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Antifungal Agents

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Antifungal Agents >

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 481). Resistance, though uncommon, can occur via a decreased level of or a structural
change in membrane ergosterol.

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FIGURE 481

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.
481.)

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

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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 481). 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.

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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

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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 912 h. The half-life of micafungin is slightly
longer, and that of anidulafungin is 2448 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 drugultra-micro-size formulations, which
have finer crystals or particles, are more effectively absorbedand 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

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Griseofulvin interferes with microtubule function in dermatophytes (Figure 481) and may also inhibit the
synthesis and polymerization of nucleic acids. Sensitive dermatophytes take up the drug by an energydependent 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.

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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 doselimiting, additive with

other nephrotoxic drugs;
infusion reactions (chills,
fever, muscle spasms,
hypotension)

Aspergillosis
(voriconazole);
blastomycosis
(itraconazole,
fluconazole);
mucormycosis
(posaconazole);
alternative drugs in
candidemia and
infections caused by
Aspergillus,
Blastomyces,
Cryptococcus,
andHistoplasma

Various topical and oral Ketoconazole rarely used

forms for
in systemic fungal
dermatophytoses
infections owing to its
inhibition of hepatic and
Oral, parenteral forms
adrenal P450s; other
for mycoses
azoles are less toxic, but
(fluconazole,
may cause GI upsets and
itraconazole,
rash; voriconazole
posaconazole,
causes visual
voriconazole)
disturbances and is class
D re pregnancy risk
Most azoles undergo

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

Azoles

Inhibit fungal
P450-dependent
Ketoconazole
enzymes
blocking
Fluconazole
ergosterol
Itraconazole
synthesis;
Posaconazole resistance can
occur with longVoriconazole term use

Echinocandins
Caspofungin
Micafungin
Anidulafungin

hepatic metabolism;
fluconazole eliminated
in urine unchanged

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