fungal infections and systemic prophylaxis for neutropenic patients at highest risk.

Early Investigations

Several early studies laid the foundation for this strategy. In a nonrandomized trial, Burke et al administered empiric amphotericin B to high-risk patients with acute leukemia and found a reduction in the incidence of invasive fungal infections, compared to historical controls.[4] Pizzo and colleagues at the National Cancer Institute conducted the first randomized controlled trial of empiric amphotericin B in persistently febrile neutropenic patients.[5] This seminal study established the need for antifungal intervention in this patient population (despite administration of a broad-spectrum antibacterial agent), based on their increased risk of developing invasive fungal infections.

A subsequent study by the European Organization for Research and Treatment of Cancer (EORTC) in a larger patient population demonstrated that empiric antifungal therapy reduced the frequency of invasive fungal infections and mycosis-related mortality.[6] Other open-label studies further refined and validated the use of empiric amphotericin B for persistently febrile neutropenic patients.[7,8] These studies were conducted with conventional amphotericin B desoxycholate, which is associated with significant dose-limiting nephrotoxicity and a high rate of infusion-related reactions.[9,10]

Improving the Therapeutic Index

The cumulative body of experimental and clinical data indicate that lipid formulations of amphotericin B are as effective but less nephrotoxic than conventional amphotericin B in the treatment of invasive fungal infections.[11,12] In order to investigate whether the lipid formulation could be effective as empiric amphotericin B therapy, the National Institute of Allergy and Infectious Diseases (NIAID) Mycoses Study Group conducted a randomized, double-blind multicenter trial of liposomal amphotericin B (AmBisome) vs conventional amphotericin B. This trial found that the liposomal formulation was as effective as the empiric formulation and resulted in a significant reduction in proven invasive fungal infections, nephrotoxicity, and infusion-related reactions.[10]

A subsequent randomized trial also found that liposomal amphotericin B had less nephrotoxicity and infusion-related toxicity than conventional amphotericin B, although the latter was only investigated at a comparatively high dose.[13] Despite its substantially greater drug acquisition cost, when targeted at high-risk patient populations, liposomal amphotericin B was shown to be cost-effective in a rigorous data-based pharmacoeconomic analysis.[14]

Antifungal azoles have less toxicity compared to amphotericin B, but historically have a limitations in spectrum or pharmacology. Indeed, ketoconazole was investigated for use as early empiric antifungal therapy and found to have erratic bioavailability and limited antifungal spectrum. First-generation triazoles (fluconazole [Diflucan] and itraconazole [Sporanox]) have also been studied but have limited utility as empiric antifungal therapy.

Fluconazole’s spectrum is restricted to yeasts, thus precluding its use in patients at risk for invasive aspergillosis (eg, allogeneic hematopoietic stem cell transplant recipients and those with hematologic malignancies). Moreover, fluconazole is already often used for prophylaxis of allogeneic stem cell transplant recipients.

Itraconazole has been studied as empiric therapy in one clinical trial but not rigorously assessed in high-risk allogeneic transplant patients. This agent requires serum therapeutic drug monitoring, and the oral cyclodextrin formulation can be associated with gastrointestinal intolerance.

Prophylaxis and Empiric Antifungal Therapy 

Fluconazole is the only antifungal compound approved by the US Food and Drug Administration for prophylaxis in bone marrow transplant recipients. In clinical trials, itraconazole has not been shown to have an impact on the frequency and outcome of invasive infections. Although fluconazole significantly reduces the frequency of invasive yeast infections, particularly those due to Candida albicans, empiric antifungal therapy with amphotericin B also targets non-albicans Candida species, as well as most Aspergillus species and other filamentous fungi. Thus, fluconazole prophylaxis and empiric antifungal therapy with amphotericin B are complementary strategies for the prevention of invasive fungal infections in high-risk patients, especially those with hematologic malignancies and those undergoing stem cell transplantation.

Timing of Empiric Antifungal Therapy

The key studies of empiric antifungal therapy have initiated treatment on days 5 to 7 of persistent fever and neutropenia. As the median time to defervescence for proven bacterial infections in most neutropenic patients is approximately 4 to 5 days, earlier initiation of therapy (eg, day 3) may not be advisable. This is particularly true if the patient is already receiving fluconazole for prophylaxis.

Target Populations

Empiric antifungal therapy in the oncology/hematopoietic stem cell transplant population is best targeted to patients at high risk for invasive fungal infections. Patients receiving chemotherapy who experience prolonged neutropenia (eg, ³ 10 days), including those with acute myelogenous leukemia and those undergoing allogeneic stem cell transplant, will benefit most from this approach.

New Antifungal Compounds

The second-generation antifungal triazoles include voriconazole, posaconazole, and ravuconazole.[15,16] Due to their broad spectrum, potent in vitro and in vivo activities, and favorable pharmacokinetic features, these compounds could potentially replace both conventional and liposomal amphotericin B as empiric antifungal therapy. In order to test this hypothesis, the NIAID Mycoses Study Group conducted a randomized multicenter study of voriconazole vs liposomal amphotericin B as empiric antifungal therapy. Voriconazole was found to be comparable to amphotericin B but was superior in preventing documented invasive fungal infections.[17]

The echinocandins are a new class of inhibitors of cell wall 1,3-beta-glucan synthase with activity against Candida and Aspergillus species. These compounds are being studied as empiric therapy.

New Diagnostic Strategies

Current approaches to antifungal prophylaxis and empiric therapy involve the treatment of more patients than would ultimately develop invasive fungal infections. Fever refractory to broad-spectrum antibacterial agents in the setting of profound neutropenia serves as the most sensitive, albeit less specific, surrogate indicator for treating patients at risk. However, more widespread use of high-resolution computed tomography scanning, improved blood culture detection systems, the development of enzyme immunoassays for detection of galactomannan antigenemia, and diagnostic polymerase chain reaction systems may permit increased refinement of target populations for empiric therapy.


1. Pizzo PA: Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 328:1323-1332, 1993.

2. Hughes WT, Armstrong D, Bodey GP, et al: 1997 Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Clin Infect Dis 25:551-573, 1997.

3. Rex JH, Walsh TJ, Sobel JD, et al: Practice guidelines for the treatment of candidiasis. Clin Infect Dis 30:662-678, 2000.

4. Burke PJ, Braine HG, Rathbun HK, et al: The clinical significance and management of fever in acute myelocytic leukemia. Johns Hopkins Med J 139:1-12, 1976.

5. Pizzo PA, Robichaud KJ, Gill FA, et al: Empiric antibiotic and antifungal therapy for cancer patients with prolonged fever and granulocytopenia. Am J Med 72:101, 1982.

6. EORTC International Antimicrobial Therapy Cooperative Group: Empiric antifungal therapy in febrile granulocytopenic patients. Am J Med 86:668-672, 1989.

7. Walsh TJ, Lee J, Lecciones J, et al: Empirical amphotericin B in febrile granulocytopenic patients. Rev Infect Dis 13:496-503, 1991.

8. Karp JE, Merz WG, Charache P: Response to empiric amphotericin B during antileukemic therapy-induced granulocytopenia. Rev Infect Dis 13:592-599, 1991.

9. Gallis HA, Drew RH, Pickard WW: Amphotericin B: 30 years of clinical experience. Rev Infect Dis 12:308-329, 1990.

10. Walsh TJ, Finberg R, Arndt C, et al, for the NIAID Mycoses Study Group: A randomized, double-blind trial of liposomal amphotericin B vs conventional amphotericin B for empirical antifungal therapy of persistently febrile neutropenic patients. N Engl J Med 340:764-771, 1999.

11. Hiemenz JW, Walsh TJ: Lipid formulations of amphotericin B: Recent progress and future directions. Clin Infect Dis 22:S133-144, 1996.

12. Leenders AC, Daenen S, Jansen RL, et al: Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol 103:205-212, 1998.

13. Wingard JR, White MH, Anaissie E, et al: A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B vs amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 3:1155-1163, 2000.

14. Cagnoni P, Walsh TJ, Prendergast M, et al: Pharmacoeconomic analysis of liposomal amphotericin B vs conventional amphotericin B deoxycholate in the empirical treatment of persistently febrile neutropenic patients. J Clin Oncol 18:2476-2483, 2000.

15. Sheehan DJ, Hitchcock CA, Sibley CM: Current and emerging azole antifungal agents. Clin Microbiol Rev 12:40-79, 1999.

16. Ghannoum MA, Hossain MA: New investigational antifungal agents for treating invasive fungal infections. Expert Opin Investig Drugs 9:1797-1813, 2000.

17. Walsh T, Pappas P, Winston D, et al, and the NIAID Mycoses Study Group: Voriconazole vs liposomal amphotericin B for empirical antifungal therapy of persistently febrile neutropenic patients: A randomized, international, multicenter trial. Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2000.

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