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ANTIFUNGAL AGENTS SYSTEMIC ANTIFUNGAL AGENTS Systemic fungal infections

are a major cause of death in patients whose immune system is compromised due to
cancer or its chemotherapy, organ transplantation, or HIV-1 infection. Fungi also
commonly cause superficial infections of the skin and other soft tissue structures. Many
antifungal agents in clinical use are targeted at distinctive components of the fungal cell
membrane; others alter cell wall synthesis or nucleic acid synthesis (see Figure 48–1).
Amphotericin B Amphotericin B is the antifungal agent with the broadest spectrum of
activity and remains the drug of choice for the vast majority of life-threatening systemic
fungal infections. Amphotericin B is a heptaene macrolide; its amphoteric behavior results
from a carboxyl group on the main ring and a primary amino group on mycosamine that
confer aqueous solubility at pH extremes.

The role of lipid formulations of amphotericin B in fungal infections remains to be

determined. The risk of adverse effects such as nephrotoxicity is decreased by ~50% with
lipid formulations, but they cost 20–50 times more and may be associated with a greater
risk of febrile infusion reactions

ANTIFUNGAL ACTIVITY Amphotericin B has useful clinical activity against a broad

range of pathogenic fungi and against the protozoa, Leishmania braziliensis and Naegleria
fowleri, but has no antibacterial activity. The antifungal activity of amphotericin B depends
principally on binding the sterol ergosterol in the membrane of sensitive fungi. By virtue of
interaction with sterols, amphotericin forms pores that increase membrane permeability
and allow leakage of small molecules (Figure 48–1). ABSORPTION, DISTRIBUTION,
AND EXCRETION Gastrointestinal (GI) absorption of amphotericin B is negligible and
intravenous delivery is used. Amphotericin B in plasma is >90% bound to proteins. Drug
elimination apparently is unchanged in anephric patients and those on hemodialysis.
Hepatic or biliary disease has no known effect on drug metabolism in humans. The
terminal phase of elimination has a t1/2 of ~15 days. Concentrations of amphotericin B in
fluids from inflamed pleura, peritoneum, synovium, and aqueous humor are approximately
two thirds of plasma trough concentrations. Little amphotericin B penetrates into
cerebrospinal fluid (CSF), vitreous humor, or amniotic fluid.

THERAPEUTIC USES The usual dose of C-AMB is 0.5–0.6 mg/kg, administered in 5%

glucose over 4 hours. Candida esophagitis in adults responds to 0.15–0.2 mg/kg daily.
Rapidly progressive mucormycosis or invasive aspergillosis is treated with doses of 1–1.2
mg/kg daily until progression is arrested. Intrathecal infusion of amphotericin B (C-AMB)
is used in patients with meningitis caused by Coccidioides. Treatment is initiated with
0.05–0.1 mg and increased on a three-times-weekly schedule to 0.5 mg, as tolerated.
Therapy is then continued on a twice-weekly schedule. Amphotericin B is the treatment of
choice for mucormycosis and is used for initial treatment of cryptococcal meningitis,
severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis,
penicilliosis marneffei, and in patients not responding to azole therapy of invasive
aspergillosis, extracutaneous sporotrichosis, fusariosis, alternariosis, and trichosporonosis.
Amphotericin B is given once weekly to prevent relapse in patients with AIDS who have
been treated successfully for cryptococcosis or histoplasmosis. ABCD is approved for
patients with invasive aspergillosis who are not responding to or are unable to tolerate C
AMB. Ambisome is approved for empiric therapy of neutopenic patients not responding to
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appropriate antibacterial agents and for salvage therapy of aspergillosis, cryptococcosis,

and candidiasis. ABLC is approved for salvage therapy of deep mycoses.

Flucytosine is an antimetabolite whose spectrum of antigungal activity is considerably

more restricted than that of amphotericin B. Flucytosine is a fluorinated pyrimidine:
ANTIFUNGAL ACTIVITY Susceptible fungi deaminate flucytosine to 5-fluorouracil, a
potent antimetabolite (Figure 48–2). Fluorouracil is metabolized to 5-fluorouracil-ribose
monophosphate (5-FUMP) by the enzyme uracil phosphoribosyl transferase (UPRTase).
5-FUMP then is either incorporated into RNA (via synthesis of 5-fluorouridine triphosphate)
or metabolized to 5-fluoro-2ÿ-deoxyuridine-5ÿ- monophosphate (5-FdUMP), a potent
inhibitor of thymidylate synthetase that thus inhibits DNA synthesis. The selective action
of flucytosine is due to the relatively low level of cytosine deaminase in mammalian cells,
which prevents metabolism to fluorouracil. Resistance arising during therapy (secondary
resistance) is an important cause of therapeutic failure when flucytosine is used alone for
cryptococcosis and candidiasis; it can result from loss of the permease necessary for
cytosine transport or decreased activity of UPRTase or cytosine deaminase (Figure 48–
2).

THERAPEUTIC USES Flucytosine (ANCOBON) is clinically useful for Cryptococcus

neoformans, Candida spp., and chromoblastomycosis. It is given orally at 100 mg/kg/day,
in divided doses at 6-hour intervals and is used predominantly in combination with
amphotericin B. An all-oral regimen of flucytosine plus fluconazole has been advocated
for therapy of AIDS patients with cryptococcosis, but the combination has substantial GI
toxicity without evidence that flucytosine improves the outcome. The combination of
flucytosine with C-AMB runs the risk of substantial bone marrow suppression or colitis if
the flucytosine dose is not promptly adjusted downward if amphotericin B–induced
azotemia occurs. It is common practice in HIV-negative patients with cryptococcal
meningitis to begin with C-AMB or AMBISOME plus flucytosine and change to fluconazole
after the patient has improved.

Imidazoles and Triazoles The azole antifungals include the imidazoles and triazoles.
These drugs have the same spectrum of antifungal activity and share a common
mechanism by inhibiting fungal CYPs that are essential for ergosterol biosynthesis (Figure
48–1). Of the drugs available in the U.S., clotrimazole, miconazole, ketoconazole,
econazole, butoconazole, oxiconazole, sertaconazole, and sulconazole are imidazoles;
terconazole, itraconazole, fluconazole, and voriconazole are triazoles.

ANTIFUNGAL ACTIVITY Azoles are active against C. albicans, C. tropicalis, C.

parapsilosis, C. glabrata, C. neoformans, Blastomyces dermatitidis, Histoplasma
capsulatum, Coccidioides species, Paracoccidioides brasiliensis, and dermatophytes.
Aspergillus spp., Scedosporium apiospermum (Pseudallescheria boydii), Fusarium, and
Sporothrix schenckii are intermediate in susceptibility. C. krusei and the agents of
mucormycosis are resistant. Azoles inhibit 14-a-sterol demethylase, a microsomal CYP
that is essential for ergosterol biosynthesis (Figure 48–1). This results in the accumulation
of 14-a-methylsterols that disrupt the packing of acyl chains of phospholipids and impair
the functions of membrane-bound enzymes such as ATPase and those of the electron
transport system, resulting in inhibited fungal growth. Azole resistance has caused clinical
failure in patients with far-advanced HIV infection and oropharyngeal or esophageal
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candidiasis. The primary mechanism of resistance in C. albicans is accumulation of

mutations in the gene encoding 14-a-sterol demethylase; cross-resistance to all azoles
results.

Ketoconazole has been replaced by itraconazole for the treatment of all mycoses except
when cost is the primary determinant. Itraconazole lacks ketoconazole’s corticosteroid
suppression, while retaining most of its properties and expanding the antifungal spectrum.

Itraconazole This synthetic triazole is an equimolar racemic mixture of four

diastereoisomers.

THERAPEUTIC USES Oral itraconazole is the drug of choice for patients with indolent,
nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and C.
immitis and also is useful for indolent invasive aspergillosis outside the CNS, particularly
following initial therapy with amphotericin B. The intravenous formulation is approved for
the initial 2 weeks of therapy with blastomycosis, histoplasmosis, and indolent
aspergillosis, and for empirical therapy of febrile neutropenic patients not responding to
antibiotics and at high risk of fungal infections.
Fluconazole is a fluorinated bistriazole. THERAPEUTIC USES Candidiasis Fluconazole,
200 mg on the first day and then 100 mg daily for at least 2 weeks, is effective in
oropharyngeal candidiasis. Esophageal candidiasis responds to 100–200 mg/day, which
also is used to decrease candiduria in high-risk patients. A single dose of 150 mg is
effective in uncomplicated vaginal candidiasis. A dose of 400 mg daily decreases the
incidence of deep candidiasis in allogeneic bone marrow transplant recipients and is
useful in treating candidemia of immunocompetent patients. Fluconazole is not proven
to be effective treatment for deep candidiasis in profoundly neutropenic patients. Cryptococcosis
Fluconazole, 400 mg/day, is used for the initial 8 weeks in the treatment of cryptococcal
meningitis in patients with AIDS after the patient has been stabilized with intravenous
amphotericin B. Thereafter, the dose is decreased to 200 mg daily and continued
indefinitely. If the patient responds to HAART, maintains a CD4 count >200/mm3 for at
least 6 months, and has no meningeal symptoms, it is reasonable to discontinue
fluconazole as long as the CD4 count is maintained and CSF culture and cryptococcal
antigen are negative. For AIDS patients with cryptococcal meningitis and favorable
prognostic signs, initial therapy with 400 mg daily may be considered. Fluconazole 400
mg/day has been recommended as continuation therapy in non-AIDS patients with
cryptococcal meningitis who have responded to an initial course of C-AMB or AMBISOME
and for patients with pulmonary cryptococcosis. Other Mycoses Fluconazole is the drug
of choice for coccidioidal meningitis and is comparable to itraconazole for other forms of
coccidioidomycosis. Fluconazole is less active than itraconazole against histoplasmosis,
blastomycosis, sporotrichosis, and ringworm and neither prevents nor treats aspergillosis
or mucormycosis.

Voriconazole (VFEND; UK-109,495) is a triazole that is similar to fluconazole but has

increased activity and an expanded spectrum. THERAPEUTIC USES Voriconazole is
superior to C-AMB as primary therapy of invasive aspergillosis. Although not approved,
voriconazole has been used for the empirical therapy of neutropenic patients whose
fever did not respond to antibacterial therapy. Voriconazole is approved for use in
esophageal candidiasis and as salvage therapy in patients with P. boydii and Fusarium infections.
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CASPOFUNGIN (cancidas, MK-0991) is a water-soluble, lipopeptide synthesized from a

fermentation product called pneumocandin Bo. In susceptible yeasts, caspofungin causes
lysis.

Griseofulvin is fungistatic in vitro for various species of the dermatophytes.

MECHANISM OF ACTION Griseofulvin inhibits fungal mitosis, presumably disrupting
the mitotic spindle by interacting with polymerized microtubules. Griseofulvin also may
bind to a microtubule-associated protein.

THERAPEUTIC USES Readily treatable mycotic infections include those of the hair (tinea
capitis) caused by Microsporum canis, M. audouinii, Trichophyton schoenleinii, and T.
verrucosum; “ringworm” of the glabrous skin; tinea cruris and tinea corporis caused by M.
canis, T. rubrum, T. verrucosum, and Epidermophyton floccosum; and tinea of the hands
(T. rubrum and T. mentagrophytes) and beard (Trichophyton species). Griseofulvin also is
effective in “athlete’s foot” or epidermophytosis involving the skin and nails, the vesicular
form of which is most commonly due to T. mentagrophytes and the hyperkeratotic type to
T. rubrum. Topical therapy is preferred. T. rubrum and T. mentagrophytes infections may
require higher-than-conventional doses. Since very high doses of griseofulvin are
carcinogenic and teratogenic in animals, it should not be used systemically to treat trivial
infections that respond to topical therapy. Griseofulvin is not effective in treatment of
subcutaneous or deep mycoses.

Imidazoles and Triazoles for Topical Use Indications for topical use include ringworm,
tinea versicolor, and mucocutaneous candidiasis. Resistance to imidazoles or triazoles is
very rare among the fungi that cause ringworm. Agents for topical use should be selected
based on cost and availability

Clotrimazole is available as a 1% cream, lotion, and solution (LOTRIMIN, MYCELEX,

others), 1% or 2% vaginal cream or vaginal tablets of 100, 200, or 500 mg (GYNE
LOTRIMIN, MYCELEX-G, others), and 10-mg troches (MYCELEX, others).

Econazole is the deschloro derivative of miconazole. Econazole readily penetrates the

stratum corneum and achieves effective concentrations down to the mid-dermis. Less
than 1% of an applied dose is absorbed into the blood. Approximately 3% of recipients
have local erythema, burning, stinging, or itching. Econazole nitrate (SPECTAZOLE,
others) is available as a water-miscible cream (1%) to be applied twice a day.

THERAPEUTIC USES Miconazole nitrate is available as an ointment, cream, solution,

spray, or powder (MICATIN, MONISTATDERM, others). To avoid maceration, only the
lotion should be applied to intertriginous areas. It is available as a 2% and 4% vaginal
cream, and as 100-mg, 200-mg, or 1200-mg vaginal suppositories (MONISTAT 7,
MONISTAT 3, others), to be applied at bedtime for 7, 3, or 1 day(s), respectively. In the
treatment of tinea pedis, tinea cruris, and tinea versicolor, the cure rate is >90%. In the
treatment of vulvovaginal candidiasis, the cure rate after 1 month is ~80–95%. Pruritus
sometimes is relieved after a single application. Some vaginal infections caused by C.
glabrata also respond.
Terconazole and Butoconazole Its mechanism of action is similar to that of the
imidazoles. The 80-mg vaginal suppository is inserted at bedtime for 3 days, while the
0.4% vaginal cream is used for 7 days and the 0.8% cream for 3 days. Clinical efficacy and
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patient acceptance of both preparations are at least as good as for clotrimazole in

patients with vaginal candidiasis. Butoconazole, an imidazole, is pharmacologically quite
comparable to clotrimazole. Butoconazole nitrate (MYCELEX 3, others) is available as a
2% vaginal cream. Because of the slower response during pregnancy, a 6-day course is
recommended (during the second and third trimester).

Tioconazole Tioconazole (VAGISTAT 1, others) is an imidazole that is marketed for

treatment of Candida vulvovaginitis. A single 4.6-g dose of ointment (300 mg) is given at
bedtime. Oxiconazole, Sulconazole, and Sertaconazole These imidazole derivatives are
used for the topical treatment of infections caused by the common pathogenic
dermatophytes.

Oxiconazole nitrate (OXISTAT) is available as a cream and lotion; sulconazole nitrate

(EXELDERM) as a solution and cream, and sertaconazole (ERTACZO) as a 2% cream.

Ciclopirox olamine (LOPROX) has broad-spectrum antifungal activity. It is fungicidal to

C. albicans, E. floccosum, M. canis, T. mentagrophytes, and T. rubrum. It also inhibits
the growth of Malassezia furfur. After application to the skin, it penetrates through the
epidermis into the dermis, but even under occlusion.

Haloprogin is a halogenated phenolic ether. It is fungicidal to Epidermophyton,

Pityrosporum, Microsporum, Trichophyton, and Candida. Irritation, pruritus, burning
sensations, vesiculation, increased maceration, and “sensitization” (or exacerbation of
the lesion) occasionally occur, especially on the foot if occlusive footgear is worn.
Haloprogin is poorly absorbed through the skin, and systemic toxicity from topical application is low.

Tolnaftate is a thiocarbamate. It is effective for most cutaneous mycoses caused by T.

rubrum, T. mentagrophytes, T. tonsurans, E. floccosum, M. canis, M. audouinii, M.
gypseum, and M. furfur but is ineffective against Candida. In tinea pedis, the cure rate is
~80%, compared with ~95% for miconazole. Toxic or allergic reactions to tolnaftate have
not been reported. Tolnaftate (AFTATE, TINACTIN, others) is available in a 1%
concentration as a cream, gel, powder, aerosol powder, and topical solution, or as a
topical aerosol liquid. Pruritus is usually relieved in 24–72 hours. Involution of interdigital
lesions caused by susceptible fungi is often complete in 7–21 days.

Naftifine is representative of the allylamine drugs that inhibit squalene-2,3-epoxidase

and thus inhibit ergosterol biosynthesis. The drug has broad-spectrum fungicidal activity.
Naftifine hydrochloride (NAFTIN) is available as a 1% cream or gel. Applied twice daily,
it is effective for the topical treatment of tinea cruris and tinea corporis. The drug is well
tolerated, although local irritation and contact dermatitis have occurred. Naftifine also
may be efficacious off label for cutaneous candidiasis and tinea versicolor.

Terbinafine 1% cream or spray is applied twice daily and is effective in tinea corporis,
tinea cruris, and tinea pedis. Terbinafine is less active against Candida species and M.
furfur, but the cream also can be used in cutaneous candidiasis and tinea versicolor. Oral
terbinafine apparently is effective in treatment of ringworm and in some cases of
onychomycosis.
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Butenafine hydrochloride (MENTAX) is a benzylamine derivative with a mechanism of

action and spectrum of antifungal activity similar to those of terbinafine, naftifine, and
other allylamines.

Polyene Antifungal Antibiotics

NYSTATIN is a tetraene macrolide that is structurally similar to amphotericin B and has

the same mechanism of action. Nystatin is not absorbed from the GI tract, skin, or vagina.
Nystatin (MYCOSTATIN, NILSTAT, others) is used only for candidiasis and is supplied in
preparations intended for cutaneous, vaginal, or oral administration for this purpose.
Infections of the nails and hyperkeratinized or crusted skin lesions do not respond. Topical
preparations include ointments, creams, and powders, each containing 100,000 units per
gram. Powders are preferred for moist lesions and are applied two or three times a day.
Imadazoles or triazoles are more effective agents than nystatin for vaginal candidiasis.
An oral suspension that contains 100,000 units per mL of nystatin is given four times a day.
Premature and low-birth-weight neonates should receive 1 mL of this preparation, infants
2 mL, and children or adults 4–6 mL per dose. Older children and adults should be
instructed to swish the drug around the mouth and then swallow. Nystatin suspension is
usually effective for oral candidiasis of the immunocompetent host. Other than the bitter
taste and occasional complaints of nausea, adverse effects are uncommon. A 200,000-
unit troche (mycostatin pastilles) is available for the treatment of oral candidiasis, and a
500,000-unit oral tablet is sold for the treatment of nonesophageal membrane GI
candidiasis.

AMPHOTERICIN B Topical amphotericin B (FUNGIZONE) also is used for cutaneous

candidiasis. A lotion, cream, and ointment are marketed that contain 3% amphotericin B
and are applied to the lesion 2–4 times daily.

Miscellaneous Antifungal Agents UNDECYLENIC ACID is 10-undecenoic acid. The

drug is fungistatic against a variety of fungi, including those that cause ringworm.
Undecylenic acid (DESENEX, others) is available in a foam, ointment, cream, powder,
spray powder, soap, and liquid. Zinc undecylenate is marketed in combination with other
ingredients. The zinc provides an astringent action that aids in the suppression of
inflammation. Compound undecylenic acid ointment contains both undecylenic acid (~5%)
and zinc undecylenate (~20%). Calcium undecylenate (CALDESENE, CRUEX) is
available as a powder. Undecylenic acid preparations are used in the treatment of various
dermatomycoses, especially tinea pedis. Concentrations of the acid as high as 10%, as
well as those of the acid and salt in the compound ointment, may be applied to the skin.
The preparations usually are not irritating to tissue, and sensitization is uncommon. In
tinea pedis, the infection frequently persists despite intensive treatment and the clinical
“cure” rate is at best ~50%. Other agents therefore are preferred. Undecylenic acid
preparations also are approved for use in the treatment of diaper rash, tinea cruris, and
other minor dermatological conditions.