Therapeutic Overview

Fungal infections (mycoses) are less frequent than bacterial or viral infections but may be prevalent in some locations that favor growth of specific pathogenic strains. However, serious infections have become increasingly common in the hospital setting. A person must almost always have a predisposing condition that disables one or more host defense mechanisms for a fungal infection to develop. Fungal infections are facilitated by a loss of mechanical barriers (burns, major surgery, and intravascular catheters), the presence of immunodeficiency conditions (malignancies and their treatments, organ transplantation and antirejection therapy, acquired immunodeficiency syndrome [AIDS]), or metabolic derangements (diabetes mellitus), and suppression of competing microorganisms (excessive

broad-spectrum antibacterial agent use). Many fungal infections are superficial and primarily annoying. Others are systemic and can be life-threatening, particularly in patients with compromised defenses, such as those receiving immunosuppressive drugs. The toxicity of many antifungal drugs limits their use, and unfortunately there are few agents useful in treating systemic fungal infections.

Fungi are more complex than bacteria or viruses. They have different ribosomes and cell wall components and possess a discrete nuclear membrane. The major classes of fungal infections and examples of prevalent species that are often causative organisms are summarized in the Therapeutic Overview Box.

Mechanisms of Action

The principal antifungal drugs are the polyenes, azoles, allylamines, echinocandins, and others including flucytosine and griseofulvin. The sites of action of these agents are shown in Figure 50-1.

FIGURE 50–1 Sites and mechanism of action of antifungal agents.

Polyenes

The polyene (i.e., multiple double bonds) drugs are macrocyclic lactones that contain a hydrophilic hydroxylated portion and a hydrophobic conjugated double bond portion. The structure of amphotericin B, the most widely used polyene antifungal drug, is shown in Figure 50-2.

FIGURE 50–2 Structure of amphotericin B.

Polyenes act by binding to sterols in the cell membrane and forming channels, allowing K⁺ and Mg⁺⁺ to leak out. The polyenes become integrated into the membrane to form a ring with a pore in the center approximately 0.8 nm in diameter. K⁺ leaks out through these pores, followed by Mg⁺⁺, and with the loss of K⁺, cellular metabolism becomes deranged (Fig. 50-3). It is thought that derangement of the membrane alters activity of membrane enzymes. The principal sterol in fungal membranes, ergosterol, has a higher affinity for polyenes than does cholesterol, the principal sterol of mammalian cell membranes. Therefore the polyenes show greater activity against fungal cells than mammalian cells, and fungi that lack ergosterol are not susceptible to amphotericin B.

FIGURE 50–3 Action of polyene agents to form pores in the fungal cell membrane through which K⁺ and Mg⁺⁺ can leak out of the cell.

Amphotericin B lipid complex (ABLC) and liposomal amphotericin were among the first amphotericin-lipid formulations to receive approval for use in the United States. ABLC is an amphotericin B-nonliposomal formulation that complexes with two phospholipids. Liposomal amphotericin incorporates the drug into small unilamellar lipid vesicles. It is postulated that by incorporating amphotericin B into these lipid moieties, active drug can be selectively transferred to ergosterol containing fungal membranes without interfering with the cholesterol-containing human membrane, thereby resulting in decreased toxicity.

Azoles

The structures of some of the principal azole antifungal agents are shown in Figure 50-4. Ketoconazole, miconazole, clotrimazole, and econazole are available, as are the newer agents fluconazole, itraconazole, and voriconazole.

FIGURE 50–4 Structure of selected antifungal drugs.

Depending on drug concentration, azoles can have fungistatic or fungicidal effects. In actively growing fungi, azoles inhibit synthesis of membrane sterols by inhibiting incorporation or synthesis of ergosterol. These agents interact with cytochrome P450-dependent 14-α-demethylase, and ergosterol is not produced as a result. At high concentrations, azoles cause K⁺ and other components to leak from the fungal cell, an action that may involve inhibition of plasma membrane adenosine triphosphatase. Because azoles inhibit fungal respiration under aerobic conditions, an alternative mechanism may be blockade of respiratory-chain electron transport.

Allylamines

Terbinafine is the first allylamine available for systemic use. It selectively inhibits fungal cell squalene epoxidase, the enzyme that converts squalene to squalene epoxide. This interferes with biosynthesis of ergosterol at an earlier step than do the azoles. Squalene epoxide inhibition results in a fungicidal intracellular accumulation of squalene and a fungistatic depletion of ergosterol.

Echinocandins

Caspofungin is the first echinocandin compound to gain approval for use in the United States. It blocks production of B-1,3-D-glucans, the major structural component of the fungal cell wall, by inhibition of glucan synthesis. Fungi have been shown to develop in vitro resistance to echinocandins through mutations in genes coding for the target enzymes.

Others

Flucytosine

Flucytosine, also called 5-fluorocytosine, is an antimetabolite that undergoes intracellular metabolism to an active form, which leads to inhibition of deoxyribonucleic acid synthesis.

Flucytosine is transported into susceptible fungi by a permease system for purines. The drug is then deaminated by cytosine deaminase to 5-fluorouracil. Because cytosine deaminase is not present in mammalian cells, the drug is not activated in humans. Fluorouracil in turn is converted by uridine phosphate pyrophosphorylase and other enzymes to 5-fluoro-2’-deoxyuridine 5’-monophosphate, which inhibits thymidylate synthase and interferes with deoxyribonucleic acid synthesis (Chapter 54).

Fungi can be resistant to flucytosine because they lack a permease, have a defective cytosine deaminase, or have a low concentration of the uridine monophosphate pyrophosphorylase. Whether the faulty ribonucleic acid produced by incorporation of fluorouracil contributes to its action is unclear.

Griseofulvin

Whether griseofulvin is fungicidal or fungistatic is not established. It enters susceptible fungi by an energy-dependent transport system and inhibits mitosis. It binds to the microtubules that form the mitotic spindle and blocks the polymerization of tubulin into microtubules. It also binds to a microtubule-associated protein, although the role of this protein is not known. The binding site for griseofulvin on tubulin differs from that of colchicine and the plant alkaloids. This effect on microtubule assembly probably explains the morphological changes, such as curling, that are observed in the fungi. Mechanisms of resistance are unknown, but may stem from decreased uptake of the drug. The structure of griseofulvin is shown in Figure 50-4.

Pharmacokinetics

Pharmacokinetic parameters for the antifungal drugs are summarized in Table 50-1.

TABLE 50–1 Pharmacokinetic Parameters for Antifungal Drugs

Polyenes

Amphotericin B is insoluble in water, has a large lipophilic domain in its structure, and is not absorbed from the gastrointestinal (GI) tract. It is administered orally only to treat fungal infections of the GI tract, which sometimes develop after depletion of bacterial microflora after administration of broad-spectrum antibacterial drugs. For parenteral use, amphotericin B is combined with the detergent deoxycholate to form a colloidal suspension.

Amphotericin B enters pleural, peritoneal, and synovial fluids, where it reaches a concentration approximately half that in serum. It crosses the placenta and is found in cord blood and amniotic fluid and also enters the aqueous but not the vitreous humor of the eye. Cerebrospinal fluid (CSF) concentrations reach one third to one half those in serum. Most amphotericin B in the body probably is bound to cholesterol-containing membranes in tissues.

The principal pathway for amphotericin B elimination is not known. Some is excreted by the biliary route, and only 3% is eliminated in urine. Renal dysfunction does not affect plasma concentrations, and amphotericin B is not removed by hemodialysis.

The pharmacokinetics of ABLC and liposomal amphotericin and their relation to clinical efficacy are less clear. ABLC is taken up rapidly by the reticuloendothelial system and achieves high concentrations in the lung, liver, and spleen. As a result, the elimination phase is much longer than with amphotericin B. Liposomal amphotericin, at similar recommended doses, achieves higher serum levels and improved penetration of the central nervous system, as well as more-rapid plasma clearance than amphotericin B or ABLC.

Azoles

Ketoconazole can be administered orally, and its absorption is favored in an acidic pH. Therefore coadministration of antacids, H₂ receptor antagonists, or proton pump inhibitors reduces absorption. The effects of food on absorption of this agent have been inconsistent, and plasma concentrations vary widely among patients receiving the same dose.

Ketoconazole is distributed in saliva, skin, bone, and pleural, peritoneal, synovial, and aqueous humor fluids. It penetrates very poorly into the CSF (~5% of plasma concentration). The plasma concentration declines biexponentially, with a distribution half-life of approximately 2 hours followed by an elimination half-life of 8 hours.

Ketoconazole is extensively metabolized by hydroxylation and oxidative N-dealkylation. It does not induce its own metabolism, as clotrimazole does. However, rifampin induces the release of microsomal enzymes that increase ketoconazole oxidation. Only 2% to 4% of a dose is excreted in urine unchanged, and renal insufficiency does not affect plasma concentrations or half-life, although half-life is prolonged in patients with hepatic insufficiency. Ketoconazole inhibits hepatic P450 enzymes and thus is known to cause many drug-drug interactions.

Miconazole is now primarily used topically and rarely by the intravenous (IV) route. It is minimally water soluble and not adequately absorbed from the GI tract. Its half-life is only 30 minutes, and it is metabolized by O-dealkylation and oxidative N-dealkylation but does not induce its own metabolism. Only 1% is excreted in the urine unchanged. Penetration into the CSF and sputum is poor, but penetration into joint fluid is good.

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