ANTIFUNGAL DRUGS

Paul M. L.
Department of Clinical Pharmacology
and Therapeutics
Faculty of Basic Clinical Sciences
College of Medical Sciences
University of Maiduguri
OBJECTIVES
• To understand the types and characteristics of fungal infections
(mycoses)
• To understand the pharmacological approaches used in treatment of
mycoses
 INTRODUCTION
• Antifungal drugs: agents used in the treatment of fungal infections (mycoses)
• Fungi characteristics
• Broad class of organisms (about 144,000 species)
• Commonest:
• Yeast (oval-shape): Candida spp & Cryptococcus (true yeasts), Pneumocystis, Dimorphics
• Molds (rod-like/filamentous): Aspergillus& Dermatophytes (true molds), Dimorphics
• Mushrooms
*Dimorphic fungi e.g Penicillium marneffei, Blastomyces, Histoplasma, Coccidioides,
Sporothrix
• Eukaryotes: have defined Nucleus & membrane-bound organelles
• Like bacteria, have rigid cell wall (chitin/N-acetylglucosamine& glucan)
• Like mammalian’s membranes, have sterols (lanosterol& ergosterol)
• Spores forming microbes
• Are saprophytic, commensals or parasitic
• Some are beneficial (saprophytes, biodegrading), others are pathogenic
• Infections: scalp, hair, skin, nails, mucus membranes and systemic
Fungal Infections
Characteristics
• Chronic
• Mostly opportunistic
• Heavy antibiotic use (esp. broad spectrum)
• Potent immunosuppressant drugs (e.g cytotoxic, steroids)
• Immunocompromised individuals (following organ transplant, HIV/TB patients)
• Use of indwelling catheters
Categories
• Superficial (dermatophytes)
• Systemic (blastomyces, histoplasma, paracoccidiodes, Coccidiodes,
sporothrix, penicillium)
Superficial fungal infections
• Affect outermost parts of the body& appendages
• Caused by dermatophytes
• Head/scalp (Tinea capitis)
• Foot (Tinea pedis/athlete’s foot)
• Skin (Tinea corporis/ring worm )
• Skin (Tinea Versiclor)
• Nails (Tinea unguium)
• Groin (Tinea cruris/jock itch)
• mucus membranes
• Oral/oesophageal (Candidiasis)
• Vulvovaginal (Candidiasis)
• Most common
• Easily spread by body contacts
• Conditions usually less severe
Systemic Fungal Infections
• Affect internal organs &deeper skin tissues (dermis, subcutaneous, muscles, fascia)
• Spread: inhaled spores (especially in immuncompromised), iatrogenic, body contacts
• Conditions: more severe
• Treatment: difficult and prolong
• Examples
• Blastomycosis
• Histoplasmosis
• Paracoccidiodes
• Coccidioidomycosis
• Cryptococcus
• Sporothrix
• Aspergillosis
• Penicillium marneffei
• Mnemonic to remember systemic mycoses
• Body heat Probably Changes ShAPe of dimorphic fungi
 Some Clinical Fungal Infections
Disease Causative organism Sites of infection

Tinea versicolor Melassia furfur Cutaneous/epidermis/dermis

Tinea pedis Trichophyton rubrum Cutaneous/foot
Candidiasis Candida albicans Cutaneous/mouth/vulvo
vaginal
Cryptococcosis Cryptococcus neoformans Systemic/respiratory/meninges
(severe case)
Coccidioidomycosis Coccidioides immitis Systemic/respiratory
Blastomycosis Blastomyces dermatitidis Systemic/respiratory/other
organs
Histoplasmosis Histoplasma capsulatum Systemic/respiratory
Aspergillosis Aspergillus fumigatus Systemic/respiratory
Sporotrichosis Sporothrix schenckii Cutaneous/systemic
CLASSIFICATION OF
ANTIFUNGAL DRUGS
Commonly classified based on
• Chemical class/nature
• Molecular target/Mechanisms
• Clinical uses

Chemical Classification
• Antibiotics
• Polyenes Macrolide e.g Ampotericin B, Nystatin, Natamycin, Hamycin
• Heterocyclic Benzofuran e.g Griseofulvin
• Azoles
• Imidazoles e.g Ketoconazole, Miconazole, Econazole, Clotrimazole
• Triazoles e.g Fluconazole, Itraconazole, Voriconazole
• Allylamines e.g Terbinafine, Naftifine
• Antimetabolites e.g 5-Flucytosine (5-FC)
• Echinocandins e.g Caspofungin, Micafungin
• Morpholines e.g Anorolfine
• Miscellaneous/others e.g Benzoic acid, Povidone Iodine, Talnaftate,
Sodium Thiosulfate
Antifungal Classification Based on Molecular Targets/Mechanisms
• Synthesis Pathway Inhibitors
• Lanosterol synthesis inhibitors: Allylamines e.g Terbinafine
• Ergosterol synthesis inhibitors: Azoles e.g Fluconazoles, Ketoconazole
Morpholines e.g Amorolfine
• Cell wall glucan synthesis inhibitors: Echinocandins e.g Caspofungin
• DNA/RNA synthesis Inhibitors: Antimetabolite e.g 5-Flucytosine

• Inhibitors of Cell division/Mitosis e.g Griseofulvin

• Disruption of Cell Membrane: Polyenes e.g Amphotericine B,

Nystatin
Antifungal Drugs Classification Based on Clinical Use
A. Systemic Antifungal Agents for Systemic Infections
i. Polyenes: Amphotericin B
ii. Azoles
• Imidazole: Ketoconazole, Miconazole
• Triazole: Fluconazole, Itraconazole, Voriconazole, Posaconazole, Ravuconazole
iii. Echinocandins: Caspofungin, Micafungin, Anidulafungin
iv. Antimetabolite: 5-Flucytosine, Nikkomycin

B. Systemic (oral) Antifungal Agents for Superficial Infections

v. Heterocylic benzofuran: Griseofulvin, Corticofunvin
vi. Allylamines: Terbinafine, Naftifine
Topical Antifungal Agents
i. Polyenes: Nystatin, Natamycin
ii. Azoles
i. Imidazoles: Ketoconazole, Miconazole, Econazole, Clotrimazole
iii. Allylamine: Terbinafine, Naftifine
iv. Miscellaneous: Tolnaftate, Povidone iodine, Sodium thiosulfate,
Benzoic acid, Gential violet, Salicylic acid
POLYENES
• First antibiotics (Macrolides) with potent antifungal activity
• Naturally derived from Streptomyces
• Structure
• Macrocyclic lactone ring (have ≥12 atoms)
• Polyenes: multiple conjugated double bonds
• Amphiphilic: have both hydrophilic (OH) & lipophilic groups (-COOH, NH2)
• Effect: Fungicidal (mostly)
• Members: Amphotericin B, Nystatin, Hamycin, Natamycin
AMPHOTERICIN B
• A polyene (heptaene) derived from Streptomyces nodosus in 1956
• Has an amphoteric property& water insoluble
• Effect: Fungicidal at high dose
• Main use: Treatment of life-threatening& invasive mycoses
(Gold standard)
• Renal toxicity limits its clinical use (liposomal formulation, a remedy)
• Formulations
• Conventional (1956): Amphotericin B deoxycholate (complexed with bile salts)
• Liposomal/non-conventional (1990s)
• Colloidal dispersion (ABCD, Amphotec®): simplest form
• Amp B + Cholestryl sufate (50:50)
• Amphotericin B liposomal complex (AmBisome®): Amp B + phopholipids +
chplesterol (50 mg: 350 mg)
Amphotericin B Spectrum
Has the broadest antifungal spectrum with effects on:
Aspergillus spp
Blastomyces dermatitidis
Candida spp (except C. lusitaniae)
Coccidioides immitis
Cryptococcus neoformans
Histoplasma capsulatum
Mucor spp
Paracoccidiodes braziliensis
Sporothrix schenkii
NB:
• Also Effective against protozoal infection leishmaniasis
• It is ineffective against Dermatophytes
• Resistance: Not common (associated with decreased ergosterol content)
Amphotericin B Mechanism of Action
The lipophilic side chain binds to fungal ergosterol, disrupts membrane
functions, creates intramembrane pores and causes leakages of ions (especially
potassium) and small molecules (e.g glucose). The resulting effect is fungicidal
(especially at high dose).

Resistance
• Rare but possible
• Naturally insensitive to drug: Dermatophytes
• Inherent resistance due to reduced membrane ergosterol& reduced drug
affinity
• Candida lusitaniae
• Aspergillus tereus
• Acquired resistance: mutants replace ergosterol with other precursor sterols
Pharmacokinetics
• Not absorbed orally
• Given by slow IV infusion (colloidal suspension) for systemic mycoses
• Binds to plasma protein, widely distributed to all tissues but poorly into CSF, eye, doesn’t
cross BBB
• Concentrates in liver and then slowly released
• Half life: 14 days
• ≥ 95% bio-transformed
• Excreted slowly via urine and bile (complete clearance ≥ 2 months)
• Dose adjustment not needed in hepatic but renal dysfunction
Side/Adverse effects
• Nephrotoxicity (main, hypokaleamia, renal tubular acidosis): reduced with liposomal
formulation, mannitol use or sodium loading
• Chills/fever (Premedication with Paracetamol 10mg/kg or corticosteroid is helpful)
• Thrombophlebitis (low dose 0.1mg/ml or heparin 500-1000 IU reduces incidence)
• Normocytic, normochromic anaemia (due to decrease erythrocyte production)
• Hyperpnea
Therapeutic Uses
Reserved for serious systemic mycoses:
• Candidiasis (systemic)
• Invasive aspergillosis
• Cryptococcal meningitis (initial treatment)
• Coccidioidomycosis
• Histoplasmosis (initial treatment)
• Mucocutaneous leishmaniasis
Topical uses
• mycotic corneal ulcers, keratitis, fungal arthritis and candidiasis
Doses
Conventional: 0.5 – 1 mg/kg/d (in 5% glucose infusion)
Liposomal: 3 – 5 mg/kg/d slow IV
NYSTATIN
• First polyene antifungal isolated from Streptomyces noursei (1949)
• Structurally, a tetraene
• Not absorbed orally or from other mucus membranes
• Use topically only owing to its high toxicity
• Uses: Intestinal, vaginal & cutaneous candidiasis
• Formulations: oral tablets, lozenge, suspension, suppositories
• Dose
• Infants (1 month to 2 years): 1-2mls qid
• Children and adults: 4-6mls qid
NB: 1ml contains 100,000 IU (20mg)
• Adverse effects: local irritation, nausea, diarrhea
• Resistance: rare
ANTIMETABOLITE
FLUCYTOSINE (5-FC)
Chemistry: a fluorinated cytosine (Pyrimidine) analogue
MOA
5-FC is converted (deaminated) to 5-FU (its active form) by cytosine deaminase (not
found in mammalian cell). The fungal membrane enzyme, cytosine permease then
actively accumulates 5-FU in the fungal cell which inhibits thymidylate synthetase and
DNA synthesis.

Effect: Fungistatic
Formulation: oral/IV
Dose: 50-150mg/kg/d po qid (250/500mg)
Antifungal Spectrum
Has a narrow spectrum
Susceptible organisms:
Crytococcus neoformans Candida albicans (few strains)
Aspergillus fumigatus chromoblastomyces spp (low effect)
Torula (candida utilis)

Clinical uses
Primarily used in combination (are synergistic) with amphotericin B (which increases cell
permeability to 5-FC) to treat cryptococcal meningitis& candidiasis
NB: it’s not used as the sole medication except in chromoblastomycosis (combination with
Itraconazole is even preferred)

Resistance: It’s common when drug is used singly (due to decrease enzyme or increase
cytosine synthesis)
AZOLES
• First introduced in the 1980s, the commonest antifungals today
• Also the largest antifungal class
• Less toxic and more tolerable than the polyenes
• Broader use: adm. orally, IV & topically
• Indication: superficial& systemic mycoses
• Effect: mostly fungistatic (could be fungicidal at higher doses)
• Resistance: common with candida
• Are teratogenic
Classification of Azoles
Imidazoles
• Older class, less efficacious (has one nitrogen atom in the azole ring)
Examples: Ketoconazole, Miconazole, Econazole, Clotrimazole

Triazoles
• Derivatives of imidazoles (have 3 nitrogen atoms in the azole ring)
• Have improved efficacy, better absorption and reduced toxicity
• First generation: Fluconazole and Itraconazole
• Broad spectrum: Yeast and molds
• Second generation: Voriconazole and Posaconazole
• Improved potency: 10-500 times
• Broader spectrum: yeast, molds, aspergillus spp
• More selective (for CYP 450 fungal enzyme)
• Better penetration into CNS
Mechanism of Action
• Azoles inhibit the enzyme, cytochrome P450 14-α demethylase (CYP 51A1) which
converts lanosterol to ergosterol required for fungal cell membrane synthesis

• The resulting effects are failure of ergosterol synthesis (an important fungal
membrane phospholipid) and accumulation of toxic 14-α methyl esters which
affects membrane fluidity and functions

• Azoles have more affinity (about 1000 times) for fungal CYP 450 than mammalian
• Triazoles have more specificity and potency than imidazoles

• Question: would you combine amphotericin B and Azole for synergistic action?
Spectrum of Antifungal Activity
• *Dermatophytes (trichophyton,epidermophyton, malassezia furfur,
microsporum)
• Candida spp (effective in mucocutaneous candidiasis)
• *Aspergillus spp (itraconazole, voriconazole more effective in vitro): resistant to
other azoles
• Blastomyces dermatitidis
• Crytococcus neoformans
• Histoplasma capsulatum
• Coccidioides spp
• Paracoccidioides brasiliensis
• Sporothrix schenckii
Resistance to Azoles
• Aspergillus species (sensitive to Voriconazole [most] and itraconazole)
• Instrinsic: Common to candida (non-albicans)
• E.g Candida lusitaniae

• Acquired
• mutation in 14-α demethylase gene (reduces drug-enzyme affinity)
• Azole efflux pumps (rare)
• Alteration in membrane lipid (ergosterol)
Pharmacokinetics
Doses
• Ketoconazole 200-400mg po daily
• Fluconazole: 200 mg/day, then 100mg daily (IV 100mg/ml)
• 150mg single dose for vaginal candidiasis
• Requires dose adjustment in renal disease
• Itraconozole: 200mg po daily for 3 days, then 100mg daily (upto 3 months).
It’s effective for aspergillosis (Voriconazole is preffered)
• Azoles not requiring dose adjustment in renal disease: Itraconazole, Ketoconazole

Question: why higher starting dose(s)?

Clinical Use
• Itraconazole
• Drug of choice in: histoplasmosis, blastomycosis, paracoccidiodomycosis, sporotrichosis
• Effective in AIDS related histoplasmosis
• Voriconazole
• Broad spectrum triazole, has deep CNS penetration
• Available in oral and IV formulatons
• Drug of choice in invasive aspergillosis (has replaced amphotericin B)
• Posaconazole
• Broad spectrum triazole with oral and IV formulations
• Antifungal effects include zygomycetes infections (only amphotericin B is equally
effective)
Adverse Effects
• Fluconazole has no antiandrogenic effect (doesn’t inhibit CYP enzymes
involved in androgens/steroid synthesis). However, it inhibits CYPs involved in
drug metabolism, raising toxic drug levels (e.g warfarin, cyclosporine,
phenytoin etc)
Pharmacokinetics
• Oral absorption: Good, >80%
• Widely distributed to all tissues including CNS and eye
• VoD: 42 litres
• T ½ : 4 hours (could increase to 200 hrs in renal failure)
• Renal excretion: 99% (require dose reduction in compromised kidneys)

Adverse effects
• Mild: headache, dizziness, confusion, nausea, vomiting, diarrhea, anorexia,
ulcerative colitis (rare), skin reashes
• Serious: Bone marrow depression, dose-related (8-13%), liver dysfunction (5-
10%), alopecia, peripheral neuritis
Contraindication: Pregnancy (teratogenicity)
HETEROCYCLIC BENZOFURANS
GRISEOFULVIN
Chemistry
An antibiotic derived from Penicillium griseofulvum
A benzofuran derivative
MOA
Inhibits growth of fungal cell (mitosis). This is achieved via the inhibition of
microtubule polymerization and disruption of mitotic spindle formation
Effect: Fungistatic
Formulation: Oral (for cutaneous mycosis)
Dose: 125-250mg/kg/d po as a single or divided doses for 4-12weeks (up to 12
months)
NB: Treatment may be continued until new healthy skin/nail replace diseased
ones
Antifungal Spectrum
Its given orally for superficial/cutaneous mycoses (for skin and nails)
Effective on dermatophytes only
Most common include:
Microsporum Epidermorphyton
Trichophyton
they have high affinity for keratinized tissues (skin, nails and hair)
NB: it’s ineffective against other fungi
Resistance: Uncommon
Pharmacokinetics
• It’s given orally. Oral absorption is poor but better with micro/ultra
fine particles or when taken with fatty food
• Drug concentrates in skin (binds to keratin)

Adverse effects:
• Hypersensitivity reactions: Urticaria, angioedema
• Photosensitive dermatitis
• GI disorders: nausea, vomiting
• Neurologic complications: headache, paraesthesia, altered sensorium.
ALLYLAMINES
• Newer class of antifungal drugs
Examples:
Terbinafine Naftifine Butenafine

MOA
Inhibits squalene epoxidase resulting in the accumulation of toxic squalene and
reduced membrane sterols (ergosterol)
*Drug is more selective for fungal squalene epoxidase than mammalian

Effect: Fungicidal (primarily), relapse rate is low

Antifungal Spectrum
Limited to dermatophytes

Clinical Uses
• Dermatophytosis of skin & nail.
• Non-fumigatous aspergillous
• It has synergistic potential with azoles against azole resistant candida
species
TERBINAFINE
Antifungal Spectrum
Given orally to treat ringworm (Tinea pedis, T. crurisor and T. corporis) or dermatophyte
infections of the nails (drug of choice in Onychomycosis)
Formulation: Oral and topical (1% cream/solution)
Dose: 250-500mg/kg po bd for 2-6weeks (may be used for longer durations in infections of the
nail bed
Preferred alternative to griseofulvin)
• Better absorbed& tolerated, more effective and requires shorter duration of treatment
Pharmacokinetics
• Well absorbed orally
• Binds plasma-protein (99%) and concentrates in corneum stratum (epidermis)
• T1/2: 17 hours
• Elimination: via hepatic metabolism, requires dose reduction in hepatic failure or when co-
administered with potent CYP 3A inhibitors (e.g HIV Protease inhibitors)
Drug interaction: Rifampicin increases its metabolism, requiring dose increase
Side effects: GI disturbances most common (nausea, diarrhoea), anorexia, rashes
Contraindication: Breastfeeding mother
ECHINOCANDINS
• Newest antifungal agents
• Well tolerated
• Examples
Caspofungin Micafungin Anidulafungin
MOA
Inhibits fungal glucan synthesis
Indication: Skin, hair and nail mycoses (requiring long treatment)
Formulations: Oral and IV
Indication: Aspergillus and most candida (including azole-resistant strain)
* second line medications after amphotericin B or azole treatment failure
Pharmacokinetics
• Absorption: about 50% absorbed orally (micronization and high fatty food aid oral absorption)
• Distribution: Mainly to keratinized tissues, negligible to other tissues
• T1/2: 24 hours
Adverse Effects: low incidence of GIT disturbances, headache , fatigue, blurred vision, vertigo, bone marrow
depression, hepatoxicity (rare), teratogenic in animals and allergic reactions
MORPHOLINES
Newer antifungals
Examples:
Amorolfine
MOA
Inhibits α14 reductase and α8-7 isomerase enzymes involved in
ergosterol synthesis
Effects: fungicidal
OTHER TOPICAL
ANTIFUNGAL
• These are fungistatic and used forAGENTS
dermatophytosis.
• Benzoic acid is used in combination with salicylic acid (Whitfield
ointment).
• Sodium thiosulfate is active against malassezia furfur
• Quinidochlor has weak antifungal and antibacterial activity and is also
used for mycosis barbae, seborrhoeic dermatitis, infected eczema,
furunculosis and pityriasis versicolor.
• Most topical antifungal drugs require 4 weeks of treatment. Infections
in some areas, particularly the spaces between toes and nails may
take up to 6 months for cure.