Page 874 - Basic _ Clinical Pharmacology ( PDFDrive )

860 SECTION VIII Chemotherapeutic Drugs

Anidulafungin has a half-life of 24–48 hours. For esophageal nail and is often followed by relapse. Adverse effects include an
candidiasis, it is administered intravenously at 100 mg on the first allergic syndrome much like serum sickness, serious skin reac-
day and 50 mg/d thereafter for 14 days. For candidemia, a loading tions, a lupus-like syndrome, hepatotoxicity, and drug interactions
dose of 200 mg is recommended with 100 mg/d thereafter for at with warfarin and phenobarbital. Griseofulvin has been largely
least 14 days after the last positive blood culture. replaced by newer antifungal medications such as itraconazole
and terbinafine.
Mechanism of Action
Echinocandins act at the level of the fungal cell wall by inhibit- TERBINAFINE
ing the synthesis of β(1–3)-glucan (Figure 48–1). This results in Terbinafine is a synthetic allylamine that is available in an oral
disruption of the fungal cell wall and cell death. formulation and is used at a dosage of 250 mg/d. It is used in
the treatment of dermatophytoses, especially onychomycosis
Clinical Uses & Adverse Effects (see Chapter 61). Like griseofulvin, terbinafine is a keratophilic

Caspofungin is currently licensed for disseminated and muco- medication, but unlike griseofulvin, it is fungicidal. Like the
cutaneous candidal infections, as well as for empiric antifungal azole drugs, it interferes with ergosterol biosynthesis, but rather
therapy during febrile neutropenia, and has largely replaced than interacting with the P450 system, terbinafine inhibits the
amphotericin B for the latter indication. Of note, caspofungin is fungal enzyme squalene epoxidase (Figure 48–1). This leads to
licensed for use in invasive aspergillosis only as salvage therapy in the accumulation of the sterol squalene, which is toxic to the
patients who have failed to respond to amphotericin B, and not organism. One 250-mg tablet given daily for 12 weeks achieves
as primary therapy. Micafungin is licensed for mucocutaneous a cure rate of up to 90% for onychomycosis and is more effec-
candidiasis, candidemia, and prophylaxis of candidal infections in tive than griseofulvin or itraconazole. Adverse effects are rare,
bone marrow transplant patients. Anidulafungin is approved for consisting primarily of gastrointestinal upset and headache, but
use in esophageal candidiasis and invasive candidiasis, including serious hepatotoxicity has been reported. Terbinafine does not
candidemia. seem to affect the P450 system and has demonstrated no signifi-
Echinocandin agents are extremely well tolerated, with minor cant drug interactions to date.
gastrointestinal side effects and flushing reported infrequently.
Elevated liver enzymes have been noted in several patients receiv-
ing caspofungin in combination with cyclosporine, and this ■ TOPICAL ANTIFUNGAL
combination should be avoided. Micafungin has been shown to THERAPY
increase levels of nifedipine, cyclosporine, and sirolimus. Anidu-
lafungin does not seem to have significant drug interactions, but NYSTATIN
histamine release may occur during intravenous infusion. Clini-
cally significant echinocandin resistance is an emerging concern Nystatin is a polyene macrolide much like amphotericin B. It
especially with invasive Candida glabrata infections in immuno- is too toxic for parenteral administration and is only used topi-
compromised patients. cally. Nystatin is currently available in creams, ointments, sup-
positories, and other forms for application to skin and mucous
membranes. It is not absorbed to a significant degree from skin,
■ ORAL SYSTEMIC ANTIFUNGAL mucous membranes, or the gastrointestinal tract. As a result,
DRUGS FOR MUCOCUTANEOUS nystatin has little toxicity, although oral use is often limited by
the unpleasant taste.
INFECTIONS Nystatin is active against most Candida sp and is most com-
monly used for suppression of local candidal infections. Some
GRISEOFULVIN common indications include oropharyngeal thrush, vaginal can-
didiasis, and intertriginous candidal infections.
Griseofulvin is a very insoluble fungistatic drug derived from a
species of penicillium. Its only use is in the systemic treatment of TOPICAL AZOLES
dermatophytosis (see Chapter 61). It is administered in a micro-
crystalline oral form at a dosage of up to 1 g/d. Absorption is The two azoles most commonly used topically are clotrimazole
improved when it is given with fatty foods. Griseofulvin’s mecha- and miconazole; several others are available (see Preparations
nism of action at the cellular level is unclear, but it is deposited in Available). Both are available over the counter and are often
newly forming skin where it binds to keratin, protecting the skin used for vulvovaginal candidiasis. Oral clotrimazole troches are
from new infection. Because its action is to prevent infection of available for treatment of oral thrush and are a pleasant-tasting
these new skin structures, griseofulvin must be administered for alternative to nystatin. In cream form, both agents are useful for
2–6 weeks for skin and hair infections to allow the replacement dermatophytic infections, including tinea corporis, tinea pedis,
of infected keratin by the resistant structures. Nail infections may and tinea cruris. Absorption is negligible, and adverse effects are
require therapy for months to allow regrowth of the new protected rare.