Antifungal Drugs:

• These are drugs used to prevent growth and multiplication of fungi.
• Pathogenic fungi are eukaryotes possessing nuclei, mitochondria and cell membranes containing sterols.
• Fungal infections are hard to treat; slowly eradicated and more toxic to host.

Classification:

Depending on the chemical structure and clinical use, they are classified into following groups:

1. Antifungal antibiotics
2. Polyene antibiotics: Amphotericin B, nystatin, natamycin, hamycin and candicidin
3. Heterocyclic benzofurans: Griseofulvin
4. Antimetabolites: Flucytosine

• Azoles:

1. Imidazoles: Ketoconazole, Miconazole, Enilconazole, Tiabendazole, Clotrimazole, Econazole, Butoconazole, Oxiconazole, Sulconazole
2. Triazole: Fluconazole, Itraconazole, Voriconazole, Posaconazole, Terconazole
3. Allylamines: Terbinafine, Butenafine and Naftifine
4. Echinocandins: Capsofungin, Anidulafungin and Micafungin
5. Iodides: Sodium iodide and Potassium iodide

• Miscellaneous

1. Organic acid: Benzoic acid, Salicylic acid
2. Fatty acid and salts: Propionates, Undecylenate
3. Dyes: Gentian violate
4. Phenols and phenolic ethers: Phenol, Thymol, Haloprogin
5. Hydroxyquinolones: Coliquinol
6. Thiocarbamate: Tolnaftate
7. Sulphur and Sulphur preparations: Sulphur and Sulfiram
8. Copper preparations: Copper sulphate and Copper naphthenate
9. Others: Ciclopirox olamine, Selenium sulphide, Dichlorophon hexitidine, Tiacetin, Polynoxylin, Sodium thiosulphate, Benzoyl disulphide, Nitrofuroxine, Nitrofurfurylmethyl ether

Amphotericin B (AMB):

• It is amphoteric polyene antibiotic obtained from Streptomyces nodusus.
• It is prototype drug of polyene antibiotics group.

Chemistry:

• It is heptaene macrolide containing seven conjugated double bonds in trans position and 3-amino-3,6-dideoxymannose connected to main ring by glycosidic bond.
• One side of ring having conjugated double bonds is lipophilic and another group containing -OH group is hydrophilic. This structure provides amphoteric nature, so called amphotericin.

Mechanism of action:

AMB interacts with membrane ergosterol of fungi

Formation of channels or pores in cell membrane

Permeability of cell membrane alters, and cellular constituents leaks out

Altered K⁺/H⁺ exchange results in efflux of potassium and influx of H⁺ ions

Acidosis occurs which halts some enzymatic process

Inhibition of enzymatic process and loss of cellular ions, sugars, amino acids from fungal cell causes irreversible damage.

Antimicrobial spectrum:

• They have broad-spectrum antifungal activity.
• It is useful against systemic fungi including Candida, Histoplasma, Cryptococcus, Blastomyces, Coccidiodes, Aspergillus and Sporothrix

Fungal resistance:

• Resistance to amphotericin B is infrequent and rarely noted
• If occurs, it may be due to decreased ergosterol content in fungal cell membrane.

Pharmacokinetics:

• It is poorly absorbed from G.I tract, so used for G.I tract fungal infection
• After IV administration, it is unevenly distributed throughout body
• It fails to achieve therapeutic concentrations in CSF, vitreous humor and amniotic fluid
• Extensively bound to plasma lipoproteins.
• Elimination of drugs is complicated. It exhibits biphasic elimination with initial plasma half-lives of 24-48 hrs followed by a longer terminal half-live of about 15 days
• Low levels of drugs appear in urine over a long period of time and some is eliminated via bile.

Side effects/Adverse effects:

• Renal function impairment
• Altered electrolyte fluxes
• Metabolic acidosis
• Polyurial polydipsia
• Systemic administration results in anorexia, nausea, vomiting, anemia, cardiac arrhythmias, CNS signs, hepatic dysfunctions and thrombophlebitis at injection site.

Contraindications and precautions:

• In patients those are hypersensitive to amphotericin
• It should be used cautiously in renal insufficiency

Drug interactions:

• It may be combined with rifampicin, minocycline to produce synergistic effect
• Combination of amphotericin and miconazole produces antagonistic effect
• It should not be combined with aminoglycosides due to enhanced nephrotoxic effects
• It is also not recommended to combine with digitalis due to cardiotoxic effects.
• Combination with neuromuscular blockers produce enhanced skeletal muscle relaxation
• Combination with antineoplastic drugs produce enhanced cytotoxicity.

Clinical uses:

• It is mainly used in life-threatening systemic infection in dogs
• Usually diluted with 5% dextrose and administered IV
• It is occasionally used for cutaneous and mucocutaneous candidiasis.

Dose:

Conventional formulations

Dogs & cats: 0.1-0.5 mg/kg, IV infusion

Horses: 0.3 mg/kg, IV on day 1 followed by 3 consecutive days

Birds: 1.5 mg/kg, IV, 2-3 times daily for 3-7 days

Lipophilic formulations

Dogs: 3 mg/kg/day, IV infusion @ 60-120 min, 3 times weekly for upto 9-12 treatments

Cats: 1mg/kg, IV, 3 times per week upto 12 treatments

Griseofulvin:

• It is systemic antifungal antibiotic obtained from Penicillium griseofulvin
• It is used to treat fungal infections of skin and nails in both humans and animals by oral route

Mechanism of action:

Drug enters into fungi through energy-dependent transport system

It then interferes the polymerization of microtubular protein with microtubules

Interference in spindle formation in dividing cells thereby arresting metaphase

Production of multinucleate fungal cells and inhibition of hyphal cell wall synthesis

Antimicrobial spectrum:

• Narrow-spectrum antifungal agent active only against dermatophytes i.e. Microsporum, Trichophyton and Epidermophyton
• Produces its action against superficial fungi
• Ineffective against deep mycoses
• Fungistatic against older and dormant fungi and fungicidal against actively metabolizing and growing young cells

Fungal resistance:

• Resistance to griseofulvin is poor
• Resistance, if occurs may be mainly due to decreased drug uptake

Pharmacokinetics:

• Variably and erratically absorbed from G.I tract mainly due to poor solubility
• After absorption, it is concentrated in skin, hair, nails, fat, skeletal muscle and liver
• Metabolized in liver via oxidative demethylation and conjugation to inactive metabolites
• About ½ of drug is excreted in urine and other half excreted in faeces
• Plasma half-lives in dogs is about 24 hrs

Side effects/Adverse effects:

• Nausea, vomiting, diarrhoea
• Hepatotoxicity
• CNS signs such as depression, ataxia
• Neutropenia, leucopenia
• Teratogenic and carcinogenic effects in cats

Contraindications and precautions:

• In patients those are hypersensitive to it
• In patients with pre-existing hepatocellular insufficiency
• In pregnant animals
• Its use in cats should be monitored closely

Drug interactions:

• It is potent inducer of microsomal enzyme, so it promotes biotransformation of oral anticoagulants
• Phenobarbital and other barbiturates reduce the antifungal activity
• Combined use of griseofulvin and ketoconazole may lead to hepatotoxicity.

Clinical uses:

• It is primarily recommended for treatment of dermatophytic fungal infection of skin, hair & claws in dogs, cats, calves, horses

Dose:

Dogs & cats: 20-50mg/kg (microsize),PO, once daily or in 2-3 divided dose with fatty meal or corn oil

Cattle and horse: 5-10mg/kg, PO, once daily for 4-6 weeks

Sheep and goats: 10-20 mg/kg, PO, once daily

Swine: 20 mg/kg, PO, once daily for 6 weeks

Antimetabolites:

Flucytosine:

• Flucytosine/5-fluorocytosine is fluorinated pyrimidine antifungal agent
• It was originally synthesized as antineoplastic drug but later found to have good antifungal activity

Mechanism of action:

Flucytosine enters fungal cell via cytosine specific permease

Inside fungal cell, they rapidly converted into 5-fluorouracil by cytosine deaminase enzyme

5-fluorouracil acts as antimetabolites by competing with uracil

They forms 5-fluorouracil monophosphate

Antimicrobial spectrum:

• It is fungistatic drug
• It has limited spectrum of activity and includes Cryptococcus, Candida, Aspergillus, Sporothrix

Fungal resistance:

• Fungal resistance develops rapidly even during course of treatment
• Although mechanism of resistance is not known exactly, decreased levels of enzymes in conversion of flucytosine to fluorouracil and beyond or increased synthesis of cytosine by fungi are important considerations.

Pharmacokinetics:

• Rapidly and almost completely absorbed after oral administration
• Peak plasma level achieved within 1-2 hrs after oral dosing
• After absorption, it is distributed widely throughout the body
• Only about 2-4% of drug is bound to plasma protein
• 80-95% of drug is excreted unchanged in urine via glomerular filtration
• Half-life is about 3-6 hrs

Side effects/Adverse effects:

• Bone marrow depression
• GI signs (nausea, vomiting, diarrhoea)
• Reversible hepatic effects such as increased liver enzymes
• Aberrant behaviour and seizures in cats

Contraindications and precautions:

• In patients those are hypersensitive to drug
• It should be used cautiously in patients with renal insufficiency and preexisting bone marrow depression
• In pregnant animals

Drug interactions:

• It has synergistic effect with amphotericin B and ketoconazole
• They shouldn’t be combined with immuno-suppressant drugs

Clinical use:

• In systemic infection caused by Candida albicans and Cryptococcus meningitis
• It is combined with amphotericin B in treatment of Cryptococcosis
• It is used alone in treating Aspergillosis and Candidiasis in psittacine birds

Dose:

Dogs & cats: 25-50 mg/kg, PO, 3-4 times daily in combination with amphotericin B

Azoles:

• These are group of five-membered heterocyclic compounds containing one or more nitrogen atoms in ring
• It has two sub-groups: imidazole and triazole
• Imidazole contains two nitrogen atoms in basic five-membered ring structure
• Triazoles have three nitrogen atoms in basic five-membered ring structure.

# Imidazole:

• These are group of organic compounds in which aromatic heterocyclic is diazole.
• They include large numbers of synthetic drugs
• They are active against fungi, bacteria, helminths and protozoa

Mechanism of action:

Imidazole inhibit 14-α-sterol demethylase

Impairment of biosynthesis of ergosterol in cytoplasmic membrane

Accumulation of 14-α-methylsterol

Disrupt the close packing of acyl chains of phospholipids

Inhibition of growth of fungi

Ketoconazole:

• It is synthetic imidazole antifungal drugs for systemic use
• First azole that could be given orally to treat systemic fungal infections
• It is considered as the prototype drug of this class

Antimicrobial spectrum:

• It has broad-spectrum of antifungal activity including Candida, Cryptococcus, Coccidiodes, Blastomyces and Histoplasma species.
• It is also effective against Candida and dermatophytes like Microsporum and Trichophyton.

Fungal resistance:

• Resistance to ketoconazole has been observed in some fungal isolates including albicans.
• Resistance is due to mutation in sterol biosynthesis pathway

Other pharmacological effects:

• It produces some endocrine effects in host animals by interfering with steroid synthesis
• Reduction in testosterone or hydrocortisone level acting as antiandrogen

Pharmacokinetics:

• Oral absorption is variable between species and individual animals and depends on factors like gastric pH, product preparations and presence of other drugs and food.
• On oral administration, they dissolves in acidic gastric contents and absorbed through gastric mucosa
• Peak plasma concentration occurs between 1-4 hrs after oral dosing
• After absorption, they are widely distributed in body, except CNS
• Drug is highly bound to plasma proteins (>95%) mostly to albumin
• Metabolized extensively in liver and excreted primarily in bile
• Some unmetabolized drug and its metabolites are excreted in urine
• Elimination half-life varies from 1-6 hrs.

Side effects/Adverse effects:

• GI disturbances like nausea, vomiting and diarrhoea
• Hepatotoxicity with cholangio-hepatitis and increased liver enzymes
• Suppress testosterone or hydrocortisone synthesis
• Reproductive disorders
• Thrombocytopenia and reversible lightening of hair coat

Contraindications and precautions:

• In patients those are hypersensitive to ketoconazole
• In severe hepatic insufficiency
• It should be used with caution in pregnant animals
• It is not recommended in horses due to poor oral absorption

Drug interactions:

• Inhibit the cytochrome phosphate-450 enzyme system and potentiate toxicities of warfarin, sulphonylurea, ciclosporine, phenytoin and H₂-blockers.
• Combination of ketoconazole and amphotericin produce high toxic effects.

Clinical use:

• It is used to treat systemic mycoses in dogs, cats, horses, birds and some other species
• Also used to treat superficial infections which donot respond to griseofulvin
• High dosages of ketoconazole used to treat hyperadrenocorticism in dogs & cats.

Dose:

Dogs: 5-20 mg/kg, PO, 2-3 times daily

Cats: 5-20 mg/kg, PO, 1-2 times daily

Horses: 10mg/kg, PO, once daily

Triazole:

These are broad-spectrum azole antifungal agents

Fluconazole:

• It is synthetic triazole antifungal drug commonly used in the treatment and prevention of superficial and systemic fungal infections.

Mechanism of action:

Fluconazole inhibit 14-α-sterol demethylase

Impairment of biosynthesis of ergosterol in cytoplasmic membrane

Accumulation of 14-α-methylsterol

Disrupt the close packing of acyl chains of phospholipids

Inhibition of growth of fungi

Antimicrobial spectrum:

• It is fungistatic agent active against a wide range of pathogenic fungi
• It is effective against local and systemic Candida species and systemic Cryptococcus, Histoplasma, Sporothrix and Blastomyces

Pharmacokinetics:

• It is rapidly and nearly completely absorbed after oral dosing.
• Binding to plasma protein is minimal
• They are distributed into body tissues and fluids
• Only 10% of drug is eliminated due to metabolism while remainder is excreted in urine and sweat.

Side effects/Adverse effects:

• GI disturbances like vomiting, diarrhoea and anorexia
• Hepatotoxicity
• Thrombocytopenia
• Rashes

Contraindications and precautions:

• In patients with renal impairment
• In pregnant and lactating animals
• In hypersensitive animal

Drug interactions:

• Concurrent use of fluconazole and warfarin may increase prothrombin time

Clinical uses:

• For treatment of fungal infections where other antifungals have failed
• It is used against dermatophytes, yeasts and variety of systemic fungi
• It is also used in prophylaxis of candidiasis in immunocompromised individuals.

Dose:

Dogs & cats: 5-10 mg/kg, PO, 1-2 times daily

Dogs: 5-10 mg/kg, IV, 1-2 times daily

Horses: 5mg/kg, PO, once daily

Birds: 5-10 mg/kg, once daily

Allylamines:

Terbinafine:

• It is a synthetic drug that belong to new allylamine class of antifungal agents
• It is lipophilic in nature and accumulates in skin, nails and fatty tissues

Mechanism of action:

Terbinafine inhibits squalene epioxide enzyme

Inhibition of synthesis of ergosterol from squalene in fungal cell wall

Accumulation of squalene within cell of susceptible fungi

Disruption of cell membranes

Fungal cell death occurs

Antimicrobial spectrum:

• It is active against yeast and wide range of dermatophytes including Aspergillus, Trichophyton and Microsporum

Pharmacokinetics:

• It is well absorbed after oral administration
• It undergoes significant first-pass metabolism that decreases its bioavailability to about 40%
• It is highly plasma protein bound (~99%).
• They are widely distributed in body including tissues such as fat, stratum corneum, hair follicles, nails and sebum rich skin
• It is excreted mainly in urine (80%) and faeces (20%)

Side effects/Adverse effects:

• GI disturbances
• Headache
• Rash
• Hepatotoxicity
• Loss of taste
• Neutropenia
• Topical application may cause itching, dryness, erythema, urticaria, etc.

Contraindications and precautions:

• In patients with hepatic insufficiency and renal failure
• In pregnant animals

Clinical uses:

• For treatment of dermatophyte infection in dogs, cats, birds and some exotic species
• Also used in ringworm infection

Dose:

Dogs & cats: 30 mg/kg, PO, once daily (with food) for 2-3 weeks

Echinocandins:

• These are newer group of antifungal agents which inhibit the synthesis of fungal cell wall and thus called penicillins of antifungal drugs.
• Important members include caspofungin, anidulafungin and micafungin.

Caspofungin:

• It is water soluble, semi-synthetic, lipopeptide antifungal drug synthesized from fermentation product of Glarea lozoyensis.
• It is administered intravenously

Mechanism of action:

It competitively inhibits enzyme 1,3-β-glucansynthase

Inhibition of synthesis of β-glucan

Integrity of fungal cell wall weakens and disturbs because β-glucan is major component of fungal cell wall

Fungistatic action due to blockade of cell wall synthesis and fungicidal action due to loss of integrity of cell wall.

Antifungal actions:

• Caspofungin and other echinocandins are fungicidal against some yeast (mostly candida), fungistatic against moulds (mostly aspergillus) and moderately against dimorphic fungi (Histoplasma and Blastomyces)

Pharmacokinetics:

• Administered intravenously due to low oral bioavailability
• They reaches to most tissues and organs when administered IV
• Catabolism is largely by hydrolysis and N-acetylation which are excreted in urine and faeces.

Side effects/Adverse effects:

• GI disturbances
• Headache
• Fever
• Phlebitis
• Thrombophlebitis
• Pain at injection site
• Dyspnea
• Hypersensitivity
• Occasionally liver damage, peripheral oedema, swelling and hypercalcemia

Contraindications and precautions:

• In patients hypersensitive to caspofungin
• In pregnant animals
• Dose reduction in patients with impaired liver function but no dose reduction required in renal impairment.

Clinical uses:

• In treatment of invasive candidiasis and aspergillosis.

List of some topical and systemic antifungal agents