A Brief Review of Antifungal Therapy for Deep Fungal Infection

ABSTRACT: With the continuing increase in clinically important fungal disease, especially seen in the neutropenic patient, the need for new and improved systemic antifungal agents marches on. A pharmacy and therapeutics committee may select an antifungal agent based on these criteria: spectrum of action, pharmacokinetic profile, toxicity, potential for resistance, and cost. A number of agents are now available for treating deep fungal infections, including amphotericin B in conventional and liposomal formulations, and the triazoles itraconazole (Sporanox) and fluconazole (Diflucan). It is important to note that there is lack of agreement in practice over what constitutes ideal therapy. The lipid formulations of amphotericin B and the improved oral solution and new intravenous formulation of itraconazole are recent additions to therapeutic options that are already having a significant influence on drug selection and treatment practices. [ONCOLOGY 15(Suppl 9):21-25, 2001]

Several antifungal agents are now available for useagainst fungal disease, including amphotericin B, itraconazole (Sporanox), andfluconazole (Diflucan). It is important to note that there is a lack ofagreement in practice over what constitutes ideal therapy. The followingoverview explains the current options along with the guidelines used atMemorial-Sloan Kettering Cancer Center (MSKCC) in New York.

General recommendations of drugs of choice for the various fungal indicationsare shown in Table 1.[1] Potential adverse reactions, contra- indications, anddrug interactions associated with these agents are shown in Table2.

Amphotericin B

Conventional Formulation

Amphotericin B is a potent broadspectrum agent that has been in clinical usefor 40 years.[2-6] Until the availability of itraconazole, it was the only agentavailable for treating Aspergillus infection. A major drawback of conventionalamphotericin B is its toxicity profile, with renal toxicity (including acutetubular necrosis) constituting the primary adverse effect associated withtreatment. Hypokalemia is a recurrent problem that warrants strict attention touse of other drugs that can affect potassium balance (eg, cisplatin [Platinol],ifosfamide [Ifex], corticosteroids, and ticarcillin/clavulanic acid [Timentin]).

Other characteristic toxicities include nausea, vomiting, and anorexia;increased erythropoietin production; phlebitis, if the drug is administeredthrough a peripheral intravenous (IV) line; and (rarely) thrombocytopenia orleukopenia. Acute reactions consist of the complex of chills, fever, tachypnea,hypoxemia, and hypotension; premedication protocols including acetaminophen,hydrocortisone, diphenylamine, or meperidine are helpful in alleviating thesereactions.

Lipid Formulations

The lipid formulations of amphotericin B that have become available areassociated with a degree of reduction in renal toxicity compared with theconventional formulation.[4,5,7] However, it is far from clear whether thisreduced toxicity and improved quality of life is worth a cost that can be up to50 times that of the standard formulation for the drug alone.

Clinical responses with lipid formulations are as good as those seen withconventional amphotericin B, and these formulations have a higher therapeuticindex, permitting the use of higher doses. It is unclear, however, whethergreater efficacy is achieved with use of higher doses. Further, the long-termtoxicities of these formulations remain unknown. Although the symptoms, whenthey occur, are similar, acute infusion-related reactions with the liposomalproducts are much less than with conventional amphotericin B. AmBisome appearsto have become the agent of choice in many medical centers. Because of its highcost, it has not been universally embraced at MSKCC. In particular, use at highdoses is limited compared with other large centers.

At MSKCC, house staff order the drug using a standardized order formrequiring Infectious Disease Service approval. Patients who are more than 70years old, have a creatinine clearance < 60 mL/min, have experienced priordefinitive toxicity to conventional amphotericin B, and have multiple myeloma donot need a formal infectious disease consult. As with almost all IV drugs, acomprehensive guideline for use is electronically available throughout thecenter.

Itraconazole

The triazole itraconazole is available in capsule form, an improved oralsolution, and a new IV form. (Intravenous itraconazole became available in theUnited States in February 2000.) The agent has activity against common andemerging fungal pathogens, including Candida, Aspergillus, Blastomyces, andHistoplasma species. Aspergillus infection has become common among patients withprolonged severe neutropenia, especially if they are receiving corticosteroidtherapy.

Comparison With Fluconazole

A comparison of characteristics of itraconazole and fluconazole is shown in Table 3.[8] Distinguishing characteristics include hepatic and nonlinearclearance of itraconazole vs the renal and linear clearance of fluconazole andthe difference in vulnerability to hepatic enzyme induction.

Advantages of itraconazole include the broader spectrum of activity,including high activity against Aspergillus and possible activity againstfluconazole-resistant Candida, and greater potency on a milligram-equivalentbasis. Advantages of fluconazole include the greater clinical experience withthe agent, its ease of administration, and advantages posed by the linearpharmacokinetics.[2,8-10]

Capsules and Oral Solution

Itraconazole in capsule form exhibits irregular absorption in some patients,with absorption being improved if the capsule is taken with food.[7,9,11-14] Theimproved oral solution is associated with an increase in bioavailability ofapproximately 60% that is independent of gastric pH. There is some evidence thatthe oral solution has topical activity that may contribute to effectiveness inoropharyngeal candidiasis.

Intravenous Administration

Intravenous administration of itraconazole results in rapid achievement oftherapeutic plasma drug concentrations. Thus far, there has been only limitedexperience with IV itraconazole at MSKCC. However, data suggest that switchingfrom IV to oral itraconazole is accompanied by maintenance of adequate plasmadrug levels, indicating flexibility in use that could be advantageous.

It is important to strictly follow the unique and detailed admixinginstructions supplied by the manufacturer.

Indications and Usage

Intravenous itraconazole is indicated for treatment of blastomycosis,histoplasmosis, and aspergillosis in immunocompromised and non-immunocompromisedpatients, and can be considered a primary treatment for fluconazole-resistantthrush, disseminated sporotrichosis, paracoccidioidomycosis, penicilliosis,coccidioidomycosis, and phaeohyphomycosis.[8]

Among the contraindications to the drug is its use in patients receivingterfenadine or cisapride (Propulsid), due to potentially fatal adverse effects.Plasma concentrations of several significant drugs are predicted to be increasedby itraconazole. These include warfarin (Coumadin), vinca alkaloids, busulfan,several anti-HIV protease inhibitors, benzodiazepines, calcium channel blockers,common cholesterol lowering agents, and immunosuppressive agents such ascyclosporine.

Cost-Effectiveness Study

It is interesting to note that a European cost-effectiveness study[15]employing data from a randomized trial of empiric treatment in 382 neutropeniccancer patients showed that IV itraconazole was associated with significant costsavings compared with both conventional amphotericin B treatment and treatmentwith liposomal amphotericin B. Intravenous itraconazole was associated withreduced need to change therapy, reduced number of tests, and decreased need forhospitalization compared with conventional amphotericin B. The acquisition costof liposomal amphotericin B was found to be too high in proportion to itsbenefits, with both cost per patient and cost per responder being lower withitraconazole.

Conclusion

Liposomal amphotericin B is a highly significant therapeutic advance in thetreatment of patients with systemic fungal infection. In the United States,however, it is clear that the liposomal amphotericin B products cost severalhundred dollars a day compared to less than $20 a day for the conventionalformulation. Fluconazole and itraconazole costs are higher than conventionalamphotericin B, but much less than liposomal amphotericin B.

Considerably more research is needed in the search for the ideal intravenousantifungal agent, but the newer agents are attractive and useful therapeuticoptions.

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