Antifungal Drugs

Drugs Used in the Treatment of
Fungal Infections
Infections due to fungi are usually confined
to the skin or mucous membranes:
local or superficial mycosis. However, in
immune deficiency states, internal organs
may also be affected: systemic or
deep mycosis.
Mycoses are most commonly due to
dermatophytes, which affect the skin,
hair, and nails following external infection.
Candida albicans, a yeast organism
normally found on body surfaces, may
cause infections of mucous membranes,
less frequently of the skin or internal organs
when natural defenses are impaired
(immunosuppression, or damage
of microflora by broad-spectrum antibiotics).
Imidazole derivatives inhibit ergosterol
synthesis. This steroid forms an
integral constituent of cytoplasmic
membranes of fungal cells, analogous to
cholesterol in animal plasma membranes.
Fungi exposed to imidazole derivatives
stop growing (fungistatic effect)
or die (fungicidal effect). The spectrum
of affected fungi is very broad. Because
they are poorly absorbed and
poorly tolerated systemically, most
imidazoles are suitable only for topical
use (clotrimazole, econazole oxiconazole,
isoconazole, bifonazole, etc.). Rarely, this
use may result in contact dermatitis. Miconazole
is given locally, or systemically
by short-term infusion (despite its poor
tolerability). Because it is well absorbed,
ketoconazole is available for oral administration.
Adverse effects are rare; however,
the possibility of fatal liver damage
should be noted. Remarkably, ketoconazole
may inhibit steroidogenesis
(gonadal and adrenocortical hormones).
Fluconazole and itraconazole are newer,
orally effective triazole derivatives. The
topically active allylamine naftidine
and the morpholine amorolfine also inhibit
ergosterol synthesis, albeit at another
step.
The polyene antibiotics, amphotericin
B and nystatin, are of bacterial
origin. They insert themselves into fungal
cell membranes (probably next to
ergosterol molecules) and cause formation
of hydrophilic channels. The resultant
increase in membrane permeability,
e.g., to K+ ions, accounts for the fungicidal
effect. Amphotericin B is active
against most organisms responsible for
systemic mycoses. Because of its poor
absorbability, it must be given by infusion,
which is, however, poorly tolerated
(chills, fever, CNS disturbances, impaired
renal function, phlebitis at the
infusion site). Applied topically to skin
or mucous membranes, amphotericin B
is useful in the treatment of candidal
mycosis. Because of the low rate of enteral
absorption, oral administration in
intestinal candidiasis can be considered
a topical treatment. Nystatin is used only
for topical therapy.
Flucytosine is converted in candida
fungi to 5-fluorouracil by the action of a
specific cytosine deaminase. As an antimetabolite,
this compound disrupts
DNA and RNA synthesis (p. 298), resulting
in a fungicidal effect. Given orally,
flucytosine is rapidly absorbed. It is well
tolerated and often combined with amphotericin
B to allow dose reduction of
the latter.
Griseofulvin originates from molds
and has activity only against dermatophytes.
Presumably, it acts as a spindle
poison to inhibit fungal mitosis. Although
targeted against local mycoses,
griseofulvin must be used systemically.
It is incorporated into newly formed
keratin. “Impregnated” in this manner,
keratin becomes unsuitable as a fungal
nutrient. The time required for the eradication
of dermatophytes corresponds
to the renewal period of skin, hair, or
nails. Griseofulvin may cause uncharacteristic
adverse effects. The need for
prolonged administration (several
months), the incidence of side effects,
and the availability of effective and safe
alternatives have rendered griseofulvin
therapeutically obsolete.