A brief summary of antifungal agents.

1. ANTIFUNGALAGENTS
Done by:
Ohood Abd Al-Nabi
Amal Alkhreisat
Dana Allan
Supervisor: Prof. Amal Albakri
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2. Introduction
• What are Fungi and Mycosis?
About 0.2% of the fungi specie are known to be
pathogenic in animals but less than this number to humans.
The most pathogenic fungi: Aspergillus fumigatus and
Candida albicans.
Fungal infections are common in immunocomporomised
patients; AIDs patients.
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3. Mechanism of action of the Antifungal
agents
1. Plasma membrane synthesis inhibitors
2. Cell wall synthesis inhibitors.
 Membrane permeability inducers.
3. Synthesis of nucleic acids inhibition.
4. Microtubule ( Mitotic spindle ) inhibitors.
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4. An overview of the modes of action of
AFs.
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5. An overview of antifungals classes.
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6. Macrolide polyene antifungals
They act by alteration of Ergosterol or the lipid composition
in the cell membrane.
1- Nystatin: Is too toxic. So, it isn’t administered parentrally.
Can be used as a DOC to treat candidiasis (oropharangeal
thrush, vaginal candidiasis and intertriginous candidal
infections). Not absorbed topically and orally.
The most susceptible species is C. Albicans.
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7. Macrolide polyene antifungals
2- Amphptericin A&B
The only medically used is Amphotericin B. Administered
as an IV infusion.
Among the various species of Candida, C. albicans
remains the most susceptible to amphotericin B. Both C.
glabrata and C. krusei exhibit decreased susceptibility to
amphotericin B compared with C. albicans.
* The resistance is by if ergosterol binding is impaired that
occurs either by decreasing ergosterol concentration in the
membrane or by modifying the sterol target molecule. Thus
reducing Amphotericin B affinity.
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8. Amphptericin B
• It binds to a sterol (Ergosterol) in
fungal plasma membrane and some protozoa .
• Amphotericin B thus increases permeability of plasma
membrane & causes leak of glucose, potassium & other
substances from the cell.
• It is the DOC to treat most systemic fungal infections like
aspergillosis, coccidioidomycosis & cryptococcosis. Also
administered intrathecally to treat fungal meningitis.
• It has a poor GIT absorption so it is given IV. It has many
side effects some are severe like kidney damage,
depression, anemia & blindness.
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9. Azoles ( Triazoles & Imidazoles)
• The azole antifungals work primarily by inhibiting the
cytochrome P450-dependent enzyme lanosterol 14-alpha-
demethylase.
1- Triazoles:
-Fluconazole: has activity limited to yeasts
and some clinical activity against the
endemic fungi (Histoplasma, Blastomyces,
Coccidioides, andParacoccidioides spp). In general, it has
excellent activity against Candida species but has less
activity against C. glabrata and no activity against C. krusei. It
has excellent activity against Cryptococcus species.
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10. Triazoles.
--Itraconazole: has a broader spectrum of activity than
fluconazole, including endemic fungi, Sporothrix schenckii,
and Aspergillus species. It is also active against the
dematiaceous (brown-black) molds.
-Voriconazole: has enhanced activity against Aspergillus
species and other hyalohyphomycoses, (Scedosporium
apiospermum and Fusarium) species.
• DOC for fluconazole-resistant
C. glabrata and against C. krusei.
-Isavoconazole & Posaconazole :
To treat Mucorales while maintaining activity against yeasts
and molds.
-Terconazole.
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11. Azoles ( Triazoles & Imidazoles)
2- Imidazoles:
• Ketokonazole: is used for the treatment and prophylaxis
of oropharyngeal candidiasis in immunocompromised
patients undergoing chemotherapy, radiotherapy, or
steroid therapy utilized in the treatment of leukemia, solid
tumors, or renal transplantation.
• Miconazole : Treatment of oropharyngeal
candidiasis used topically, orally and IV.
• The only injectable azole.
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12. Imidazoles
• Ketoconazole: used in blastomycosis, histoplasmosis,
paracoccidioidomycosis, coccidioidomycosis, and
chromomycosis in patients who have failed or who are
intolerant to other antifungal therapies.
• Ketoconazole has an off-Label Cushing syndrome and
Prostate cancer.
• Oxiconazole
• Econazole
• Tioconazole
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13. 5-Fluorocytosine (5-FC)
• 5-FC with amphotericin B is recommended for the initial
management of severe cryptococcal pneumonia and
meningoencephalitis and, less frequently, for select
invasive candidal infections administered orally and
parentrally.
• Due to the high incidence of primary and/or acquired
resistance, use of flucytosine as monotherapy is
significantly restricted.
• Interferes with both DNA and protein synthesis.
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14. Mechanism of resistance of 5-FC
• Resistance to 5-FC can be intrinsic or acquired.
Intrinsic resistance is due to impaired cellular uptake
due to a mutation in cytosine permease.
• Acquired resistance results from defects in 5-FC
metabolism through mutations in cytosine deaminase or
uracil phosphoribosyl transferase and is thought to be a
result of either failure of the organism to metabolize the
agent or loss of pyrimidine biosynthesis feedback
control.
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15. Echinocandins
• MOA is through blocking the b-(1,3)-D-glucan synthesis
by binding to the Fks p subunit of the enzyme.  Osmotic
instability.
• Capsofungin, micafungin and anidulafungin are active
against mucocutaneous Candida and Aspergillus
infections and as an empiric antifungal therapy dutinf
febrile neutropenia.
• Administered IV for invasive candidiasis, especially in
critically ill and neutropenic patients .Active against
fluconazole-resistant C. glabrata and C. krusei. They have
a relatively low potential for renal or hepatic toxicity or
serious drug-drug interactions.
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16. Allylamines
• MOA: Inhibition of epoxidation of squalene (squalene
epoxidase) Selective toxicity to the fungus.
• Naftifine , Terbinafine and Tolnaftate.
• Used for the Tx of Dermatophytes that are filamentous
fungi in the genera Trichophyton, Microsporum, and
Epidermophyton. Dermatophytes metabolize and subsist
upon keratin in the skin, hair, and nails ,
Why? (Different Tinea infections).
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17. Griseofulvin
• MAO: Inhibits fungal cell mitosis at metaphase; binds to
human keratin making it resistant to fungal invasion.
• Dermatophyte infections: Treatment of the following
dermatophyte infections of the skin, hair, and nails not
adequately treated by topical therapy. Tx of Tinea
infection.
• Low solubility and many side effects. Administered as
microsize suspension.
• Although there have been reports of dermatophyte
resistance to Griseofulvin, the clinical significance is
unknown.
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18. Ending question
• What is Pneumocystis jirovecii (previously P. carinii)?
• What is the DOC?
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19. References
• Uptodate website.
• Katzung book.
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