ANTIFUNGAL AGENTS

Fungal infections have increased in incidence and severity in recent years, due to increased in
the use of broad-spectrum antimicrobials and the HIV epidemic. The antifungal drugs fall into
two groups: antifungal antibiotics and synthetic antifungals.
Antifungal antibiotics
Amphotericin B
Amphotericin B is poorly absorbed from the gastrointestinal tract. Oral amphotericin B is thus
effective only on fungi within the lumen of the tract. The drug is widely distributed in tissues, but
only 2-3% of the blood level is reached in CSF, thus occasionally necessitating intrathecal
therapy for certain types of fungal meningitis.
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Mechanism of Action: Amphotericin B binds to ergosterol (a cell membrane sterol) and alters
the permeability of the cell by forming amphotericin B-associated pores in the cell membrane.
The pore allows the leakage of intracellular ions and macromolecules, eventually leading to cell
death.
Adverse Effects: The toxicity of amphotericin B which may occur immediately or delayed include
fever, chills, muscle spasms, vomiting, headache, hypotension (related to infusion), renal
damage associated with decreased renal perfusion (a reversible) and renal tubular injury
(irreversible). Anaphylaxis, liver damage, anemia occurs infrequently.
Antifungal Activity: Amphotericin B is a broad-spectrum antifungal agent. It has activity against
yeasts including; Candida albicans and Cryptococcus neoformans; molds, Aspergillus
fumigatus.
Clinical Use: Amphotericin B remains the drug of choice for nearly all life-threatening mycotic
infections. Used as the initial induction regimen for serious fungal infections
(immunosuppressed patients, severe fungal pneumonia, and cryptococcal meningitis with
altered mental status).
Nystatin
Nystatin has similar structure with amphotericin B and has the same pore-forming mechanism
of action. It is too toxic for systemic use and is only used topically. It is not absorbed from skin,
mucous membranes, or the gastrointestinal tract. Nystatin is active against most Candida
species and is most commonly used for suppression of local candidal infections. Nystatin is
used in the treatment of oropharyngeal thrush, vaginal candidiasis, and intertriginous candidal
infections.
Griseofulvin
Griseofulvin is a fungistatic and used is in the treatment of dermatophytosis. Absorption is
improved when it is given with fatty foods. Griseofulvin is deposited in newly forming skin where
it binds to keratin, protecting the skin from new infection. It must be administered for 2-6 weeks
for skin and hair infections to allow the replacement of infected keratin by the resistant
structures. Nail infections may require therapy for months to allow regrowth of the new
protected nail and is often followed by relapse. Adverse effects include an allergic syndrome
much like serum sickness, hepatitis, and drug interactions with warfarin and phenobarbital.
Griseofulvin has been largely replaced by newer antifungal medications such as itraconazole
and terbinafine.

Synthetic Antifungal Agents
Flucytosine
Flucytosine is related to fluorouracil (5-FU). Its spectrum of action is much narrower than that of
amphotericin B. It is well absorbed orally. It is poorly protein-bound and penetrates well into all
body fluid compartments including the CSF. It is eliminated by glomerular filtration. Toxicity is
more likely to occur in AIDS patients and in the presence of renal insufficiency.
Flucytosine is converted intracellularly first to 5-FU and then to 5-fluorodeoxyuridine
monophosphate (F-dUMP) and fluorouridine triphosphate (FUTP), which inhibit DNA and RNA
synthesis, respectively.
Clinical Use: Active against Cryptococcus neoformans, some Candida species, and the
dematiaceous molds that cause chromoblastomycosis. Clinical use at present is confined to
combination therapy, either with amphotericin B for cryptococcal meningitis or with itraconazole
for chromoblastomycosis.
Adverse Effects: The adverse effects of flucytosine result from metabolism (intestinal flora) to
the toxic antineoplastic compound flucytosine. Bone marrow toxicity with anemia, leukopenia,
and thrombocytopenia are the most common adverse effects, with derangement of liver
enzymes occurring less frequently.
Azoles
Azoles are synthetic compounds that can be classified as imidazoles and triazoles. The
imidazoles consist of ketoconazole, miconazole, and clotrimazole. The triazoles include
itraconazole and fluconazole.
The antifungal activity of azole drugs results from the reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450 enzymes. The specificity of azole drugs results from their
greater affinity for fungal than for human cytochrome P450 enzymes. Imidazoles exhibit a lesser
degree of specificity than the triazoles, accounting for their higher incidence of drug interactions
and side effects.
Azoles are active against many Candida species, Cryptococcus neoformans, the endemic
mycoses (blastomycosis, coccidioidomycosis), the dermatophytes, and, Aspergillus infections
(itraconazole). Adverse Effects: The azoles are relatively nontoxic. The most common adverse
reaction is minor gastrointestinal upset. Most azoles cause abnormalities in liver enzymes and,
very rarely, clinical hepatitis.

Imidazoles
Ketoconazole
Ketoconazole is less selective for fungal P450 than are the fluconazole and itraconazole (inhibit
mammalian cytochrome P450 enzymes).
Clinical use: it has limited use because of the drug interactions, endocrine side effects, and of
its narrow therapeutic range. Oral formulation that is best absorbed at a low gastric pH.
Ketoconazole is used in treatment of mucocutaneous candidiasis and nonmeningeal
coccidioidomycosis. It is also used in the treatment of seborrheic dermatitis and pityriasis
versicolor (Topical/ shampoo).
Adverse effects: First, ketoconazole inhibition of human cytochrome P450 enzymes interferes
with biosynthesis of adrenal and gonadal steroid hormones, producing significant endocrine
effects such as gynecomastia, infertility, and menstrual irregularities. Second, the interaction
with P450 enzymes can alter the metabolism of other drugs, leading to enhance toxicity of
those agents (eg. increased levels and enhanced arrhythmogenic effects of the nonsedating
antihistamines, and terfenadine).
Clotrimazole and miconazole
Clotrimazole and miconazole are available over-the-counter and are often used for vulvovaginal
candidiasis. Oral clotrimazole troches are available for treatment of oral thrush and are a
pleasant-tasting alternative to nystatin. In cream form, both agents are useful for dermatophytic
infections, including tinea corporis, tinea pedis, and tinea cruris. Absorption is negligible, and
adverse effects are rare.
Triazoles
Itraconazole
Itraconazole is available in an oral formulation and its absorption is increased by food and by
low gastric pH. Undergoes extensive hepatic metabolism. Itraconazole is the azole of choice in
the treatment of dermatophytoses and onychomycosis and is the only agent with significant
activity against Aspergillus species.
Fluconazole
Fluconazole has good cerebrospinal fluid penetration. Can be given by the intravenous or the
oral route. Fluconazole has the least effect on hepatic microsomal enzymes. Thus, has a wide
therapeutic window. Fluconazole is the azole of choice in the treatment and secondary
prophylaxis of cryptococcal meningitis. It is also effective for mucocutaneous candidiasis.