Chapter 48: Antifungal Agents

A. Amphotericin B

Amphotericin B continues to be an important drug for the treatment of systemic fungal infections. However, several azoles and echinocandins are proving to be just as effective in some systemic mycoses with less risk of toxic effects.

1. Classification and pharmacokinetics

Amphotericin B is a polyene antibiotic related to nystatin. Amphotericin is poorly absorbed from the gastrointestinal tract and is usually administered intravenously as a nonlipid colloidal suspension, as a lipid complex, or in a liposomal formulation. The drug is widely distributed to all tissues except the central nervous system (CNS). Elimination is mainly via slow hepatic metabolism; the half-life is approximately 2 wk. A small fraction of the drug is excreted in the urine; dosage modification is necessary only in extreme renal dysfunction. Amphotericin B is not dialyzable.

2. Mechanism of action

The fungicidal action of amphotericin B is due to its effects on the permeability and transport properties of fungal membranes. Polyenes are molecules with both hydrophilic and lipophilic characteristics (ie, they are amphipathic). They bind to ergosterol, a sterol specific to fungal cell membranes, and cause the formation of artificial pores (Figure 48–1). Resistance, though uncommon, can occur via a decreased level of or a structural change in membrane ergosterol.

3. Clinical uses

Amphotericin B is one of the most important drugs available for the treatment of systemic mycoses and is often used for initial induction regimens before follow-up treatment with an azole. It has the widest antifungal spectrum of any agent and remains the drug of choice, or codrug of choice, for most systemic infections caused by Aspergillus, Blastomyces, Candida albicans, Cryptococcus, Histoplasma, and Mucor. Amphotericin B is usually given by slow intravenous infusion, but in fungal meningitis intrathecal administration, though dangerous, has been used. Local administration of the drug, with minimal toxicity, has been used in treatment of mycotic corneal ulcers and keratitis.

4. Toxicity

a. Infusion related

Adverse effects related to intravenous infusion commonly include fever, chills, muscle spasms, vomiting, and a shock-like fall in blood pressure. These effects may be attenuated by a slow infusion rate and by premedication with antihistamines, antipyretics, meperidine, or glucocorticoids.

b. Dose limiting

Amphotericin B decreases the glomerular filtration rate and causes renal tubular acidosis with magnesium and potassium wasting. Anemia may result from decreases in the renal formation of erythropoietin. Although concomitant saline infusion may reduce renal damage, the nephrotoxic effects of the drug are dose-limiting. Dose reduction (with lowered toxicity) is possible in some infections when amphotericin B is used with flucytosine. Liposomal formulations of amphotericin B have reduced nephrotoxic effects, possibly because of decreased binding of the drug to renal cells.

c. Neurotoxicity

Intrathecal administration of amphotericin B may cause seizures and neurologic damage.

B. Flucytosine (5-Fluorocytosine [5-FC])

1. Classification and pharmacokinetics

5-FC is a pyrimidine antimetabolite related to the anticancer drug 5-fluorouracil (5-FU). It is effective orally and is distributed to most body tissues, including the CNS. The drug is eliminated intact in the urine, and the dose must be reduced in patients with renal impairment.

2. Mechanism of action

Flucytosine is accumulated in fungal cells by the action of a membrane permease and converted by cytosine deaminase to 5-FU, an inhibitor of thymidylate synthase (Figure 48–1). Selective toxicity occurs because mammalian cells have low levels of permease and deaminase. Resistance can occur rapidly if flucytosine is used alone and involves decreased activity of the fungal permeases or deaminases. When 5-FC is given with amphotericin B, or triazoles such as itraconazole, emergence of resistance is decreased and synergistic antifungal effects may occur.

3. Clinical uses

The antifungal spectrum of 5-FC is narrow; its clinical use is limited to the treatment, in combination with amphotericin B or a triazole, of infections resulting from Cryptococcus neoformans, possibly systemic candidal infections and chromoblastomycosis caused by molds.

4. Toxicity

Prolonged high plasma levels of flucytosine cause reversible bone marrow depression, alopecia, and liver dysfunction.

C. Azole Antifungal Agents

1. Classification and pharmacokinetics

The azoles used for systemic mycoses include ketoconazole, an imidazole, and the triazoles fluconazole, itraconazole, posaconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Fluconazole, posaconazole, and voriconazole are more reliably absorbed via the oral route than the other azoles. Most triazoles are available in both oral and intravenous formulations. The drugs are distributed to most body tissues, but with the exception of fluconazole, drug levels achieved in the CNS are very low. Liver metabolism is responsible for the elimination of ketoconazole, itraconazole, and voriconazole. Inducers of drug-metabolizing enzymes (eg, rifampin) decrease the bioavailability of itraconazole. Fluconazole is eliminated by the kidneys, largely in unchanged form.

2. Mechanism of action

The azoles interfere with fungal cell membrane permeability by inhibiting the synthesis of ergosterol. These drugs act at the step of 14α-demethylation of lanosterol, which is catalyzed by a fungal cytochrome P450 isozyme. With increasing use of azole antifungals, especially for long-term prophylaxis in immunocompromised and neutropenic patients, resistance is occurring, possibly via changes in the sensitivity of the target enzymes.

3. Clinical uses

a. Ketoconazole

Because it has a narrow antifungal spectrum and causes more adverse effects than other azoles, ketoconazole is now rarely used for systemic mycoses. The drug is not available in parenteral form. However, ketoconazole continues to be used for chronic mucocutaneous candidiasis and is also effective against dermatophytes.

b. Fluconazole

Fluconazole is a drug of choice in esophageal and oropharyngeal candidiasis and for most infections caused by Coccidioides. A single oral dose usually eradicates vaginal candidiasis. Fluconazole is the drug of choice for treatment and secondary prophylaxis against cryptococcal meningitis and is an alternative drug of choice (with amphotericin B) in treatment of active disease due to Cryptococcus neoformans. The drug is also equivalent to amphotericin B in candidemia.

c. Itraconazole

This azole is currently the drug of choice for systemic infections caused by Blastomyces and Sporothrix and for subcutaneous chromoblastomycosis. Itraconazole is an alternative agent in the treatment of infections caused by Aspergillus, Coccidioides, Cryptococcus, and Histoplasma. In esophageal candidiasis, the drug is active against some strains resistant to fluconazole. Itraconazole is also used extensively in the treatment of dermatophytoses, especially onychomycosis.

d. Voriconazole

Voriconazole has an even wider spectrum of fungal activity than itraconazole. It is a codrug of choice for treatment of invasive aspergillosis; some studies report greater efficacy than amphotericin B. Voriconazole is an alternative drug in candidemia with activity against some fluconazole-resistant organisms and in AIDS patients has been used in the treatment of candidial esophagitis and stomatitis.

e. Posaconazole

The broadest-spectrum triazole, posaconazole has activity against most species of Candida and Aspergillus. It is the only azole with activity against Rhizopus, one of the agents of mucormycosis and is used for prophylaxis of fungal infections during cancer chemotherapy and in salvage therapy in invasive aspergillosis.

4. Toxicity

Adverse effects of the azoles include vomiting, diarrhea, rash, and sometimes hepatotoxicity, especially in patients with preexisting liver dysfunction. Ketoconazole is a notorious inhibitor of hepatic cytochrome P450 isozymes and may increase the plasma levels of many other drugs, including cyclosporine, oral hypoglycemics, phenytoin, and warfarin. Inhibition of cytochrome P450 isoforms by ketoconazole interferes with the synthesis of adrenal and gonadal steroids and may lead to gynecomastia, menstrual irregularities, and infertility. The other azoles are more selective inhibitors of fungal cytochrome P450. Although they are less likely than ketoconazole to cause endocrine dysfunction, their inhibitory effects on liver drug-metabolizing enzymes have resulted in drug interactions. Voriconazole causes immediate but transient visual disturbances including blurring of vision of unknown cause in more than 30% of patients. Based on animal studies voriconzole is a class D drug in terms of pregnancy risk. Visual dysfunction has not been reported with posaconazole, but the drug is an inhibitor of CYP3A4, increasing the levels of cyclosporine and tacrolimus.

D. Echinocandins

1. Classification and pharmacokinetics

Caspofungin is an echinocandin, the first of a novel class of antifungal agents. Other echinocandins include anidulafungin and micafungin. Used intravenously, the drugs distribute widely to the tissues and are eliminated largely via hepatic metabolism. Caspofungin has a half-life of 9–12 h. The half-life of micafungin is slightly longer, and that of anidulafungin is 24–48 h.

2. Mechanism of action

The echinocandins have a unique fungicidal action, inhibiting the synthesis of β(1-3)glucan, a critical component of fungal cell walls.

3. Clinical uses

Caspofungin is used for disseminated and mucocutaneous Candida infections in patients who fail to respond to amphotericin B and in the treatment of mucormycosis. Anidulafungin is used for esophageal and invasive candidiasis. Micofungin is used for mucocutaneous candidiasis and for prophylaxis of Candida infections in bone marrow transplant patients.

4. Toxicity

Infusion-related effects of caspofungin include headache, gastrointestinal distress, fever, rash, and flushing (histamine release). Micafungin also causes histamine release and elevates blood levels of the immunosuppressant drugs cyclosporine and sirolimus. Combined use of echinocandins with cyclosporine may elevate liver transaminases.

Ketoconazole has the unenviable reputation of association with multiple drug interactions because of its inhibition of cytochromes P450 involved in drug metabolism (See Chapters 4 and 61).

1. List drugs that have their metabolism via such enzymes inhibited by ketoconazole.

2. List other drugs that inhibit hepatic cytochromes P450.

The Skill Keeper Answers appear at the end of the chapter.

Drugs used orally in the treatment of dermatophytoses include griseofulvin, terbinafine, and several azole antifungals.

A. Griseofulvin

1. Pharmacokinetics

Oral absorption of griseofulvin depends on the physical state of the drug—ultra-micro-size formulations, which have finer crystals or particles, are more effectively absorbed—and is aided by high-fat foods. The drug is distributed to the stratum corneum, where it binds to keratin. Biliary excretion is responsible for its elimination.

2. Mechanism of action

Griseofulvin interferes with microtubule function in dermatophytes (Figure 48–1) and may also inhibit the synthesis and polymerization of nucleic acids. Sensitive dermatophytes take up the drug by an energy-dependent mechanism, and resistance can occur via decrease in this transport. Griseofulvin is fungistatic.

3. Clinical uses and toxicity

Griseofulvin is not active topically. The oral formulation of the drug is indicated for dermatophytoses of the skin and hair, but has been largely replaced by terbinafine and the azoles. Adverse effects include headaches, mental confusion, gastrointestinal irritation, photosensitivity, and changes in liver function. Griseofulvin should not be used in patients with porphyria. Griseofulvin decreases the bioavailability of warfarin, resulting in decreased anticoagulant effect, and it also causes disulfiram-like reactions with ethanol.

B. Terbinafine

1. Mechanism of action

Terbinafine inhibits a fungal enzyme, squalene epoxidase (Figure 48-1). It causes accumulation of toxic levels of squalene, which can interfere with ergosterol synthesis. Terbinafine is fungicidal.

2. Clinical uses and toxicity

Terbinafine is available in both oral and topical forms. Like griseofulvin, terbinafine accumulates in keratin, but it is much more effective than griseofulvin in onychomycosis. Adverse effects include gastrointestinal upsets, rash, headache, and taste disturbances. Terbinafine does not inhibit cytochrome P450.

C. Azoles

The azoles other than voriconazole and posaconazole are commonly used orally for the treatment of dermatophytoses. Pulse or intermittent dosing with itraconazole is as effective in onychomycoses as continuous dosing because the drug persists in the nails for several months. Typically, treatment for 1 wk is followed by 3 wk without drug. Advantages of pulse dosing include a lower incidence of adverse effects and major cost savings. Topical forms of various azoles are also available for use in dermatophytoses.

A number of antifungal drugs are used topically for superficial infections caused by C albicans and dermatophytes. Nystatin is a polyene antibiotic (toxicity precludes systemic use) that disrupts fungal membranes by binding to ergosterol. Nystatin is commonly used topically to suppress local Candida infections and has been used orally to eradicate gastrointestinal fungi in patients with impaired defense mechanisms. Other topical antifungal agents that are widely used include the azole compounds miconazole, clotrimazole, and several others.

1. Interactions between this drug and cell membrane components can result in the formation of pores lined by hydrophilic groups present in the drug molecule.

   • (A) Caspofungin

   • (B) Flucytosine

   • (C) Griseofulvin

   • (D) Nystatin

   • (E) Terbinafine

2. Which statement about fluconazole is accurate?

   • (A) Does not penetrate the blood-brain barrier

   • (B) Drug of choice in treatment of aspergillosis

   • (C) Induces hepatic drug-metabolizing enzymes

   • (D) Has the least effect of all azoles on drug metabolism

   • (E) Oral bioavailability is less than that of ketoconazole

   Questions 3–5. A 37-year-old woman with leukemia was undergoing chemotherapy with intravenous antineoplastic drugs. During treatment, she developed a systemic infection from an opportunistic pathogen. There was no erythema or edema at the catheter insertion site. A white vaginal discharge was observed. After appropriate specimens were obtained for culture, empiric antibiotic therapy was started with gentamicin, nafcillin, and ticarcillin intravenously. This regimen was maintained for 72 h, during which time the patient’s condition did not improve significantly. Her throat was sore, and white plaques had appeared in her pharynx. On day 4, none of the cultures had shown any bacterial growth, but both the blood and urine cultures grew out Candida albicans.

3. At this point, the best course of action is to

   • (A) Continue current antibiotics and start griseofulvin

   • (B) Continue current antibiotics and start amphotericin B

   • (C) Stop current antibiotics and start itraconazole

   • (D) Stop current antibiotics and start amphotericin B

   • (E) Stop current antibiotics and start terbinafine

4. If amphotericin B is administered, the patient should be premedicated with

   • (A) Diphenhydramine

   • (B) Ibuprofen

   • (C) Prednisone

   • (D) Any or all of the above

   • (E) None of the above

5. Candida is a major cause of nosocomial bloodstream infection. The opportunistic fungal infection in this patient could have been prevented by administration of

   • (A) Caspofungin

   • (B) Flucytosine

   • (C) Nystatin

   • (D) Voriconazole

   • (E) None of the above

   Questions 6–7. A 28-year-old man living on the East Coast was transferred by his employer to California for several months. On his return, he complains of having influenza-like symptoms with fever and a cough. He also has red, tender nodules on his shins. His physician suspects that these symptoms are due to coccidioidomycosis contracted during his stay in California.

6. This patient should be treated immediately with

   • (A) Amphotericin B

   • (B) Caspofungin

   • (C) Ketoconazole

   • (D) Terbinafine

   • (E) None of these drugs

7. Which is the drug of choice if this patient is suffering from persistent lung lesions or disseminated disease caused by Coccidioides immitis?

   • (A) Amphotericin B

   • (B) Flucytosine

   • (C) Itraconazole

   • (D) Micofungin

   • (E) Terbinafine

8. Which drug is least likely to be effective in the treatment of esophageal candidiasis if it is used by the oral route?

   • (A) Clotrimazole

   • (B) Griseofulvin

   • (C) Ketoconazole

   • (D) Itraconazole

   • (E) Nystatin

9. Serious cardiac effects have occurred when this drug was taken by patients using the antihistamines astemizole or terfenadine

   • (A) Amphotericin B

   • (B) Griseofulvin

   • (C) Ketoconazole

   • (D) Terbinafine

   • (E) Voriconazole

10. Regarding the clinical use of liposomal formulations of amphotericin B, which statement is accurate?

    • (A) Amphotericin B affinity for these lipids is greater than affinity for ergosterol

    • (B) Less expensive to use than conventional amphotericin B

    • (C) More effective in fungal infections because they increase tissue uptake of amphotericin B

    • (D) They decrease the nephrotoxicity of amphotericin B

    • (E) They have a wider spectrum of antifungal activity than conventional formulations of amphotericin B

1. The polyene antifungal drugs amphotericin B and nystatin are amphipathic molecules that can interact with ergosterol in fungal cell membranes to form artificial pores. In these structures, the lipophilic groups on the drug molecule are arranged on the outside of the pore, and the hydrophilic regions are located on the inside. The fungicidal action of the polyenes derives from this interaction, which results in leakage of intracellular constituents. The answer is D.

2. The azoles with activity against Aspergillus are itraconazole and voriconazole. Fluconazole is the best absorbed member of the azole group by the oral route and the only one that readily penetrates into cerebrospinal fluid. Although fluconazole may inhibit the metabolism of some drugs, it has the least effect of all azoles on hepatic microsomal drug-metabolizing enzymes. The answer is D.

3. The antibiotic regimen should be stopped immediately, since the condition of the patient did not improve after 3 d of such treatment, the cultures were negative for bacteria, and the clinical picture suggested that the patient had a fungal infection. This was subsequently confirmed by blood culture. The answer is D.

4. Infusion-related adverse effects of amphotericin B include chills and fevers (the “shake and bake” syndrome), muscle spasms, nausea, headache, and hypotension. Analgesic-antipyretics, antihistamines, and glucocorticoids all have been shown to be helpful. The administration of a 1-mg test dose of amphotericin B is sometimes useful in predicting the severity of infusion-related toxicity. The answer is D.

5. In the case of opportunistic candidal infections in the immunocompromised patient, no prophylactic drugs have been shown to be clinically effective. Prophylaxis against other fungi may be effective in some instances, including suppression of cryptococcal meningitis in AIDS patients with fluconazole. However, prophylactic use of azoles may contribute to the development of fungal resistance. The answer is E.

6. A travel history can be important in the diagnosis of fungal disease. If this patient has a fungal infection of the lungs, it is probably due to C immitis, which is endemic in dry regions of the western United States. Pulmonary symptoms of coccidioidomycosis are usually self-limiting, and drug therapy is not commonly required in an otherwise healthy patient. Tender red nodules on extensor surfaces constitute a good prognostic sign. Erythema nodosum is a delayed hypersensitivity response to fungal antigens. No organisms are present in the lesions, and it is not a sign of disseminated disease. The answer is E.

7. In progressive or disseminated forms of coccidioidomycosis, systemic antifungal drug treatment is needed. Until recently, amphotericin B was the recommended therapy, but fluconazole or itraconazole are now generally preferred. Note that the risk of dissemination is much greater in African Americans (10% incidence) and in pregnant women during the third trimester. The answer is C.

8. Griseofulvin has no activity against C albicans and is not effective in the treatment of systemic or superficial infections caused by such organisms. “Swish and swallow” formulations of clotrimazole and nystatin have been used commonly. Most of the azoles are effective in esophageal candidiasis. The answer is B.

9. Ketoconazole was the first oral azole introduced into clinical use, but it has a greater propensity to inhibit human cytochrome P450 enzymes than other azoles and is no longer widely used in the United States. Cardiotoxicity may occur when ketoconazole is used by patients taking astemizole or terfenadine as a result of the ability of ketoconazole to inhibit their metabolism via hepatic cytochromes P450. The answer is C.

10. Liposomal formulations of amphotericin B result in decreased accumulation of the drug in tissues, including the kidney. As a result, nephrotoxicity is decreased. With some lipid formulations, infusion-related toxicity may also be reduced. Lipid formulations do not have a wider antifungal spectrum; their daily cost ranges from 10 to 40 times more than the conventional formulation of amphotericin B. The answer is D.

1. A sampling of commonly used drugs with cytochrome P450-mediated metabolism inhibited by ketoconazole (and to a much lesser extent by other azoles) includes chlordiazepoxide, cisapride, cyclosporine, didanosine, fluoxetine, loratadine, lovastatin, methadone, nifedipine, phenytoin, quinidine, tacrolimus, theophylline, verapamil, warfarin, zidovudine, and zolpidem (See Chapters 4 and 61).

2. Other drugs that inhibit hepatic cytochromes P450 include chloramphenicol, cimetidine, clarithromycin, disulfiram, erythromycin, ethanol, ethinyl estradiol, fluconazole, furanocoumarins (in grapefruit juice), isoniazid, itraconazole, MAO inhibitors, phenylbutazone, and secobarbital.

When you complete this chapter, you should be able to:

• ❑ Describe the mechanisms of action of the azole, polyene, and echinocandin antifungal drugs.

• ❑ Identify the clinical uses of amphotericin B, flucytosine, individual azoles, caspofungin, griseofulvin, and terbinafine.

• ❑ Describe the pharmacokinetics and toxicities of amphotericin B.

• ❑ Describe the pharmacokinetics, toxicities, and drug interactions of the azoles.

• ❑ Identify the main topical antifungal agents.