ANTIFUNGAL DRUGS

PHARM 514

Douglas Black, Pharm.D.

Associate Professor
School of Pharmacy
University of Washington
dblack@u.washington.edu
 THESE CATEGORIES ARE A CONVENIENT WAY TO
ORGANIZE THE KINGDOM OF FUNGI IN YOUR HEAD

Yeasts Dimorphic fungi Molds

Candida* Blastomyces Aspergillus

Cryptococcus Coccidioides Fusarium

Trichosporon Histoplasma Rhizopus

Sporothrix Mucor

Absidia

Pseudallescheria
(Scedosporium)

*C. albicans, C. tropicalis, C. glabrata

= Zygomycetes
are common species
WE SEE ALL OF THESE SPECIES OF
CANDIDA EVERY YEAR

C. albicans
C. tropicalis
C. parapsilosis
C. kefyr
C. glabrata
C. krusei
C. guillermondii
C. lusitaniae
DRUG CLASS YR APPROVED
Nystatin Polyene 1954
Amphotericin B deoxycholate Polyene 1958
Griseofulvin Inhibitor of mitosis 1959
Miconazole, clotrimazole Imidazole 1969
Flucytosine Substituted pyrimidine 1972
Ketoconazole Imidazole 1981
Fluconazole Triazole 1990
Itraconazole (capsules) Triazole 1992
Terbinafine (topical) Allylamine 1993
Terbinafine (oral) Allylamine 1996
Amphotericin B lipid complex Polyene 1996
Liposomal amphotericin B Polyene 1997
Itraconazole (oral solution) Triazole 1997
Caspofungin Echinocandin 2001
Voriconazole Triazole 2002
Micafungin Echinocandin 2004
MOST OF OUR ANTIFUNGAL DRUGS HAVE AN
ONGOING LOVE AFFAIR WITH ERGOSTEROL

NOTE: voriconazole probably inhibits additional pathways

THE AZOLE ANTIFUNGALS MAKE ORAL TREATMENT
OF SERIOUS FUNGAL INFECTIONS POSSIBLE

Four systemic drugs:

Ketoconazole (Nizoral) … obsolete
Fluconazole (Diflucan) … now generic
Itraconazole (Sporanox) … almost obsolete
Voriconazole (Vfend) … doing great

Generally considered fungistatic

Many topical azoles are available to treat vulvovaginal candidiasis

(VVC); there are few clinically significant differences among
these products.

All topical azole antifungals are considered safe in pregnancy, but

the systemic drugs should be avoided.
 FLUCONAZOLE IS PRETTY GOOD AND
IT IS NOW DIRT CHEAP

• An effective drug for yeast (Candida); not useful for molds

• Resistance is becoming a problem in some situations
• Oral, IV (1:1 dosing conversion)
• Excellent pharmacokinetics, easy-to-use drug
– good absorption, unaffected by gastric pH
– half-life 20-30 hours
– eliminated by the kidneys
• One of the least toxic antifungals we have
• Drug interactions (inhibition of metabolism) are of minor
significance unless the dose is escalated
• Pregnancy category C (animal data shows toxicity, human
studies inadequate, benefit outweighs risk)
• Really cheap: 400 mg IV $11.30, 400 mg PO $0.94
 VORICONAZOLE IS SO AWESOME WE ARE
WILLING TO PUT UP WITH ITS CRAP

• An enormously successful drug that is active against many

molds (e.g. Aspergillus) and yeast. The big hole is the class of
fungi known as the Zygomycetes.
• Oral, IV (not a simple conversion)
• Lousy pharmacokinetics
– half-life only 6 hours
– nonlinear
– wide interpatient variability (e.g. 15-20% of Asians are
expected to be slow metabolizers)
• Significant drug interactions (CYP2C19 substrate, inhibitor
of CYP3A4)
• Unusual side effect: visual disturbances in 8-44% of patients
• Pregnancy category D (evidence of human risk, but benefits
may outweigh)
• Expensive: 400 mg IV $200, 200 mg PO $33
ONYCHOMYCOSIS IS A CHALLENGE TO TREAT

• Pathogen: Trichophyton rubrum

• Griseofulvin was DOC for
decades (lots of ADR, took a
year of therapy at least)
• Best drug now is oral
terbinafine (Lamisil)
– good nail distribution
– not active vs Candida,
otherwise better than
itraconazole
– dose 250 mg po qd (6 wks
for fingers, 12 wks for toes)
– ADR: HA, GI, rash, LFT
abnormalities
– the only oral antifungal to
be category B
 YOU CAN TRY TERBINAFINE FOR THAT NAIL
INFECTION, BUT DON’T EXPECT MIRACLES

• Terbinafine (Lamisil): drug of choice for onychomycosis (tinea

unguium), usually caused by Trichophyton rubrum (not
effective for Candida)
• Highly lipophilic, well concentrated in skin, fat, nails
• More effective than itraconazole (Sporanox), and much more
effective than the nail lacquer Penlac. Far from 100%
effective, however.
• Serious (but rare) hepatotoxicity has been reported; avoid
terbinafine in patients with chronic or active liver disease.
Liver function tests should be monitored.
• 250 mg po qd x6 weeks for fingernails, x12 weeks for toenails
• Pregnancy category B (the only oral antifungal with this
rating)
SOPHIE WANTS TO KNOW IF YOU HAVE ANY
QUESTIONS.