Antifungal Drugs

Chairunnisa Tawadhu Rizal

Pengampu : Yeva Rosana, Dr. dr. M.S., Sp.MK(K)
 Antifungal Target

Plasma membran
• Polyenes
• Azole
• Allylamine

Cell wall
• echinocandin

Nucleic acid synthesis

• Pyrimidine

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Plasma Membrane Antifungal Target

• Membran sitoplasma (sel) sel eukariotik adalah

bilayer fosfolipid khas di mana molekul protein
tertanam yang bertindak sebagai penghalang
selektif permeabel untuk pengangkutan molekul
hidrofilik masuk dan keluar dari sel jamur
• Selain fosfolipid, membran eukariotik juga
mengandung sterol dari berbagai jenis. Ergosterol
adalah sterol utama yang ditemukan di membran
jamur
• Ergosterol sangat penting untuk integritas dan
fungsi membran dengan mengatur fluiditas dan
asimetri nya.

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Site of action antifungal

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 Polyenes
(Amphotericine B, Nystatin)

Mechanisms of action :
• Bind directly to ergosterol and form ionic transmembrane
channels, cause an increase in membrane permeability that
leads leakage of intacelullar contents, including potassium,
and eventual cell death.
• Interfere with membrane associated oxidative enzyme
function
• AmB stimulates release of cytokines suxh as tumor necrosis
factor and interleukin-1 from mammalian phagocytic cells
• AmB stimulates release of macrophage superoxide ion Mechanisms of action of amphotericin B.

• Amphotericin B is considered to be fungicidal against most

fungi
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Amphotericine B
• The polyenes (amphotericine B, nystatine)
are large (26-28 molecule carbon)
macrolide structure with many hydroxyl
group
• Amphotericin B is derived from a
fermentation product of Streptomyces
nodosus

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• Amphotericin B also binds to cholesterol, the main membrane sterol of
mammalian cells, but does so less avidly than to ergosterol  toxicity to
humans
• The lipid formulations of amphotericin B offer an improved efficacy-to-toxicity
profile

1. liposomal amphotericin B (AmBisome)

drug is encapsulated in small phospholipid containing liposomes
2. amphotericin B lipid complex (ABLC)
drug is complexed with phospholipids to form much larger ribbon-like
structures
3. amphotericin B colloidal dispersion (ABCD)
drug is complexed with cholesterol sulphate to form small lipid discs

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Mode of administration
Parenteral administration :

reconstituted with
Diluted with 5%
Lyophilized form sterile water (for
dextrose solution
injection)

 To avoid precipitation, AmBisome, ABLC and ABCD must not be reconstituted or diluted with saline and
should not be mixed with other drugs.
 Existing lines must be flushed with 5% dextrose solution prior to the infusion or, if this is not feasible, a
separate line should be used.

Gradual In patients who are not immunocompromised or

escalation suffering a serious lifethreatening infection
Initial dose
Rapid In immunosuppressed patients and others with a
escalation serious infection Your Logo or Name Here 9
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 Therapeutic use
Amphotericine B

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Liposomal amphotericin B

Amphotericin B colloidal dispersion

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Amphotericin B lipid complex

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Nystatin

Nystatin is used only topically or orally to treat candidiasis of the skin and
mucous membranes, but it is not useful for subcutaneous or systemic fungal
infections or for ringworm.

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 Azole
Mechanisms of action :
• Interact with cytochrome P450 (CYP) – dependent 14α –
demethylase, which catalyze the demethylation of ergosterol
precursors, cause depletion of ergosterol and the
accumulation of sterol precursors, including 14α – methylated
sterol (lanasterol, 14-dimethyl lanasterol, and 24-
methylenedihydrolanasterol)
• The inhibition results in the formation of a plasma membrane
with diminished structural integrity and altered function
• Depending on the organism and specific azole, inhibition of
ergosterol synthesis results in inhibition of fungal cell growth
(fungistatic) or cell death (fungicidal)
• All azoles act much more slowly than polyenes. Thus they are
used less often than polyenes in treatment fulminating fungal
infections.
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• The azole class of antifungals may be divided in
terms of structure into the imidazoles (two
nitrogens in the azole ring) and the triazoles (three
nitrogens in the azole ring)
• Imidazole : ketoconazole
• Triazole : fluconazole, itraconazole, voriconazole,
and posaconazole

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Ketoconazole

• Orally absorbed, lipophilic member of the imidazole class of antifungal agents

• Spectrum of activity includes the endemic dimorphic pathogens, Candida spp., C.
neoformans, and Malassezia spp
• Highly (>99%) protein bound, it penetrates poorly into the central nervous system.
• Ketoconazole may cause serious adverse effects, including gastric and hepatic
toxicity, nausea, vomiting, and rash. At high doses, significant endocrine side effects
have been observed secondary to suppression of testosterone and cortisol levels.
• A second-line agent for the treatment of non–life-threatening, nonmeningeal forms
of histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis in
immunocompetent individuals. Similarly, it may be used in the treatment of
mucocutaneous candidiasis and lymphocutaneous sporotrichosis.
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Fluconazole
• first-generation triazole with excellent oral bioavailability and low toxicity.
• low toxicity, ease of administration, and fungistatic activity against most yeastlike
fungi, fluconazole has an important role in the treatment of candidiasis,
cryptococcosis, and coccidioidomycosis.
• Used as primary therapy for candidemia and mucosal candidiasis and as prophylaxis
in selected high-risk populations.
• Maintenance therapy of cryptococcal meningitis in patients with acquired
immunodeficiency syndrome (AIDS)
• Agent of choice in the treatment of meningitis caused by C. Immitis
• A second-line agent in the treatment of histoplasmosis, blastomycosis, and
sporotrichosis.
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Itraconazole
• is a lipophilic triazole that may be administered orally in capsule or in solution.
• a broad spectrum of antifungal activity, including against Candida spp., C. neoformans, Aspergillus
spp., dermatophytes, dematiaceous molds, P. boydii, Sporothrix schenckii, and the endemic
dimorphic pathogens
• highly protein bound and exhibits fungistatic activity against yeastlike fungi and fungicidal activity
against Aspergillus spp.
• often used in the treatment of dermatophytic infections and is the treatment of choice for
lymphocutaneous sporotrichosis and non–life-threatening, nonmeningeal forms of histoplasmosis,
blastomycosis, and paracoccidioidomycosis.
• a second-line agent for the treatment of invasive aspergillosis; however, it is not useful in the
treatment of infections caused by Fusarium spp., the Mucormycetes, or S. prolificans.
• In contrast to fluconazole, drug interactions are common with itraconazole. Severe hepatotoxicity is
rare, and other side effects, such as gastrointestinal intolerance, hypokalemia, edema, rash, and
elevated transaminases, occur infrequently.

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Voriconazole
• a new broad-spectrum triazole with activity against Candida spp., C. neoformans, Trichosporon spp., Aspergillus
spp., Fusarium spp., dematiaceous fungi, and the endemic dimorphic pathogens
• exhibits fungistatic activity against yeastlike fungi and is fungicidal against Aspergillus spp  a primary indication for
the treatment of invasive aspergillosis

Posaconazole
• triazole derivative with a chemical structure similar to itraconazole.
• demonstrates potent activity against Candida, Cryptococcus, dimorphic fungi, and filamentous fungi, including
Aspergillus as well as the Mucormycetes.
• exhibits fungistatic activity against yeastlike fungi and is fungicidal against Aspergillus spp.
• prophylaxis of invasive fungal infection in hematopoietic stem cell transplant (HSCT) recipients with graft-versus-
host disease (GVHD) and patients with hematologic malignancies and prolonged neutropenia, oropharyngeal
candidiasis.
• approved for the following fungal infections refractory to amphotericin B and/or itraconazole: aspergillosis,
fusariosis, chromoblastomycosis, mycetoma, and coccidioidomycosis. Your Logo or Name Here 21

.
 Clotrimazole and
Ketokonazole Itraconazole
Fluconazole miconazole
(oral, topical) (oral)
(topical)
• Cutaneous mycoses • selected patients for • infections in the skin, • fungal infections of the
• Vaginal and oral AIDSrelated mycoses mouth, and vagina nails and systemic
candidiasis such as aspergillosis candidiasis
• Some systemic and cryptococcus
mycoses meningitis

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 Allylamines
• Inhibition of squalane epoxidase (enzyme involved in ergosterol biosynthesis) which results in a
decrease in ergosterol and an increase in squalene within the fungal cell membrane .
• Terbinafine is a lipophilic antifungal agent with a broad spectrum of activity that includes
dermatophytes, Candida spp., Malassezia furfur, C. neoformans, Trichosporon spp., Aspergillus
spp., S. schenckii, and P. marneffei
• It is available in oral and topical formulations and achieves high concentrations in fatty tissues,
skin, hair, and nails.
• Terbinafine is efficacious in the treatment of virtually all forms of dermatomycoses, including
onychomycosis, and exhibits few side effects. It has shown clinical effectiveness in the treatment
of sporotrichosis, aspergillosis, and chromoblastomycosis and has shown promise for the
treatment of infections caused by fluconazole-resistant Candida spp. when used in combination
with fluconazole.

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 Daftar Pustaka

1. Anaissie EJ, et al. Clinical Mycology. 2nd ed. 2009.

2. Murray PR, et al. Medical Microbiology. 7th ed. 2013
3. Talaro KP, et al. Foundation in Microbiology. 8th ed. 2012.
4. Richardson MD, et al. Fungal Infections, Diagnosis and Management. 3rd ed. 2003.

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Thank You