Antifungal Agents: Introduction
Fungal infections are difficult to treat, particularly in the immunocompromised or neutropenic patient. Most fungi are resistant to conventional antimicrobial agents, and relatively few drugs are available for the treatment of systemic fungal diseases. Amphotericin B and the azoles (fluconazole, itraconazole, ketoconazole, and voriconazole) are the primary drugs used in systemic infections. They are selectively toxic to fungi because they interact with or inhibit the synthesis of ergosterol, a sterol unique to fungal cell membranes.
Drugs for Systemic Fungal Infections
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.
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.
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.
FIGURE 48-1
Targets of antifungal drugs. Except for flucytosine (and possibly griseofulvin, not shown), all available antifungal drugs target the fungal cell membrane or cell wall.
(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 48-1.)
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.
Toxicity
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.
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.
Neurotoxicity
Intrathecal administration of amphotericin B may cause seizures and neurologic damage.
Flucytosine (5-Fluorocytosine [5-FC])
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.
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.
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.
Toxicity
Prolonged high plasma levels of flucytosine cause reversible bone marrow depression, alopecia, and liver dysfunction.
Azole Antifungal Agents
Classification and Pharmacokinetics
The azoles used for systemic mycoses include ketoconazole, an imidazole, and the triazoles fluconazole, itraconazole, and voriconazole. Oral bioavailability is variable (normal gastric acidity is required). Fluconazole and voriconazole are more reliably absorbed via the oral route than the other azoles. The 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.
Mechanism of Action
The azoles interfere with fungal cell membrane permeability by inhibiting the synthesis of ergosterol. These drugs act at the step of 14
-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.
Clinical Uses
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.
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.
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.
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. Voriconzole 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.
Posaconazole
The broadest-spectrum triazole, posaconazole has activity against most species of Candida and Aspergillus. It is the only azole with activity against the agent of mucormycosis and is used for prophylaxis of fungal infections during cancer chemotherapy and in salvage therapy in invasive aspergillosis.
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.
Echinocandins
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.
Mechanism of Action
The echinocandins have a unique fungicidal action, inhibiting the synthesis of 
(1-2)glycan, a critical component of fungal cell walls.
Clinical Uses
Caspofungin is used for disseminated and mucocutaneous Candida infections in patients who fail to respond to amphotericin B. 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.
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.
Skill Keeper: Inhibitors of Cytochromes P450
(See Chapters 4 and 61)
Ketoconazole has the unenviable reputation of association with multiple drug interactions because of its inhibition of cytochromes P450 involved in drug metabolism.
1. How many drugs can you identify that have their metabolism via such enzymes inhibited by ketoconazole?
2. How many other drugs that inhibit hepatic cytochromes P450 can you recall?
The Skill Keeper Answers appear at the end of the chapter.
Systemic Drugs for Superficial Fungal Infections
Drugs used orally in the treatment of dermatophytoses include griseofulvin, terbinafine, and several azole antifungals.
Griseofulvin
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.
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.
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.
Terbinafine
Mechanism of Action
Terbinafine inhibits a fungal enzyme, squalene epoxidase. It causes accumulation of toxic levels of squalene, which can interfere with ergosterol synthesis. Terbinafine is fungicidal.
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.
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.
Topical Drugs for Superficial Fungal Infections
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.
Skill Keeper Answers: Inhibitors of Cytochromes P450
(See Chapters 4 and 61)
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.
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.
Checklist
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 pharmokinetics, toxicities, and drug interactions of the azoles.
Identify the main topical antifungal agents.
Drug Summary Table: Antifungal Drugs
Drug/Drug Class Mechanism of Action Clinical Applications Pharmacokinetics & Interactions Toxicities Amphotericin B Binds to ergosterol in fungal cell membranes, forming "leaky pores" Candidemia and infections caused by Aspergillus, Blastomyces, Cryptococcus, Histoplasma, Mucor, etc Multiple forms, IV for systemic infections (liposomal forms less nephrotoxic); topical for ocular/bladder infections Nephrotoxicity is dose-limiting, additive with other nephrotoxic drugs; infusion reactions (chills, fever, muscle spasms, hypotension) Azoles Ketoconazole Fluconazole Itraconazole Posaconazole Voriconazole Inhibit fungal P450-dependent enzymes blocking ergosterol synthesis; resistance can occur with long-term use Aspergillosis (voriconazole); blastomycosis (itraconazole, fluconazole); mucormycosis (posaconazole); alternative drugs in candidemia and infections caused by Aspergillus, Blastomyces, Cryptococcus, andHistoplasma Various topical and oral forms for dermatophytoses Oral, parenteral forms for mycoses (fluconazole, itraconazole, posaconazole, voriconazole) Most azoles undergo hepatic metabolism; fluconazole eliminated in urine unchanged Ketoconazole rarely used in systemic fungal infections owing to its inhibition of hepatic and adrenal P450s; other azoles are less toxic, but may cause GI upsets and rash; voriconazole causes visual disturbances and is class D re pregnancy risk Echinocandins Caspofungin Micafungin Anidulafungin Inhibit -glucan synthase decreasing fungal cell wall synthesis Treatment of candidemia; caspofungin is also used as "salvage" therapy in apergillosis IV forms; micafungin increases levels of nifedipine and cyclosporine Gastrointestinal (GI) distress, flushing from histamine release Flucytosine Inhibits DNA and RNA polymerases Synergistic with amphotericin B in candidemia and cryptococal infections Oral; enters cerebrospinal fluid; renal elimination Bone marrow suppression Terbinafine Inhibits epoxidation of squalene Mucocutaneous fungal infections; accumulates in keratin Oral; long duration of action (weeks) GI upsets, headache