Chemotherapeutic Agents /Antimicrobial Drugs/

Antifungal Drugs

© 2022 Takele B Tufa, AAU-CVMA.

Learning Objectives
• Understand the general principles of Antifungal
therapy,
• Know the classification of Antifungal agents:
• as topical and systemic agents
• Know PK, MoA and clinical indications of different
Antifungal agents

© 2022 Takele B Tufa, AAU-CVMA.

 Overview

 Infectious D+s caused by fungi are called mycoses, & they are often chronic in
nature.

 Fungal organisms are characterized by a low invasiveness and virulence. Factors

that contribute to fungal infection include necrotic tissue, a moist environment
and immunosuppression.

 In animals, both the importance of fungal infections and opportunistic fungal

infections due to immunosuppression increase need for antifungal drugs.

 Some mycotic infections are superficial & some involve the skin tissues

 Systemic mycosis are difficult to be treated, often life threatening

 Fungi are eukaryotic, unlike bacteria

o Have rigid cell walls composed of chitin
o The cell m/m contains Ergosterol rather
© 2022 Takele Bthan cholesterol in mammalian cell m/m
Tufa, AAU-CVMA.
Overview
 Antifungal drug treatment is usually given for long period of time often because of
 the slow growth properties of fungus and
 most of the antifungal drugs are fungistatic rather than fungicidal.
 Long-term treatment is therefore useful to inhibit fungal growth and allow for the
animal’s immune system, which is often compromised, to eradicate the infection.
 e.g deep mycoses continued for months
 Sometimes, disease worsens in the first week of treatment, because of the host’s
inflammatory response to killed organisms. So additional use of anti- inflammatory
drug is important.

 Because both the antifungal target organism and the host cells are eukaryotic,
antifungal drugs tend to be more toxic than antibacterial drugs.
 Fungal infections are generally resistant to antibiotics used in the t/t of bacterial
infections
 Antifungal drugs can be used topically to treat skin, mucus m/m, or corneal
infections caused by fungus
 Common fungal infections include:
• Aspergillosis, Candida, Microsporium

© 2022 Takele B Tufa, AAU-CVMA.

Classification of Antifungal Agents
Azole groups:
• Triazoles (Systemic):
• Fluconzole, Itraconazole, Ketoconazole, etc
• Imidazoles(Topical):
• Clotrimazole, Econazole, Miconazole
Polyene Antibiotics:
• Amphotericin B (AMB), Nystatin, Natamycin, candicidin.
Flucytosine (5-FC) Antimetabolite:
Griseofulvin: Hetrocyclic Benzofuran
Allylamine: Terbinafine
Echinocandins
Other Topical Agents: Tolnaftate, povidone–iodine, Undecylenic Acid,
Benzoic Acid, Quiniodochlor, Ciclopirox, Olamine Sod. , Thiosulfate

© 2022 Takele B Tufa, AAU-CVMA.

Mechanism of actions

© 2022 Takele B Tufa, AAU-CVMA.

I. Azole Antifungals
MoA
 inhibit the synthesis of primary steroid of the fungal
cell m/m, ergosterol by blocking demethylation (14-
demethylase) of lanosterol –
 also inhibit cytochrome activity.
 Fungistatic at therapeutic dose

 Spectrum: broad against yeasts & filamentous fungi

(systemic fungi, dermatophytes)

 Resistance: may develop by

altered demethylase or
enhanced removal from the fungal cell

© 2022 Takele B Tufa, AAU-CVMA.

 Acetyl CoA

Squalene
Squalene Allylamine drugs
monooxygenase

Squalene-2,3 oxide

Lanosterol
14-a-demethylase Azoles

(ergosterol)

© 2022 Takele B Tufa, AAU-CVMA.

 Ketoconazole
 Use:
o blastomycosis, coccidioidomycosis, ringworm, candidiasis
o Affordable (low cost)
PK:
• given orally, acid environment is needed to dissolve drug,
• Best absorbed with food
• does not enter the CNS well (highly protein bound).
• Metabolized and has a half-life of 3-6 hrs.
• Mostly fecal excretion after metabolism.
ADR and DI
• Cats appear to be more sensitive
• Nausea, vomiting, Allergic rash, Hormone imbalance, Fluid retention,
Hepatitis
• Teratogenic
• Inhibits drug metabolism
• Absorption reduced by H2 antihistamines and omeprazole and antacids
© 2022 Takele B Tufa, AAU-CVMA.
 Itraconazole
• It is a triazoles of a broad antifungal spectrum
PK:
• variable absorption when given orally, approx. 30 hr. half-life.
• fecal and renal excretion after extensive metabolism
• hydroxyitraconazole - an active metabolite.
SE:
• Nausea, vomiting, Liver dysfunction, Hypokalemia,
Hypertriglyceridemia,
DDI: similar to ketoconazole but to lesser degree

Uses: Histoplasmosis, Sporotrichosis, Aspergillosis, Blastomycosis

Additional: Leishmania and Trypanosoma

© 2022 Takele B Tufa, AAU-CVMA.

 Fluconazole
• A triazole
• Not affect mammalian hormone synthesis

PK:
• Oral and IV based formulation
• Small molecular size and low lipophilic…> Well absorbed orally,
• Not highly protein bound, enters CNS
• t½ = 25 – 30 hours & excreted unchanged via kidney

SE:
• headache, N&V, rash, alopecia, rarely liver failure
• Least effect of all azoles on liver enzymes

Uses:
• Cryptococcal meningitis, candidiasis, coccidioidomycosis /Histoplasma &
Blastomyces/
© 2022 Takele B Tufa, AAU-CVMA.
Voriconazole
• Given iv and orally
• Similar to itraconazole in spectrum-broad
• Little interaction at CYP450
Use: Aspergillosis, fusarium

Posaconazole
• New drug

• Use: Invasive candidiasis, aspergillosis & Zygomycetes infections

• PK: Only orally available, Inhibits CYP3A4

• SE: GI effects, dizziness, cardiac arrhythmias, abnormal liver

function
© 2022 Takele B Tufa, AAU-CVMA.
Topical Azoles
• Clotrimazole
• Miconazole
• Econazole
• Oxiconazole
• Sertaconazole
• Terconazole
• Sulconazole
• Tioconazole
• Butoconazole

© 2022 Takele B Tufa, AAU-CVMA.

 II. Polyene Antibiotics
 A. Amphotericin B (Fungizone)
 Fungicidal antibiotic (produced by Streptomyces
nodusus)

 Used to treat serious systemic mycoses, fungal

septicemia or fungal UTI

 Chemical properties – amphoteric

 Aqueous insolubility at neutral pH

© 2022 Takele B Tufa, AAU-CVMA.

 Amphotericin B…cont’d
MoA

 It binds to fungal membrane sterols (ergosterol) and alters

permeability selectively to K+ and Mg2+  allows leakage of
electrolytes, resulting in cell death
 Resistance
o altered sterols or decreased sterols

Ergosterol
Ergosterol
with pore

+ a polyene

© 2022 Takele B Tufa, AAU-CVMA.

 Amphotericin B…cont’d
 PK
Poorly absorbed from the GIT
Highly plasma protein binding affinity: does not readily pass the
BBB
Route: i.v., topical and i.t. (t½ - 24 hours)
mostly metabolized and some is excreted by kidney
Affinity for amphotericin B
• Ergosterol > Lipid Formulation > Cholesterol
Use:
• Topical preparations may be used for the treatment of superficial
Candida infections

• Spectrum: Amphotericin B may be combined with flucytosine or

minocycline for treatment of Candida and Cryptococcus.

• Rifampin potentiates the effect of amphotericin on Aspergillus,

Candida, and Histoplasma.© 2022 Takele B Tufa, AAU-CVMA.
Amphotericin B…cont’d

Untoward effects
Hypersensitivity-anaphylaxis- hematologic
Fever, chills, headache, nausea, thrombophlebitis,
hemolytic anemia
Nephrotoxicity due to renal vsoconstriction, direct
tubular damage, reduced GFR (severity reduced with
sodium loading)
Hepatic damage
Toxicity is reduced by using liposomal preparation or dilute with
soya bean solution

© 2022 Takele B Tufa, AAU-CVMA.

 Polyenes…cont’d
 B. Nystatin and Natamycin
• Similar to amphotericin B
• used topically (for oral candida) and for GI use
• used against candida and dermatophytes
(Epidermophyton, Trichophyton, Microsporum).

• Natamycin: the only approved drug from ocular

fungal infection (fungal keratitis)

© 2022 Takele B Tufa, AAU-CVMA.

3. Flucytosine
MoA
Disrupt nucleic acid and protein synthesis
Fungistatic

Uses H
N O
• Systemic fungi, mainly candida, and
Cryptococcus.
• Used with N
• Amphotericin B (cryptococcal meningitis, candida) and F
• Itraconazole (chromoblastomyosis )

NH2

Flucytosine

© 2022 Takele B Tufa, AAU-CVMA.

 MOA of Flucytosine:

5-flucytosine permease 5-flucytosine

(outside) (inside)
Cytosine deaminase

5-Flurodeoxyuridylic acid
5-fluorouracil
Phosphoribosyl
(-) transferase
Thymidylate
dTMP synthase dUMP 5-FUMP

DNA RNA
 Flucytosine is taken up into the fungal cell by means of permease
 converted to 5-fluorouracil (5-FU) by cytosine deaminase
 5-FU eventually inhibits thymidylate synthase
 synthesized to 5-FUTP
 incorporated into© 2022
fungal RNA, disrupt NA and protein synthesis
Takele B Tufa, AAU-CVMA.
 Flucytosine…cont’d

PK
• Given orally
• T ½ ~ 3-6 hours
• Penetrates into CNS
• Excreted in urine-80% unchanged

Untoward effects
• Nausea, vomiting, colitis
• Bone marrow suppression, Thrombocytopenia, alopecia,
• Decreased liver function

 Resistance to flucytosine can develop quite rapidly, especially when it is

used alone against Cryptococcus.

© 2022 Takele B Tufa, AAU-CVMA.

4. Griseofulvin
• It is a heterocyclic benzofuran
• Is a systemic antifungal agent effective against the
common dermatophytes

MOA:
• Binds to microtubules comprising the spindles and inhibits
mitosis.
• Incorporates into keratin and protects newly formed skin.

• Fungistatic

© 2022 Takele B Tufa, AAU-CVMA.

Griseofulvin…cont’d

PK:
 used orally, not topically
 Microsize and ultramicrosize preparations are used.
 Metabolized, then renal excretion
 t½ ~ 24 hours
 Several weeks of therapy are needed.
 6X faster in dogs liver metabolism than humans
• CYP 450 inducer
• Increase absorption by high fatty foods

Untoward effects:
Nausea, headache, hepatoxicity, renal toxicity,
photosensitivity, hypersensitivity
possibly teratogenic: CI in pregnancy
 Induces metabolism of some other drugs

© 2022 Takele B Tufa, AAU-CVMA.

 5. Allylamines
• Used to treat dermatophyte infections
• Fungicidal, human prepn
• MoA:
• Inhibit squalene epoxidase, resulting in blocking ergosterol
biosynthesis
Terbinafine N

• Used orally for dermatophytes

• Metabolized then excreted in urine
• Rare SE: hepatitis and rashes.
Terbinafine

Naftifine, Amorolfine, and Butenafine

• For topical use

© 2022 Takele B Tufa, AAU-CVMA.

 MoA: Acetyl CoA
 Inhibit squalene-2,3-epoxidase

Squalene
Allylamines
Squalene epoxidase

Squalene-2,3 oxide

Lanosterol
14-a-demethylase Azoles

(ergosterol)

© 2022 Takele B Tufa, AAU-CVMA.

 6. Echinocandins
Caspofungin
• A large cyclic compound
• Inhibits 1,3-b-D-glucan synthase, which is required for
glucan polymerization in the wall of certain fungi
• Used for aspergillosis and candidiasis
• Used for empiric antifungal therapy
• This drug that may be synergistic with amphotericin B and the
azoles. It has activity against Candida species and Aspergillus
species
• SE: fever, histamine release, hypokalemia
Mycafungin & Anidulafungin
• Use: for candidiasis
• SE: effects are similar to caspofungin
.

© 2022 Takele B Tufa, AAU-CVMA.

 7. Other Drugs
• Ciclopirox olamine-
• may block amino acid transport -
• penetrates well –
• useful for candida and dermatophytes
• Haloprogin-
• useful for dermatophytes and candida,
• may cause burning
• Tolnaftate–
• useful for dermatophytes
• inhibits synthesis of macromolecules
• Undecylenic acid -
• dermatophytes
• KI –
• taken orally for cutaneous sporotrichosis –
• may cause a rash and irritation of salivary and lacrimal glands

© 2022 Takele B Tufa, AAU-CVMA.

 Iodides
• Systemic administration
• The antimicrobial mechanism of iodides is unknown but may result from enhancement of the
immune response of the host by prompting the halide–peroxide killing system of phagocytic cells.

• NaI and KI have both been used to treat selected bacterial like actinomycete and fungal
infections.

• Topical iodine:
• Povidone–iodine is an antiseptic agent effective against bacteria, fungi, viruses and protozoa.
• NaI has been used successfully to treat cutaneous and cutaneous/lymphadenitis
forms of sporotrichosis; attempts to control various other mycotic infections with
iodides yield equivocal results.
• Ketoconazole and sodium iodide administered together seem to have additive effects
against sporotrichosis.

• Clinical signs of iodinism include

• lacrimation, salivation, increased respiratory secretions, coughing, inappetence, dry scaly skin,
and tachycardia.

© 2022 Takele B Tufa, AAU-CVMA.

 Topical antifungal agents
That have been used with success include:
• Iodine prepn: tincture I2 & NaI
• Copper prepn: CuSO4
• Sulfur prepn: monosulfiram
• Organic acids: bezoic acid, salicylic acid
• Dyes: crystal violet, carbol fuchsin
• Nitrofurans: nitrofuroxine
• Imidazoles: miconazole, clotrimazole, etc
• Polylene antibiotics: AMB, nystatin, candicidin
• Miscellaneous: tolnfate, chlorhexidine

© 2022 Takele B Tufa, AAU-CVMA.

Summary of Treatments
Pathogen Primary Secondary

Aspergillus fumigatus Voriconazole, Posaconazole Itraconazole, aspofungin

AMB
Blastomyces dermatidis Itraconazole or AMB Fluconazole
Candida albicans Fluconazole, AMB, Caspofungin, Voriconazole, traconazole,
Posaconazole Anidulafungin Ketoconazole (topical )

Coccidioides immitis Itraconazole, Fluconazole or

Amphotericin B
Cryptococcus Amphotericin B ± Flucytosine Itraconazole or
neoformans followed by Fluconazole Amphotericin B
Histoplasma capsulatum Itraconazole or Amphotericin B Fluconazole

Mucomycosis Amphotericin B Posaconazole

Sporothrix schenckii Amphotericin B Itraconazole SSKI*

* Saturated solution of potassium iodide

© 2022 Takele B Tufa, AAU-CVMA.