Antifungal Antimicrobics that Affect Membrane Sterols

ANTIFUNGAL ANTIMICROBICS THAT AFFECT MEMBRANE STEROLS

Polyenes

The polyenes nystatin and amphotericin B are lipophilic and bind to sterols in the cytoplasmicmembrane of eukaryotic cells. Following binding, they form annular channels, which penetrate the membrane and lead to leakage of essential small molecules from the cytoplasm and cell death. The basis of their selective toxicity is their greater affinity for the sterols of fungal membranes, such as ergosterol, than the sterols of human cells. This difference is relative, because they also bind cholesterol in mammalian membranes, which creates the considerable toxicity that limits their use.

At physiologic pH, amphotericin B is insoluble in water and must be administered  ntravenously as a colloidal suspension. Amphotericin B is not absorbed from the gastrointestinal tract. Almost all fungi are susceptible to amphotericin B, and the development of resistance is too rare to be a consideration in its use. The major limitation to amphotericin B therapy is the toxicity created by its affinity for mammalian as well as fungal membranes. Infusion is commonly followed by chills, fever, headache, and dyspnea. The most serious toxic effect is renal dysfunction and is seen in virtually every patient receiving a therapeutic course. Experienced clinicians learn to titrate the dosage for each patient to minimize the nephrotoxic effects. For obvious reasons, use of amphotericin B is limited to progressive, life-threatening fungal infections. In these cases, despite its toxicity, it often remains the antifungal agent of choice. Preparations that complex amphotericin B with phospholipids to form liposomes have been used as a way to limit toxicity. The even greater toxicity of nystatin limits its use to topical preparations.

Azoles

The azoles are a large family of synthetic organic compounds, which includes members with antibacterial, antifungal, and antiparasitic properties. The important antifungal azoles are the imidazole, ketoconazole, and the triazoles, fluconazole and itraconazole. Others are under development or evaluation. Their activity is based on inhibition of a cy-tochrome enzyme (P450 demethylase) responsible for conversion of lanosterol to ergos-terol, the major component of the fungal cytoplasmic membrane. This leads to lanosterol accumulation and the formation of a defective cell membrane with altered permeability characteristics.

Ketoconazole was the first azole to be useful in systemic infections but is now being supplanted by either fluconazole or itraconazole for most systemic mycoses, including as-pergillosis and candidiasis, for which ketoconazole was not effective. Ketoconazole and itraconazole are given orally, and fluconazole, either orally or intravenously. Although nausea, vomiting, and elevation of hepatic enzymes complicate the treatment of some pa-tients, the azoles are much less toxic than amphotericin B. Endocrinologic defects can be a problem because of inhibition of conversion of lanosterol to cholesterol, a precursor of several hormones. Central nervous system penetration of ketoconazole is poor, which limits its effectiveness in systemic coccidioidomycosis and cryptococcosis, but flucona-zole has been more effective. Currently, fluconazole and itraconazole are the primary al-ternates to amphotericin B for treatment of systemic fungal infections. Azoles are also effective for superficial and subcutaneous mycoses in which the initial therapy either fails or is not tolerated by the patient. Two other azoles, clotrimazole and miconazole, are used in over-the-counter topical preparations.

Voriconazole, a second-generation azole, inhibits both 14- -sterol demethylase and24-methylene dihydrolanosterol demethylation, providing a broader spectrum of activity against some yeasts and molds that are resistant to the other azoles. It can be given intra-venously or orally.

Allylamines

The allylamines are a group of synthetic compounds that act by inhibition of an enzyme (squalene epoxidase) in the early stages of ergosterol synthesis. Their lethal effect is due to accumulation of squalene precursors rather than a deficiency of ergosterol. The allylamines include an oral agent, terbinafine, and a topical agent, naftifine. Both are used in the treat- ment of dermatophyte (ringworm) infections.