Download most of our antifungal drugs have an ongoing love affair

ANTIFUNGAL DRUGS
PHARM 514
Douglas Black, Pharm.D.
Associate Professor
School of Pharmacy
University of Washington
[email protected]
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
are common species
= Zygomycetes
WE SEE ALL OF THESE SPECIES OF
CANDIDA EVERY YEAR
C.
C.
C.
C.
C.
C.
C.
C.
albicans
tropicalis
parapsilosis
kefyr
glabrata
krusei
guillermondii
lusitaniae
DRUG
CLASS
YR APPROVED
Nystatin
Polyene
1954
Amphotericin B deoxycholate
Polyene
1958
Inhibitor of mitosis
1959
Imidazole
1969
Substituted pyrimidine
1972
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
Anidulafungin
Echinocandin
2006
Posaconazole
Triazole
2006
Griseofulvin
Miconazole, clotrimazole
Flucytosine
Ketoconazole
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
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•
•
•
•
•
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.