Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 50 Antifungal Agents

MAJOR DRUG CLASSES

Polyenes

Azoles

Allylamines

Echinocandins

Others (Flucytosine, Griseofulvin)

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

Therapeutic Overview

Cutaneous and Subcutaneous Mycoses

Treat with dermatological preparations, occasionally systemic agents

Epidermophyton species

Microspora species

Sporothrix species

Trichophyton species

Systemic Mycoses

Difficult to treat; available drugs often cause deleterious side effects; often need long-term therapy

Aspergillus species

Candida species

Blastomyces dermatitidis

Cryptococcus neoformans

Coccidioides immitis

Fusarium species

Histoplasma capsulatum

Paracoccidioides brasiliensis

Mucormycosis

Abbreviations

ABLC

Amphotericin B lipid complex

AIDS

Acquired immunodeficiency syndrome

CSF

Cerebrospinal fluid

GI

Gastrointestinal

IV

Intravenous

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.

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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.

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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.

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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.

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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

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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.

Fluconazole is water soluble and rapidly absorbed after oral administration, with approximately a 90% bioavailability and a half-life of 25 to 30 hours. Fluconazole does not require an acidic environment for absorption. Although it does not induce metabolism of most other drugs, it does alter metabolism of orally administered hypoglycemic agents. Approximately 70% is eliminated unchanged through the kidneys, with small amounts of metabolites present in urine and feces. Fluconazole is widely distributed, with therapeutic concentrations attained in CSF, lung, and many other areas of the body.

Voriconazole is also rapidly absorbed, with greater than 90% bioavailability that decreases when the drug is taken with food. More than 95% of this drug is metabolized by cytochrome P450 enzymes to inactive compounds in the liver, with only a small amount excreted unchanged in the urine. This can cause interactions with other drugs. Dosage is adjusted in patients with liver disease and in patients with kidney disease receiving the IV formulation, because it is administered with a cyclodextrin carrier that accumulates with lower renal clearance rates.

Allylamines

Terbinafine is well absorbed from the GI tract and has an initial distribution half-life of approximately 1.1 hours and an elimination half-life of approximately 16 hours. Similar to the polyenes, it has a prolonged terminal half-life of approximately 16 days. Terbinafine is highly lipophilic and keratophilic, resulting in high concentrations in the stratum corneum, sebum, hair, and nails. The drug may be detected in nails for up to 90 days after treatment is discontinued. It is extensively metabolized by the liver and excreted in the urine and feces as inactive metabolites. Clearance is decreased in patients with renal or hepatic impairment. It is currently used for treating fungal infections of the nails, and prolonged courses lasting 6 to 12 weeks are necessary to effect cure.

Echinocandins

Caspofungin is rapidly distributed to tissues after intravenous administration with extensive binding to plasma serum albumin. It is metabolized by hydrolysis and N-acetylation in the liver to inactive metabolites that are excreted in both bile and urine. Dose adjustment is required for patients with impaired hepatic function, and there are important drug interactions with certain immunosuppressive agents that require careful monitoring.

Others

Flucytosine

Flucytosine is well absorbed from the GI tract and is widely distributed in the body, with CSF concentrations 70% to 85% of those in plasma. It enters the peritoneum, synovial fluid, bronchial secretions, saliva, and bone.

Approximately 85% to 95% is excreted unchanged by glomerular filtration, with a normal half-life of 3 to 6 hours, which increases greatly as creatinine clearance diminishes. For special conditions the drug can be removed by hemodialysis and peritoneal dialysis. A small fraction of the dose may be converted by intestinal bacteria to 5-fluorouracil and lead to hematological toxicity.

Griseofulvin

Griseofulvin is insoluble; however, approximately half of an oral dose passes from the GI tract into the circulation. This uptake is related to particle size and is increased when the drug is ingested with a full meal. Whether it diffuses through the intestinal wall or is taken up as micelles is not clear. When applied topically, griseofulvin penetrates the stratum corneum, but this does not result in effective local concentrations.

Griseofulvin is widely distributed and becomes concentrated in fat, liver, and muscle. It is deposited in the keratin layer of the skin; becomes concentrated in keratin precursor cells in the stratum corneum of the skin, nails, and hair; and is secreted in perspiration. New keratin formed during treatment with griseofulvin is resistant to fungus, but griseofulvin does not destroy fungi in previously infected outer layers of skin. Thus a dermatophyte infection can be cured only when infected skin, nails, or hair is shed and the new keratin containing the griseofulvin replaces all the old keratin. Skin and hair infections require 4 to 6 weeks of therapy, fingernails require up to 6 months, and toenails require up to a year.

Most absorbed griseofulvin is metabolized in the liver by dealkylation, and the inactive metabolite is excreted in the urine as a glucuronide.

Relation of Mechanisms of Action to Clinical Response

Polyenes

Amphotericin was once the treatment of choice for most serious systemic mold infections and most endemic fungal infections because of its broad spectrum of activity, and it remains an important agent for most life-threatening mycoses, although newer, less toxic antifungals are beginning to be preferred over amphotericin. Amphotericin B inhibits most fungi listed in Table 50-2Candida and Aspergillusare likely to be a cause of a systemic mycosis, as are Mucor, Rhizopus, and Absidia species, which are often present as opportunistic pathogens in debilitated patients. Amphotericin B also inhibitsSporothrix as well as some ameboflagellates and the freshwater ameba Acanthamoeba. It has variable activity against Trichosporon species, and treatment failures have been reported. A few fungal species, such as Pseudallescheria boydii and Fusarium species, show resistance.

TABLE 50–2 Activity of Various Antifungal Agents Against Systemic Fungal Pathogens

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For serious infections amphotericin is still the initial drug of choice for induction therapy, with a systemic azole for chronic therapy or prevention of relapse. Disseminated cryptococcal infections, including meningitis, are treated either with amphotericin B alone or in combination with flucytosine. Amphotericin B acts synergistically with flucytosine against Candida organisms and cryptococci. Synergy of amphotericin B with other agents, such as rifampin and tetracyclines, can be demonstrated in vitro, but there are no clinical studies to support this. Severe cases involving the endemic fungi, including Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides immitis, should be treated with amphotericin B. This is also the drug of choice for Zygomycetes infections. In addition to these fungi, amphotericin remains active against most other fungi that cause severe illness, with notable exceptions including P. boydii, Fusarium species, Candida lusitaniae, and Aspergillus terreus.

The lipid formulations of amphotericin are active against a spectrum of fungi similar to that of amphotericin B. It is unclear whether lipid formulations result in improved activity against fungal pathogens broadly, but limited clinical data suggest that they may show improved efficacy for select fungi, including Histoplasma capsulatum, Cryptococcus neoformans, and Aspergillus fumigatus. Also, the lipid formulations may be superior to amphotericin B in certain clinical scenarios, including fungal infections of the central nervous system (due to better penetration) and those occurring in patients with a low neutrophil count. Lipid formulations of amphotericin are indicated for patients who are failing therapy with amphotericin B or who suffer unacceptable toxicity. They may also be indicated as first-line therapy for specific fungal infections as more data become available, including endemic fungi. Recent data suggest a possible synergistic role for treatment of Aspergillus species with amphotericin lipid formulations and newer antifungal agents, particularly caspofungin.

Nystatin has a mode of action and antifungal spectrum of activity similar to those of amphotericin B. However, it is too toxic for parenteral administration and is only used topically to treat Candidainfections of the skin and mucous membranes. It is effective for oral candidiasis, vaginal candidiasis, and Candida esophagitis. Although it is used prophylactically in neutropenic patients, it is ineffective except at very large daily doses.

Azoles

The azoles inhibit many dermatophytes, yeasts, dimorphic fungi, and some phycomycetes. Interpretative standards for the in vitro inhibition of several fungi by these drugs are now available, although more data are needed to confidently correlate these cutoffs with in vivo responses.

Ketoconazole, the oldest of the azoles, inhibits most of the common dermatophytes and many of the fungi that cause the systemic mycoses listed in Table 50-2. Ketoconazole is effective for treatment of cutaneous mycoses and oral and esophageal candidiasis in immunocompromised patients. However, it is less effective than fluconazole and is not active against Aspergillus organisms or Phycomycetes, such as Mucor species. The membrane actions of ketoconazole also block the formation of branching hyphae, which may aid in white blood cell attack on the fungi. Because ketoconazole interferes with synthesis of ergosterol, it should not be used with amphotericin B because it would antagonize its effect. This has been demonstrated in vitro and in an animal model of Cryptococcus infection. As a result of its reduced selectivity for fungal P450 enzymes, ketoconazole can significantly inhibit the human P450 enzymes as well. Although the other azoles may also inhibit the cytochrome P450 system, they are not as potent as ketoconazole. For this reason, ketoconazole is rarely used systemically these days.

Miconazole, econazole, and clotrimazole have activity similar to that of ketoconazole, but miconazole also inhibits P. boydii. Miconazole is used only topically, primarily for vulvovaginal candidiasis. It is comparable to clotrimazole in the management of cutaneous candidiasis, ringworm, and pityriasis versicolor. The only systemic infection for which IV miconazole is appropriate is that caused by P. boydii.

Voriconazole has a higher affinity for the 14-α-demethylase enzyme than other azoles and also inhibits both 24-methylene dehydrolanosterol demethylation and formation of conidial structures by certain molds. As a result, the drug has improved activity compared with other azoles, including fluconazole, for Candida and Aspergillus species, Pseudoallescheria boydii, and Fusarium and should be used as first-line therapy for these infections. Because of data suggesting synergy with other antifungal agents, it is also used in combination with caspofungin for treatment of severe infections with Aspergillus fumigatus. Voriconazole is likely also effective for most Candida isolates that are resistant to fluconazole.

Fluconazole remains an effective treatment for serious Candida infections, including candidemia, esophagitis, and peritonitis. Furthermore fluconazole is effective for preventing serious fungal infections in select hosts, including liver transplant patients. Some Candida species are less susceptible to fluconazole, including Candida krusei. Fluconazole is also active against Cryptococcus neoformans and is used for maintenance therapy after initial amphotericin therapy.

Itraconazole is effective therapy for histoplasmosis, paracoccidioidomycosis, blastomycosis, coccidioidomycosis, and sporotrichosis, and it is approved for oral administration for the treatment of fungal nail infections.

Clotrimazole is available only for topical use because it is poorly absorbed and induces the release of microsomal enzymes, which inactivate it. It is used topically for Candida infection and superficial dermatophyte (ringworm) infections. It is also effective prophylactically for oral Candida colonization and infection in neutropenic patients.

Allylamines

Terbinafine is highly active in vitro against all dermatophytes of the Trichophyton, Epidermophyton, and Microsporum genera, showing greater activity than itraconazole. Moreover, some isolates ofAspergillus species, Candida species, Sporothrix schenckii, and Malassezia furfur are inhibited by achievable concentrations. Terbinafine is approved only for the treatment of fungal nail infections.

Echinocandins

Caspofungin inhibits Candida and Aspergillus species and exhibits dose-dependent fungicidal activity, although the drug is fungistatic for Aspergillus species. Caspofungin is indicated for treatment of serious Candida infections, particularly those involving azole-resistant CandidaCryptococcus neoformans and other molds show reduced sensitivity to caspofungin, possibly related to either reduced amounts of β-glucans in the cell wall of these fungi or alterations in cell wall binding of the drug. Caspofungin is also used in combination with voriconazole or amphotericin for treatment of Aspergillusinfection because of its fungistatic and apparently synergistic effects.

Others

Flucytosine

Flucytosine inhibits Cryptococcus neoformans, many strains of Candida albicans, and Cladosporium and Phialophora species, which cause chromoblastomycosis. Resistance of Candida species to this drug is extremely variable. Flucytosine does not inhibit Aspergillus and Sporothrix organisms, Blastomyces dermatitidis, Histoplasma capsulatum, or Coccidioides immitis. This drug acts synergistically with amphotericin B against Cryptococcus organisms.

Griseofulvin

Griseofulvin inhibits dermatophytes of Microsporum, Trichophyton, and Epidermophyton species. It has no effect on filamentous fungi such as Aspergillus, yeasts such as Candida organisms, or dimorphoric species such as Histoplasma. It is used to treat only dermatophyte infections of the skin, nails, or hair. Mild infections can be effectively handled topically.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The clinical problems and major side effects encountered with the antifungal agents are summarized in the Clinical Problems Box.

Polyenes

Amphotericin B

The IV administration of amphotericin B causes many adverse effects. The initial reactions, usually fever to as high as 40° C, chills, headache, malaise, nausea, and occasionally hypotension, can be controlled by antipyretics, antihistamines, antiemetics, and glucocorticoids.

Some degree of renal toxicity develops in most patients treated with amphotericin B. This is manifested by an early decrease in glomerular filtration rate resulting from vasoconstrictive actions on afferent arterioles. It may also have an effect on the distal renal tubule, leading to K+ loss, hypomagnesemia caused by failure to reabsorb Mg++, or tubular acidosis. Drug-induced changes in the kidney include damage to the glomerular basement membrane, hypercellularity, fibrosis, and hyalinization of glomeruli with nephrocalcinosis. The extent of renal damage is related to the total dose of drug, and although most renal function recovers even if therapy is continued, some residual damage occurs. Hydration may reduce the degree of toxicity, but mannitol infusions have not been of benefit. Pentoxifylline may reduce the degree of renal toxicity.

A normochromic, normocytic anemia with hematocrits of 22% to 35% develops in most patients who receive a normal course of therapy. This is the result of reduced erythropoiesis caused by inhibition of erythropoietin production. Red blood cell production returns to normal after therapy is stopped.

Other toxicities include neurotoxicity (rare), cardiac dysrhythmias, pulmonary infiltrates, rash, and anaphylaxis. Hepatotoxicity has been reported.

Lipid formulations of amphotericin B are better tolerated with fewer infusion-related effects and considerably less nephrotoxicity than amphotericin B. As a result, these agents are preferred in situations where significant renal toxicity is likely or has developed, or in patients who cannot tolerate the infusion-related effects of amphotericin B.

Nystatin

Nystatin has minimal side effects, except for a bad taste when used as an oral rinse, which in large doses can produce nausea. It is not allergenic on the skin.

Azoles

Common side effects of ketoconazole, which occur in 3% to 20% of those treated systemically, are nausea and vomiting, though the severity of nausea can be reduced if the drug is taken with food. The most serious toxicity is hepatic, which is seen as transient elevations of serum aminotransferase and alkaline phosphatase concentrations and occurs in 5% to 10% of patients. Fulminant hepatic damage is uncommon, with an incidence of 1 in 12,000, although jaundice, fever, liver failure, and even death have occurred in a few patients. Thus ketoconazole is rarely used for systemic mycoses, because the newer azoles are less toxic.

Ketoconazole can cause transient gynecomastia and breast tenderness by blocking testosterone synthesis. High doses can lead to azoospermia and impotence and may block cortisol secretion and suppress adrenal responses to adrenocorticotropic hormone.

In a principal drug-drug interaction, ketoconazole interferes with metabolism of cyclosporin, which can lead to nephrotoxicity. In contrast, warfarin metabolism is not changed.

Intravenous infusion of miconazole produces nausea and vomiting in 25% of patients. It may also cause chills, malaise, tremors, confusion, dizziness, or seizures.

Fluconazole absorption is decreased 15% to 20% by cimetidine, and warfarin-adjusted prothrombin times are altered by fluconazole.

Voriconazole causes transient visual disturbances in approximately 40% of patients that are reversible upon discontinuation of the drug. These visual changes usually occur immediately after a dose and include blurred vision and alterations in color vision. These effects usually resolve within 30 minutes. Rash and hepatotoxicity occur at rates similar to those with other triazoles. Severe dermatological manifestations are rare.

Allylamines

The most commonly reported adverse effects of terbinafine are headache, diarrhea, dyspepsia, and abdominal pain. Some patients experience disturbances in taste, which may persist for several weeks after discontinuing the drug. Rashes, including toxic epidermal necrolysis, have been described. Increases in liver transaminase concentrations occur in less than 5% of patients, but rare cases of severe hepatotoxicity have been reported. Finally, anaphylaxis, pancytopenia, and agranulocytosis have rarely been reported.

Echinocandins

The most common adverse effects for caspofungin include fever and thrombophlebitis. Hepatoxicity also occurs, although serious liver damage appears less common than what has been reported with other antifungals, including triazoles.

Flucytosine

Occasionally patients taking flucytosine experience nausea, vomiting, and diarrhea. Serious side effects are hematological and include anemia, leukopenia, and thrombocytopenia. Because this drug is usually coadministered with amphotericin B, there may be reduced renal clearance. Toxicity is attributable to the metabolite 5-fluorouracil. Some cases of transient hepatotoxicity have been reported.

CLINICAL PROBLEMS

Drug

Adverse Effects

Polyenes

Amphotericin B

Nephrotoxicity; fever, chills; phlebitis; hypokalemia; anemia; GI disturbance

Azoles

Imidazoles

Miconazole

Headache; pruritus; thrombophlebitis; hepatotoxicity; autoinduction of hepatic metabolizing enzymes

Ketoconazole

GI disturbance; hepatotoxicity, inhibition of hepatic P450 enzymes

Triazoles

Itraconazole

GI disturbance; rare hepatotoxicity

Fluconazole

GI disturbance; rare hepatotoxicity; rare Stevens-Johnson syndrome

Voriconazole

Reversible photopsia, mild rash, Stevens-Johnson syndrome, toxic epidermal hepatotoxicity, necrolysis, visual hallucinations

Echinocandins

Caspofungin, micafungin, anidulafungin

Fever, thrombophlebitis, rare hepatotoxicity

Others

Flucytosine

Bone marrow suppression; hepatotoxicity; GI disturbance

Griseofulvin

Many patients receiving griseofulvin initially complain of headaches, but the symptoms may disappear as therapy continues. Other central nervous system side effects include lethargy, confusion, memory lapses, and impaired judgment. Nausea, vomiting, bad taste, occasionally leukopenia or neutropenia, hepatotoxicity, skin rashes, and photosensitivity also may occur. Although renal function is not decreased, albuminuria has developed. Griseofulvin administered in very large doses is teratogenic and carcinogenic in animals. Although no similar reports in humans are available, griseofulvin should not be given to pregnant women.

Griseofulvin may interact and increase the metabolism of warfarin by inducing the release of microsomal enzymes.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Amphotericin B (Fungizone)

Amphotericin B lipid complex (Abelcet)

Liposomal amphotericin (AmBisome)

Anidulafungin (Eraxis)

Caspofungin (Cancidas)

Clotrimazole (Lotrimin, Mycelex)

Econazole nitrate (Spectazole)

Fluconazole (Diflucan)

Flucytosine (Ancobon)

Griseofulvin (Grifulvin)

Haloprogrin (Halotex)

Itraconazole (Sporanox)

Ketoconazole (Nizoral)

Miconazole (Monistat)

Micafungin (Mycamine)

Nystatin (Mycostatin, Nystex, Nilstat)

Terbinafine (Lamisil)

Tolnaftate (Tolnate)

Voriconazole (Vfend)

New Horizons

The echinocandins have provided a new class of antifungal agents, with less toxicity for mammalian cells. By selectively inhibiting a fungal enzyme that is absent in mammalian cells, these drugs provide clinical effectiveness with greatly reduced toxicity as compared with older classes of antifungal drugs. As fungus and yeast continue to develop resistance to current drugs, the need exists for more specific agents and combinations for these organisms. In addition, immunocompromised patients are at high risk for colonization by fungus, yet the toxicity of currently available drugs limits the duration and dose that can be used to treat these patients. Thus studies are in progress to evaluate combinations for synergism, effectiveness against resistant species, and reduced toxicity.

FURTHER READING

Johnson MD, Perfect JR. Caspofungin: First approved agent in a new class of antifungals. Expert Opin Pharmacother. 2003;4:1-17.

Menichetti F. Combining antifungal drugs: The future of antifungal therapy? Abstr Intersci Conf Antimicrob Agents Chemother. 2002;42:27-30. Sep

Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis. 2003;37(suppl 3):S157-187.

SELF-ASSESSMENT QUESTIONS

1. A 24-year-old man presented to the emergency department reporting chest pain and a nonproductive cough that began approximately 1 week ago. His symptoms are progressing, and he now has a low-grade fever, productive cough, hemoptysis, weakness, and anorexia. A chest x-ray reveals an infiltrate in the upper left lobe of the lungs. Culture of the infiltrate reveals fungal elements of Blastomyces dermatitidis. The patient was started on an intravenous antifungal. Two weeks later the patient’s serum creatinine is significantly elevated to 3.0 mg/dL. Which of the following antifungal agents was most likely prescribed for this patient?

A. Caspofungin

B. Colloidal amphotericin B

C. Flucytosine

D. Itraconazole

E. Voriconazole

2. An HIV-infected patient develops rapidly progressing cryptococcal meningitis, for which he was hospitalized and administered amphotericin B and flucytosine. Which of the following drugs would be best for this patient as prophylactic therapy when he is released from the hospital?

A. Clotrimazole

B. Fluconazole

C. Itraconazole

D. Metronidazole

E. Voriconazole

3. A 48-year-old woman presents to your office with an obvious case of onychomycosis of the toes. Which of the following would be the most appropriate drug to prescribe?

A. Caspofungin

B. Fluconazole

C. Miconazole

D. Nystatin

E. Terbinafine

4. A 19-year-old student presents to the emergency department reporting that while driving to work, he suddenly experienced blurred vision and a loss of ability to distinguish color. His history reveals that he is currently taking an antifungal medication. Which of the following drugs would result in these effects?

A. Flucytosine

B. Griseofulvin

C. Nystatin

D. Terbinafine

E. Voriconazole

5. The most recently developed class of antifungal drugs inhibits glucan synthesis, thereby blocking production of the major structural component of the fungal cell wall. Which of the following drugs has this mechanism of action?

A. Amphotericin B

B. Capsofungin

C. Fluconazole

D. Flucytosine

E. Nystatin