Amphotericin B is poorly absorbed orally and may only be given intravenously
for systemic fungal infections.
Mechanism of Action -- The primary sterol in fungi is ergosterol whereas
in mammals it is cholesterol. Amphotericin B binds to ergosterol,
destroying fungal membrane integrity. The structure of the drug forms
a large oval, one side of which is lipophilic. This side binds to
the ergosterol. The other side is hydrophilic. The binding
of additional molecules will form a pore in the fungal membrane, allowing
the efflux of intracellular fungal ions and macromolecules. At lower
doses this action is fungistatic. At higher concentrations amphotericin
will exert fungicidal activity.
Spectrum of Activity -- Amphotericin is a broad spectrum anti-fungal
with activity against Candida spp., Cryptococcus, Histoplasma,
Blastomyces, Coccidioides, and Aspergillus.
Adverse Effects -- Amphotericin may produce severe side effects including
fever, chills, muscle spasm, vomiting, headache, hypotension, hypokalæmia,
and thrombophlebitis. These actions are common upon IV infusion.
They may be attenuated by either pre- or concurrent-administration of antipyretics,
antihistaminics, glucocorticoids, and heparin. Other adverse reactions
include nephrotoxicity and hepatotoxicity. Continuous infusion of
normal saline between doses of amphotericin will minimise the risk for
Flucytosine (5-FC) -- Flucytosine is available only for oral
Mechanism of Action -- Flucytosine is metabolised to 5-fluorouracil.
In the fungal cell, this is further metabolised to 5-fluorodeoxyuridinemonophosphate
(5-F-dUMP) and 5-fluorouridinetriphosphate (5-FUTP). The former inhibits
DNA synthesis while the later inhibits RNA synthesis, thereby inhibiting
fungal replication and protein synthesis respectively.
Spectrum -- Flucytosine is most effective against Cryptococcus
and some spp. of Candida. It is used only in combination with
other antifungals (i.e. amphotericin) when is shows greater efficacy,
possibly due to increased entry into the fungal cell by the pores created
by amphotericin or other compromises in membrane integrity.
Adverse Effects -- Flucytosine may cause GI upset, anæmias, nephrotoxicity,
ataxia, and paræsthesias. At least some of these effects may
be mediated by the anti-metabolite action of 5-fluorouracil.
Griseofulvin -- Griseofulvin is used orally to provide systemic treatment
for dermal fungal infections. It is moderately well absorbed.
Taking the drug with a fatty meal will greatly increase its absorption.
Additionally, it is available in microsize and ultramicrosize formulations,
which also increases the absorption of the drug.
Mechanism of Action -- Griseofulvin is fungistatic. It
inhibits fungal mitosis by inhibiting mitotic spindle formation (similar
to colchicine). It is highly distributed to dermal tissues (keratophilic),
which is beneficial in the treatment of dermal fungal infections.
NOTE that therapy is long term (up to one year) and that the fungus may
return when the drug is discontinued. This is due at least in part
to the fungistatic nature of griseofulvin.
Spectrum -- Griseofulvin is effective against Microsporum, Epidermophyton,
and Trichophyton spp. (All of which are common spp. of fungus
that cause dermal infections.) It is predominantly used in the treatment
of onychomycosis (tinea unguium or fungal infection of the nail bed).
Adverse Effects -- Headache is the most common side effect. It
usually diminishes with continued therapy.
Imidazole/Triazole Antifungals -- The mechanism of action and spectrum
of agents belonging to these two chemical classes of anti-fungals are identical.
The primary difference between the classes is that the newer triazole antifungals
are metabolised at a slower rate than the older imidazoles. Additionally,
the triazoles exhibit fewer side effects and at a reduced incidence than
the imidazoles. The triazole antifungals include terconazole, itraconazole,
and fluconazole. All others are imidazoles. The imidazole/triazole
antifungals that are available for systemic use include ketoconazole (oral),
miconazole (parenteral), itraconazole (oral), and fluconazole (oral and
Mechanism of Action -- These agents inhibit the enzyme 14-alpha-demethylase,
a cytochrome P450 enzyme that catalyses the synthesis of ergosterol.
Consequently, ergosterol synthesis is inhibited and membrane integrity
and function is compromised.
Spectrum -- These classes of antifungals are effective against some
spp. of Candida (including albicans), Cryptococcus, Blastomyces,
Histoplasma, Coccidioides, and the dermatophytes (including Trychophyton
and other species that commonly cause cutaneous fungal infections).
Adverse Effects -- These drugs primarily cause GI upset.
They may also inhibit mammalian cytochrome P450 enzymes, resulting
in inhibition of cortisone, androgen, and œstrogen synthesis. Side
effects that may arise from these actions include gynecomastia, menstrual
irregularities, infertility, and adrenal insufficiency. Ketoconazole
is the agent with the greatest incidence of these side effects (it may
even be used as a treatment in mild Cushing's disease). These agents
may also precipitate torsade de pointes when administered with the non-sedating
antihistaminics (again ketoconazole is the most prominent, although the
others may pose a danger for arrhythmias).
Allylamines -- One antifungal in this chemical class is used systemically
for fungal infections.
Topical Use of Antifungals
Mechanism of Action -- Terbinafine inhibits the fungal enzyme squalene
2, 3 epoxidase, which ultimately decreases the synthesis of ergosterol,
thus structurally and functionally compromising the fungal cell membrane.
Like griseofulvin, it is also keratophilic, allowing distribution to infected
Spectrum -- Terbinafine is a broad spectrum antifungal agent.
However it is used primarily for the treatment of onychomycoses.
Adverse Effects -- The primary side effects of terbinafine is GI upset.
It does not inhibit human microsomal enzymes.
The mechanisms of action and anti-fungal spectra for the drugs below
are identical to those described above. Typically, systemic absorption
does not occur. Therefore the major side effects are associated with
their topical administration.
Oral thrush or candidiasis is an infection of the mouth and upper throat
by Candida albicans.
Nystatin -- Nystatin is poorly absorbed from the GI tract.
Mechanism of Action -- Nystatin works by a mechanism similar to that
Spectrum -- Similar to amphotericin
Adverse Effects -- When used as directed, nystatin is relatively side
effect free. The most frequently reported side effects are bad taste
and dry mouth (these are rare).
Imidazole/Triazole Antifungals -- Clotrimazole, butaconazole, miconazole
(available as a 3-day regimen), terconazole (3-day regimen), and tioconazole
Nystatin is also available for use in vaginal candidiasis.
Adverse Effects -- Vulvovaginal burning, irritation, itching.
Dermatological Infections -- Athlete's foot (tinea pedis), jock itch
(tinea cruris), barber's itch (tinea barberis), and scalp itch (tinea capitis)
are the most common infections treated with topical antifungals.
Imidazole/Triazole -- ketoconazole, miconazole, econazole, clotrimazole,
oxiconazole, and sulconazole.
Allylamine -- terbinafine, naftifine
Macromolecular -- nystatin and amphotericin
Tolnaftate -- The mechanism of action of tolnaftate is unknown.
It is presumed to interfere with membrane structure and function.
This is an older drug that is still effective in the treatment of some
fungal infections. However, some resistant strains have developed
to the efficacy of tolnaftate.
Older Topical Antifungals
Ophthalmic Fungal Infections
Undecylenic Acid -- The mechanism is unknown. It is not as effective
as the newer agents, due at least in part to resistant strains of fungi.
The drug is yellow and chronic use may stain the patient's skin.
Clioquinol (Iodochlorhydroxyquin) -- A derivative of chloroquine, this
drug works by a mechanism similar to chloroquine (inhibition of DNA structure/function).
It is also less effective than newer agents and may also stain the skin
yellow. It may also produce irritation at the application site.
Triacetin -- Fungistatic by an unknown mechanism.
Gentian Violet -- This dye is also fungistatic. Application will
cause temporary staining of the skin or clothes. If gentian violet
is applied to an area of ulceration, it may permanently stain the skin
Benzoic Acid (Often used with Salicylic Acid) -- The former is fungistatic
while the later has beneficial keratolytic effects.
Natamycin -- an antibiotic similar to the aminoglycosides. Natamycin
binds to the fungal membrane, compromising its structural and functional
integrity. It is relatively side effect free.
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