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Fungal infections are particularly serious and common among neutropenic, immunocompromised patients who have received prolonged broad-spectrum antibiotics.

A number of systemic fungal infections (e.g., histoplasmosis, coccidioidomycosis, and paracoccidioidomycosis) can also afflict otherwise healthy persons. Until recently, only amphotericin B was available to treat systemic fungal infection. However, with the rapid development and clinical assessment of azole compounds, a number of these agents are also considered appropriate for treatment of fungal infections. Amphotericin B is a polyene antibiotic that exerts its antifungal effect by binding to sterol moieties in the membranes of fungi.

Antifungal Drugs

This causes pores in the cell wall, eventually causing leakage of low-molecular-weight cytoplasmic components.

This effect, coupled with amphotericin's ability to stimulate granulocytes and T and B cells, ultimately leads to the death of fungi. Amphotericin B has a wide spectrum of antifungal activity. Susceptible fungi include species of Candida, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitides, Paracoccidioides brasiliensis, Sporothrix schenckii, and many strains of Aspergillus. It is still considered the drug of choice for any life-threatening disseminated fungal disease.

This choice may well change with greater experience with the newer azole agents since amphotericin B causes considerable toxicity, most notably anaphylaxis, other allergic reactions, renal insufficiency, and bone marrow suppression. It was observed in animal models that amphotericin B toxicity was decreased if it was bound to surfactants before administration.

As a result of this observation a number of amphotericin B–lipid formulations have been developed. These products are extremely expensive, but they appear to be more effective and less toxic than conventional amphotericin B in the treatment of invasive aspergillus. The newer antifungal agents include ketoconazole, miconazole, itraconazole, and fluconazole. These agents are azoles, and they exert their antifungal activity by inhibiting ergosterol synthesis. Ketoconazole is available in oral form, and in normal patients is often erratically absorbed from the gastrointestinal tract.

Achlorhydria caused by any mechanism significantly reduces its absorption.

Ketoconazole is metabolized primarily in the liver. To prevent toxicity it must be judiciously employed in patients with hepatic failure, or in those who receive other drugs that are also metabolized in the liver. A major adverse effect of ketoconazole is it effect on the endocrine system (e.g., blunting of cortisol and androgen synthesis, and production of gynecomastia).

Antifungal Drugs

Ketoconazole is particularly effective in treating certain forms of histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and candidiasis. It is not recommended for treating central nervous system fungal infections because it penetrates the cerebrospinal fluid poorly, or for serious life-threatening diseases because gastrointestinal absorption can be erratic.

Table Lipid-Based Formul 14. ations of Amphotericin B
 
Product Form Ratio Percent amb by weight S ize (NM) Dose AWP ($/Day)
AMB–lipid complex (ABLCTM) (Abelcet®) Nonliposomal 7:3 DMPC:DMPG 33% 1,600–11,000 5 mg/kg/day $520
AMB colloidal dispersion (ABCDTM) Nonliposomal 4:3:1 50% 120–140 1–5 mg/kg/day $223 (1.5 mg/kg)
(Amphocil®) EP:Chol:SA
L-AMB Liposomal spherical, 2:0.8:0.4 10% 80 1–5 mg/kg $1,070 (5 mg/kg)
(AmBisome®) Unilamellar, vesicle HSP:DPG:Chol
(ABLETM) Spherical vesicles EP:SFO:SBO Variable 300–500 1 mg/kg
Glycerol
Amphotericin B (Fungizone intravenous® Fungizone® Topical) N/A N/A 100% N/A 0.5–1 mg/kg/day $22
ABBREVIATIONS: AMB, amphotericin B; Chol, cholesterol sulfate; DMPC, dimyristoyl phosphatidylcholine; DMPG, dimyristoyl phosphatidylglycerol; DPG, distearoyl phosphatidylglycerol; EP, egg phosphatidylcholine; HSP, hydrogenate soy phosphatidylcholine; SA, SBO, SFO, N/A, not applicable.

Miconazole is rarely employed systemically because of its serious adverse effects and the availability of other agents.

However, parenteral miconazole is the drug of choice for infections due to Pseudoallescheria boydii. In addition, topical miconazole is frequently used as an effective antimicrobial for vaginal yeast infections. Itraconazole is administered orally and is well distributed within the body with the exception of penetration into the cerebrospinal fluid. Itraconazole should not be used in patients with central nervous system fungal infections. Its spectrum of activity is similar to that of amphotericin B. Clinical studies to date suggest that it is useful to treat selected cases of disseminated candidiasis, histoplasmosis, coccidiomycosis, selected infections with Aspergillus, sporotrichosis, blastomycosis, and paracoccidioidomycosis. It has the advantage over amphotericin B of being relatively safe.

Fluconazole is unique among the azoles in that it can penetrate into the cerebrospinal fluid in high concentration. Parenteral and oral forms of fluconazole therapy are available. Its spectrum of activity is very similar to that of other azoles and amphotericin B. Clinical experience to date suggests that it is the drug of choice for treatment of oroesophageal and mucocutaneous candidiasis and for suppressive therapy of cryptococcal meningitis in acquired immunodeficiency syndrome patients.

 
Table Summary — Antifungal Drugs
Drug Route Advantages Comments
Ketoconazole PO Oral treatment of histoplasmosis, coccidioidomycosis, candidiasis; cheaper than itraconazole and fluconazole Erratic oral absorption; do not rely on for central nervous system or serious systemic infections.
Fluconazole intravenous, PO Good oral absorption, excellent central nervous system penetration Can be used as suppressive therapy of cryptococcal meningitis in human immunodeficiency virus-infected patients. Drug interactions are common.
Itraconazole PO Only one of the imidazoles with activity against Aspergillus Poor central nervous system penetration
Miconazole intravenous, T Drug of choice (intravenous) for treatment of Pseudallescheria boydii
ABBREVIATIONS: intravenous, intravenous; PO, oral; T, topical.

Antifungal Drugs

 

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