ANTIFUNGAL

AGENTS
Halia Wanadiatri, dr., M.Si.
FUNGAL INFECTIONS
• Difficult to diagnose & eradicate; slow onset
• In devitalized/avascular tissues; long duration of tx.
• Opportunistic or primary; systemic or local
• Symptoms vary cosmetic to life threatening
• Type of mycoses:
• SUPERFICIAL
• Dermatophytes/Onychomycoses:
• Keratin layer of skin, hair, nail
• Candidiasis:
• Stratum corneum/squamous mucosa/cornea
• SYSTEMIC
• Internal organs: lung, heart, brain, urinary tract, bone
ANTIFUNGAL
• Fungi = eukaryotic
with unique cell walls (glucans & chitin)

• Host ~ Fungi (metabolic pahways)

ANTIFUNGAL AGENTS
SYSTEMIC TOPICAL
(Deep Mycoses) (Superficial Mycoses)

POLYENE Amphotericin B (+ Flucytosine) Nystatin

IMIDAZOLE Ketoconazole/ Clotrima/ Micona/ Econa/ Butocona/ Tiocona/

Oxicona/ Sulcona/ Sertaconazole

TRIAZOLE - fluconazole/ itraconazole/ Terconazole

Voriconazole
- Posaconazole “o”

ECHINOCANDIN Caspofungin/ Anidulafungin/ Micafungin “iv”

ALLYLAMINE/ Terbinafine “o”/ Naftifine/ Butenafine
BENZYLAMINE
Griseofulvin “o”
AMPHOTERICIN B
• Amphotericin A and B are antifungal antibiotics produced by
Streptomyces nodosus. Amphotericin A is not in clinical use.
• Broadest spectrum of action
• Tx: yeasts (Candida albicans and Cryptococcus neoformans);
the organisms causing endemic mycoses, (Histoplasma
capsulatum, Blastomyces dermatitidis, and Coccidioides
immitis); and the pathogenic molds (Aspergillus fumigatus and
mucor).
• It is nearly insoluble in water  colloidal suspension.
• A: poorly absorbed GI, effective for mycoses of GIT
• Systemic infections: slow iv, infusion
• CNS infections: intrathecal
• Corneal ulcers & keratitis: drops & intraocular injection
• Arthritis: local injection
• Candiduria: bladder irrigation
• D: poorly crossing BBB
• E: excreted slowly in urine, over a period of several days
Adverse Effects
• INFUSION-RELATED TOXICITY
• fever, chills, muscle spasms, vomiting, headache, and
hypotension. Premidication.
• CUMULATIVE TOXICITY
• Azotemia (80%)
• Nephrotoxic: dose-dependent, transient↑: concurremt therapy
w/ nephrotoxic agents (aminoglycosides, cyclosporine)
• Renal tubular acidosis & renal wasting of K+ & Mg2+  during &
several weeks after tx.
• Hypochromic, normoccytic anemia (> 2 w after tx): anemia ~
production of erythropoietin ↓
LIPOSOMAL PREPARATIONS
• Binding to human cell membrane ↓  renal toxicity↓
• Infusion-relates reaction are not consistently reduce

• Fungizone (conventional): colloid amp-B (C-AMB)

• Amphotec: amph-B colloidal dispersion (ABCD)
• Ambisome: liposomal amph-B (L-AMB)
• abelcet: amph-B lipid complex (ABLC)
FLUCYTOSINE
• Syntetic pyrimidine antimetabolite (cytotoxic drug)
• The spectrum of activity of flucytosine is restricted to
Cryptococcus neoformans, some candida species, and the
dematiaceous molds that cause chromoblastomycosis
• Narrow-spectrum
• Well absorbed orally
• Widely distributed (CSF)
• T ½ is 3-6 h
• AE:
• Bone marrow supression  leukopenia
• Rash, diarrhea, severe enterocolitis, hepatic enzim ↑
AZOLES

• The antifungal activity of azole drugs results

from the reduction of ergosterol synthesis by
inhibition of fungal cytochrome P450 enzymes
Ketoconazole
• Replaced by itraconazole (except: cost↓)
• Inhibits adrenocortical steroids & testosterone synthesis. Dose ↑:
gynecomastia, impotence, sperm counts ↓, diminished libido,
irregular menses
• For Cushing’s syndrome (inhibit excessive production of
glucocorticoids)
Itraconazole
• Like other lipid-soluble azoles, it interacts with hepatic microsomal
enzymes, though to a lesser degree than ketoconazole
• DI: reduced bioavailability of itraconazole when taken with rifamycins
(rifampin, rifabutin, rifapentine)
• While itraconazole displays potent antifungal activity, effectiveness can be
limited by reduced bioavailability.
• Newer formulations, including an oral liquid and an intravenous
preparation, have utilized cyclodextran as a carrier molecule to enhance
solubility and bioavailability.
• Tx (dosage: 100-400 mg/d):
• dimorphic fungi histoplasma, blastomyces, and sporothrix.
• Aspergillus sp, but it has been replaced by voriconazole as the azole of
choice for aspergillosis.
• dermatophytoses and onychomycosis.
Fluconazole
• Po, iv (dosage = 100-800 mg/d)
• high degree of water solubility and good CSF penetration.
• oral bioav is high. Bioav is unaltered by food/gastric acidity
• DI <<  fewer hepatic enzyme interactions & better GI tolerance 
the widest therapeutic index of the azoles, permitting more
aggressive dosing in a variety of fungal infections.
• Tx & secondary prophylaxis of cryptococcal meningitis. Tx
mucocutaneous candidiasis.
• Prolonged maintenance tx (reversible alopecia!)
• Prophylactic: bone marrow transplant recipients and AIDS patients,
but the emergence of fluconazole-resistant fungi!
Voriconazole
• newest triazole (USA).
• Po, iv. (dosage is 400 mg/d). ~ itraconazole in its spectrum of
action: Candida sp (fluconazole-resistant species such as C krusei)
• Voriconazole << toxic than amphotericin B: invasive aspergillosis
• A: well absorbed orally (biov 90%), and it exhibits less protein
binding than itraconazole.
• M: hepatic, but the propensity for inhibition of mammalian P450
appears to be low.
• AE:
• Rash, elevated hepatic enzymes.
• Visual disturbances (30%).
• Photosensitivity dermatitis is commonly observed in patients
receiving chronic oral therapy
ECHINOCANDINS
• Caspofungin, micafungin, and anidulafungin
• These agents are active against both candida and aspergillus,
but not Cryptococcus neoformans
• Echinocandins act at the level of the fungal cell wall by
inhibiting the synthesis of β(1–3) glucan disruption of the
fungal cell wall and cell death
• IV.
• Caspofungin: single loading dose of 70 mg, daily dose of 50 mg.
• Caspofungin is water-soluble and highly protein-bound.
• T ½ = 9–11 hours
• I: disseminated and mucocutaneous candida infections, invasive aspergillosis (failed to
respond to amphotericin B)
• E: kidneys & GIT. Dosage adjustments are required only in the presence of severe hepatic
insufficiency.
• AE: +cyclosporine  Elevated liver enzymes
• Micafungin~ Caspofungin.
• T ½ = 11–15 hours.
• mucocutaneous candidiasis, prophylaxis of candida infections in bone marrow transplant
• Tx dose 150 mg/d, prophylaxis 50 mg/d.
• AE: increase levels of nifedipine, cyclosporine, and sirolimus.
• Anidulafungin
• T ½ = 24–48 hours.
• esophageal candidiasis and invasive candidiasis (septicemia)
• esophageal candidiasis, iv 100 mg on the first day & 50 mg/d thereafter for 14 days.
• systemic candidemia, a loading dose of 200 mg, 100 mg/d thereafter for at least 14 days
after the last positive blood culture.
• AE: histamine release may occur during IV infusion
SYSTEMIC ANTIFUNGAL DRUGS FOR
MUCOCUTANEOUS INFECTIONS
GRISEOFULVIN
• Fungistatic
• Better absorption when it is given with fatty foods
• Griseofulvin's mechanism of action at the cellular level is unclear, but it
is deposited in newly forming skin where it binds to keratin, protecting
the skin from new infection.  deposited in keratin precursor cells.
• Micro-sized/ultra-micro-sized powders for better biov.
• Dosage: 4 x 500-1000mg
• 1 mo for scalp & hair ringworm
• 6-9 mo for fingernails
• At least a year for toenails.
• AE: allergic syndrome much like serum sickness, hepatitis, and drug
interactions with warfarin and phenobarbital.
• Griseofulvin has been largely replaced by newer antifungal medications
such as itraconazole and terbinafine.
TERBINAFINE
• synthetic allylamine
• Fungicidal. Po. Well absorbed, biov (40%) due to first-pass
metab.
• T ½ : 12 h but extends to 200-4– h at steady state.
• inhibits the fungal enzyme squalene epoxidase
• Onychomycosis: 1 x 250 mg/d, 6-12 w. (90%)
• AE: well tolerated, (GI distress, headache).
• CI: azotemia, hepatic failure
• Topical:
• Terbinafine: 1% cream/spray; twice daily
TOPICAL ANTIFUNGAL
THERAPY
NYSTATIN
• polyene macrolide~amphotericin B.
• IV >>> toxic. Po, topical.
• creams, ointments, suppositories.
• It is not absorbed to a significant degree from skin, mucous
membranes, GIT.
• unpleasant taste
• > candida sp. oropharyngeal thrush, vaginal candidiasis, and
intertriginous candidal infections.
TOPICAL AZOLES
• clotrimazole and miconazole.
• Both are available over-the-counter and are often used for
vulvovaginal candidiasis.
• Oral clotrimazole troches Tx oral thrush and are a pleasant-
tasting alternative to nystatin.
• cream  dermatophytic infections (tinea corporis, tinea pedis,
and tinea cruris)
• Absorption is negligible, AE are rare.
• Topical and shampoo forms of ketoconazole  seborrheic
dermatitis and pityriasis versicolor.
SUPERFICIAL MYCOSES
TOPICAL ORAL
Candidiasis vulvovagina Nystatin/clotrimazole Itraconazole
tab/ miconazole supp/
azole cream (once daily,
3-7 d; at bedtime)
Candidiasis Nystatin/clotrimzole
oropharingeal troche (5 times a day,
14d)
Candidiasis cutaneous Nystatin/azole topical
(bid, 3-6 weeks)
Ring worm/ - allylamine/benzylami Griseofulvin/ terbinafine
dermatophytes/ ne topical oral/ itraconazole
onchomycoses - Azole topical
- Ciclopirox/haloprogin/
tolnafte
TERIMA KASIH
&
SELAMAT BELAJAR