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Last edited: 7/8/2022

7. ANTIFUNGALS
Antifungals Medical Editors: Sarah and Donya

OUTLINE
I) MECHANISM OF ACTION II) CLINICAL USE III) ADVERSE EFFECTS IV) SUMMARY
(A) GRISEOFULVIN (A) CANDIDIASIS (A) AMPHOTERICIN B V) REVIEW QUESTIONS
(B) FLUCYTOSINE (B) ASPERGILLOSIS (B) TERBINAFINE
(C) CRYPTOCOCCUS (C) ECHINOCANDINS
VI) REFERENCES
(C) ECHINOCANDINS
(D) TERBINAFINE (D) BLASTO / HISTO/ COCCIDIO (D) AZOLES
(E) AZOLES (E) MUCORMYCOSIS (E) GRISEOFULVIN
(F) POLYENES (F) TINEA VERSICOLOR (F) FLUCYTOSINE
(G) DERMATOPHYTE INFECTIONS

I) MECHANISM OF ACTION
(A) GRISEOFULVIN (C) ECHINOCANDINS
● In the reproductive phase of fungi (cell division), the cell ● Drugs ending in (-fungin):
nucleus utilizes microtubules, which are essential o Micafungin
components that enable continuous and rapid growth. o Caspofungin
→ MoA: These microtubules, are the site of action for ● The polysaccharide beta (1,3)-glucan is a component of
griseofulvin the cell wall of fungi, and it is integral to the cell wall
→ The drug molecule binds onto the tubulin structure. It is generated by the enzyme beta (1,3)-
protein and inhibits it, therefore leading to glucan synthase.
decreased cell division.

(B) FLUCYTOSINE ● MoA: Echinocandins act by inhibiting this enzyme,

leading to:
● MoA: Flucytosine acts within the cell nucleus, where it → (↓) beta (1,3)-glucan
gets converted by C.D. (Cytosine deaminase) into 5-FU → (↓) Cell wall activity
(5-Fluorouracil) → (↓) Resistance to osmotic forces
→ 5-FU binds to specific components of the nucleic → Cell death by cell lysis
acids and inhibits them from being able to function
properly, therefore inhibiting DNA replication and
transcription

Figure 1. MoA of Griseofulvin and Flucytosine

Figure 2. Echinocandins inhibits beta (1,3)-glucan synthase
ultimately leading to cell death

(D) TERBINAFINE
● Ergosterol, which is a cholesterol-like molecule, is the most abundant sterol in the fungal cell membranes. It plays a role for the
stability of the cell membrane, and regulates permeability and fluidity.
o It is synthesized in a particular pathway: ● MoA: Terbinafine inhibits squalene epoxidase, ultimately
1. Squalene is converted by squalene inhibiting the production of ergosterol, which leads to
epoxidase to squalene epoxide decreased stabilization of the cell membrane, followed by
2. then it is converted into Lanosterol cell death.
3. Lanosterol is converted to Ergosterol

Figure 3. MoA of Terbinafine resulting in cell death.

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 (E) AZOLES
● In the last step of the production of Ergosterol, an enzyme ● The drug classes are classified as follows:
called CYP 450 14-alpha demethylase mediates the Azoles
conversion of Lanosterol to Ergosterol Triazoles Imidazoles
● MoA: they inhibit CYP 450 14-alpha demethylase
Voriconazole Miconazole
enzyme, thereby inhibiting the subsequent production of
Ergosterol, which leads to decreased stabilization of the Itraconazole Clotrimazole
cell membrane, followed by cell death. Isavuconazole Ketoconazole
Posaconazole
Fluconazole

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Figure 4. Azoles inhibit CYP 450 14-alpha demethylase leading to cell destabilization.

(F) POLYENES
● MoA: Polyene molecules have two surfaces:
o Lipophilic surface: which binds to the lipids
(ergosterol)
o Hydrophilic surface: which interacts with water and
water-soluble molecules.
→ This structure enables it to fit perfectly on the cell
membrane making a pore molecule in the membrane
→ This allows different types of ions to move in and
out of the fungal cell
→ Resulting in electrolyte imbalances
→ Ultimately, cell death by cell lysis
● Polyene drugs:
o Amphotericin-B Figure 5. Polyenes structures allow them to fit perfectly in the
cell membrane to create pores and destabilize the cell, leading
o Nystatin
to cell death

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II) CLINICAL USE
(A) CANDIDIASIS (B) ASPERGILLOSIS
Depending on where the infection is, different medications ● Mold infection
may be used Sites of Involvement
o Most commonly involve the lungs (Pulmonary
(1) Oropharyngeal
Aspergillosis)
Treatment ▪ Aspergilloma
● Nystatin
o Not IV, Super powerful if administered IV
o Suspension → Swish and swallow An aspergilloma is a fungus
ball composed of Aspergillus
● Clotrimazole hyphae, fibrin, mucus, and
o Lozenge cellular debris, constituting a
huge biofilm structure, found
within a pulmonary cavity.
[UpToDate]
Figure 6. Oropharyngeal and Figure 10.
Esophageal Candidiasis Aspergilloma
(2) Esophageal Treatment
→ May cause esophageal lesions ● 1st Voriconazole
● Isavuconazole
Treatment
● Echinocandins
● Fluconazole(PO)
● Amphotericin B (for severe or refractory cases. )
● Itraconazole (PO)
(C) CRYPTOCOCCUS
(3) Vulvovaginal
● Yeast
Treatment
● 1st Topical
Sites of Involvement
o Miconazole
o Lungs → Pulmonary Infection ( pneumonia),
o Clotrimazole
o Meningitis
● Fluconazole (PO)
● Flucytosine (PO)
Treatment
Figure 7. Vulvovaginal Candidiasis.
● Induction therapy( first 2 wks.)
o Amphotericin B + Flucytosine
(4) Intertriginous
● Maintenance therapy
● Moist sites of the body o Fluconazole
o axillary, Figure 11. Cryptococcus infection,
o anal-genital area lungs and CNS involvement.

(D) BLASTOMYCOSIS / HISTOPLASMOSIS /

Treatment COCCIDIOIDOMYCOSIS
● Nystatin ● Endemic Fungi
o Topical Sites of Involvement
o Lungs *B, *H, *C
Figure 8. Intertriginous Candidiasis.
o CNS (meningeal involvement) H, C
(5) Systemic /Invasive o Skin B, H
→ Most often associated with Candidemia o Bone lesions B, H
→ Primarily occurs in immunocompromised patients
(ex: HIV, Transplants, Severe DM,..)
→ Sites of Involvement
→ Endocarditis
→ UTI
→ Ocular Candidiasis

Treatment
● 1st Echinocandins
● Fluconazole (PO) Figure 12. Sites of involvement in Blastomycosis,
● Amphotericin B Histoplasmosis and coccidioidomycoses infections.

Treatment
● 1st Itraconazole
● Fluconazole
● Amphotericin B ( for Severe or refractory cases)

*B=Blastomycosis
*H=Histoplasmosis
*C= coccidioidomycosis

Figure 9. Systemic or Invasive Candidiasis.

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 (E) MUCORMYCOSIS (G) DERMATOPHYTE INFECTIONS
● Type of Mold ● Tinea infections
● Seen in DM, especially in DM patients with Ketoacidosis ● Superficial
Sites of Involvement o Mostly skin, hair, and nails
2) Rhino -orbital-cerebral infection Sites of Involvement
o All the sinuses become involved and spread to brain 4) Near the head (scalp hair) = Tinea capitis
tissues 5) Beard hair = Tinea barbae
o Black eschar (which results from necrosis of tissues 6) Actual body = Tinea corporis
after vascular invasion by the fungus)
o Epidermal dermatophyte infections in sites other than
o May need debridement feet, groin, face, or hand
3) Pulmonary infection 7) Near groin = Tinea cruris
8) Feet = athlete’s foot = Tinea pedis
9) Nails = Tinea unguium / Onychomycosis

Figure 13. Mucormycosis infections.

Treatment
● 1st Isavuconazole
● Amphotericin B ( only if there is a particular contradiction
with the first line medication )
● Debridement

(F) TINEA VERSICOLOR

● Common superficial fungal infection
● Is not a dermatophyte infections
Site of involvement
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o Mostly trunk and proximal upper proximities
→ Hypopigmented or Hyperpigmented lesions

Treatment
● Ketoconazole (Topical) - Preferred
● Miconazole (Topical )

Figure 15 . Dermatophyte Infections

Treatment
We can treat all with same medications
● Topical
o Miconazole
Figure 14. Tinea Versicolor superficial infection. o Clotrimazole
o Ketoconazole
● Oral
o Itraconazole
o Griseofulvin
o Terbinafine for toenail( sometimes Griseofulvin)

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III) ADVERSE EFFECTS
(A) AMPHOTERICIN B (D) AZOLES
= Amphoterrible! → The adverse effects are mostly seen with Triazoles that
are administered systemically
→ in specific cases, Ketoconazole can be administered PO
(1) Extremely Nephrotoxic
(1) Hepatotoxic
● monitor patients' renal function
●  LFTs → monitor LFTs
(2) Phlebitis
(2) CYP450 - inhibitors
● Inflammation and irritation of the
blood vessels ● Increase the concentration and
→ fever and chills during potency of other medications
infusion that metabolized by CYP450
o ex: dangerous in patients
(3) Anemia using Warfarin
● Suppress the bone marrow, →  Bleeding
particularly the formation of
(3) Gynecomastia
RBCs
● With Ketoconazole PO
(4)  Risk of Arrhythmias,
Torsade de points (4)  Risk of Arrhythmia
●  K+, Mg 2+ →  QT-I ● K+ →  QT-I
→ Torsade de points → Torsade de points
Figure 16. Side effects
of Amphotericin B. (5) Adrenal Insufficiency

(B) TERBINAFINE ● With Ketoconazole PO

→ involved in steroid
(1) Hepatotoxic production pathways
→ decreasing the body’s
●  LFTs → monitor LFTs
production of glucocorticoids
(2) Dysgeusia (cortisol, aldosterone)
● Change or loss of taste
Ketoconazole can be used
Figure 17. Side effects as an initial treatment of
of Terbinafine. hypercortisolism (Cushing’s
Syndrome)!
(C) ECHINOCANDINS
(1) Hepatotoxic
(6) Visual dysfunction
●  LFTs
→ monitor LFTs ● Mostly seen with Voriconazole
● Reversible
(2) Flushing Figure 19. Azole's
● Activate mast cells Side effects.
→ release of histamine
→ may cause histamine
response during infusion
→ vasodilation
→ flushing
Figure 18. Echinocandins'
side effects.

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 (E) GRISEOFULVIN (F) FLUCYTOSINE
(1) Hepatotoxic (1) Pancytopenia
o  LFTs → monitor ● Suppress the bone marrow
LFTs → inhibit the production of all
(2) CYP450 Inducers cell lines
→ WBCs
o Decrease the → RBCs
concentration and → Platelets
efficacy of the
medications that (2) Teratogenic
metabolized by CYP450
▪ ex: dangerous in patients using Warfarin Figure 20. Side effects of
→  clotting Flucytosine.

(3) Teratogenic
(4) Carcinogenic
(5) Disulfiram reaction
o Concomitant ethanol use may cause disulfiram reaction
▪ causes flushing, tachycardia, palpitations, nausea,
and vomiting

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IV) SUMMARY

Table 1 Summary of Antifungals Please Fill your Part TIA

Mechanisms of Action Clinical Uses Adverse Effects

● Invasive Candidiasis ● Nephrotoxicity
● Aspergillosis (severe or refractory) ● phlebitis
Act as a pore molecule which allows passage of ● Cryptococcus Infections (Induction Therapy) ● Anemia
Amphotericin B ions in and out of the cell leading to electrolyte ● Blastomycosis/ Histoplasmosis/ Coccidiodicomosis ● Arrhythmias
imabalance and eventual cell death (severe or refractory) ● Torsade de point
● Mucormycosis

Nystatins ● Oropharyngeal Candidiasis

● Intertriginious Candidasis

● Candidiasis ● Hepatotoxicity
● Aspergillosis ● CYP45 inhibitors
Inhibits CYP 450 14-alpha demethylase, which ● Cryptococcus ● Arrhythmias
converts Lanosterol to Ergosterol, thereby inhibiting → maintenance therapy ● Visual Dysfunction → Voriconazole
Azoles ● Blastomycosis/ Histoplasmosis/ Coccidiodicomosis ● Adrenal Insufficiency → Ketoconazole (po)
the end production of Ergosterol, which decreases
● Mucormycosis ● Gynecomastia → Ketoconazole (po)
cell membrane stabilization and leads to cell death ●
● Tinea Versicolor (Topical)
● Dermatophyte infections

Inhibits squalene epixodase, thereby inhibiting the Onychomycosis ● Hepatotoxicity

Terbinafine end production of Ergosterol, which decreases cell ● Dysgeusia
membrane stabilization and leads to cell death

Inhibit the Beta (1,3)-glucan synthase, inhibiting ● Invasive Candidiasis ● Hepatotoxicity

Echinocandins the glucan molecules that are important to the cell ● Aspergillosis ● Flushing (Activate Mast cell)
wall structure, which leads to cell death by cell lysis

● Dermatophyte infections ● Hepatotoxicity

● CYP450 inducers
Inhibits the microtubules, which are essential for
Griseofulvin ● Teratogenic
cell division ● Carcinogenic
● Disulfiram reaction ( if used with Ethanol)

Forms 5-FU which inhibits DNA replication and ● Vulvovaginal candidiasis ● Pancytopenia
Flucytosine ● Cryptococcus infection ● Teratogenic
transcription
→ Induction therapy with Amphotericin B

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 V) REVIEW QUESTIONS
1) Terbinafine inhibits which of the following enzymes?
a) CYP 450 14-alpha demethylase
b) Squalene Epixodase
c) Beta (1,3)-glucan synthase
d) Cytosine deaminase
2) Which of the following drugs get converted to 5-FU
and acts on the nucleic acids?
a) Griseofulvin
b) Flucytosine
c) Caspofungin
d) Clotrimazole
3) True or false? Echinocandins act by inhibiting the
action of microtubules:
a) True
b) False
4) Which of the following drug pairs have the same end
result, and that is the inhibition of the production of
Ergosterol?
a) Terbinafine and Amphotericin B
b) Micafungin and Nystatin
c) Clotrimazole and Terbinafine
d) Flucytosine and Fluconazole
5) In a patient with Aspergilloma, and acute liver failure,
which antifungal medication is preferred?
a) Voriconazole
b) Isavuconazole
c) Amphotericin B
d) Caspofungin
6) Which of the following is the side effect of
Terbinafine?
a) Fever
b) Taste and smell disturbances
c) Anemia
d) Torsade de Pointes
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7) Isavuconazole is the first-line medication in the
treatment of :
a) Histoplasmosis
b) Tinea corporis
c) Candidiasis
d) Mucormycosis
8) Which statement is not true?
a) Decreasing the amount of the body’s cortisol can be
seen in patients taking Ketoconazole cream.
b) Renal function should be monitored in patients using
Amphotericin B.
c) In Tinea Versicolor, the preferred treatment is
Ketoconazole Topical.
d) Griseofulvin is forbidden during pregnancy.
9) First-line treatment for invasive candidiasis is
a) Fluconazole
b) Amphotericin B
c) Micafungin
d) Flucytosine

VI) REFERENCES
● UpToDate 2022

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