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Here is a list of various antifungal agents.
Topical Agents:
Benzoic Acid and Salicylic Acid:
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Benzoic acid is used as a preservative in foodstuff because of its bacteriostatic and fungi static properties. Benzoic acid (6%) is combined with salicylic acid (3%) to make Whitfield’s ointment (Compound ointment of Benzoic acid) for use in ringworm infection caused by Trichophyton in cattle and man. Salicylic acid has keratolytic effects which softens the crust and then acts on the organisms.
Undecylenic Acid:
It is a yellow liquid having fungi static property. However, long exposure with high concentrations may have fungicidal effect. High concentrations of the acid also have irritant effect and therefore, zinc or copper salts of the acid are often used to minimize the irritant effect. It is effective against Microsponun.
Natamycin:
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It is a polyene antibiotic derived from Streptomyces natiliensis. It is effective against the dermatophytes, bovine yeast mastitis and mycotic keratitis. In mastitis caused by Candida species 20 ml of 2.5% solution of natamycin is infused into affected teat once daily for 3 days and it is used as a suspension containing 0.1 mg/ml to treat ringworm in animals.
Animals should be treated indoors or in the evening to avoid inactivation which occurs in sunlight. Metal containers are also to be avoided to prevent inactivation.
Nystatin:
Nystatin is another polyene antibiotic obtained from Streptomyces noursei. It is not ‘absorbed either from the mucous membrane or from the skin. It is used to treat equine metritis, canine otitis, bovine mastitis and avian crop mycosis. It is not effective against dermatophytes.
Dichlorophen:
Besides being effective as taenicide, dichlorophen is a useful fungicide. It is used at a concentration of 2% either as an ointment or as alcoholic solution against dermatomycoses caused by both Trichophyton and Microsporum species. The main advantage with dichlorophen is the low number of dressings required. Only two dressings can clear up bovine ring worm.
Monosulfiram:
Monosulfiram is an insecticide (miticide). It is included in some ear preparations for its fungicidal and miticidal activity.
Copper Sulphate:
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Copper sulphate is strongly fungicidal and has astringent and caustic property. Copper sulphate was used earlier for treatment of ringworm as 5% ointment or 1-2% aqueous solutions.
Crystal Violet:
Crystal violet is an effective fungistat against Microsporum and Trichophyton Species. Chemically it is hexamethyl-pararosaniline hydrochloride. Methyl violet is the pentamethyl derivative with some hexa- and tetra-methyl derivatives. Gentian violet is a mixture of methyl and crystal violet.
As a fungistat, crystal violet is used as a 1% alcoholic solution on to the ringworm lesions and recovery occurs within two to three weeks.
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Azoles: Cotrimazole, econazole, ticonazole and sulconazole are azole antifungal agents used only for topical application. Clotrimazole interferes with amino acid transport into the fungus by an action on the cell membrane and is active against a wide range of fungi, including candidal organisms.
Systemic Agents:
Antifungal antibiotics:
Amphotericin:
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Amphotericin was first used against fungal infection about 50 years ago. Amphotericin is a macrolide antibiotic of complex structure containing many membered carbon ring.
Mode of action:
Like other polyene antibiotics, amphotericin binds to ergosterol of fungal cell membranes and forms a pore in the membrane interfering with the permeability with consequent loss of K+. Mammalian cells are not affected as amphotericin does not have affinity for cholesterol, the main sterol in the plasma membrane of animal cells.
Amphotericin is poorly absorbed when given orally; therefore, it is used by this route for fungal infections of the gastrointestinal tract. It can also be used topically. For intravenous infusion, amphotericin is complexed with lipids or with p-cyclodextrin or encapsulated in liposomes or nanospheres.
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Amphotericin is highly protein bound and is fairly found in high concentration in inflammatory exudates. It can also penetrate BBB only when the meninges are inflamed and therefore, intravenous amphotericin, used with flucytosine, is effective in cryptococcal meningitis.
Unwanted effects:
Renal toxicity is the most common and serious unwanted side effect of amphotericin. Hypokalaemia, hypomagnaesemia and anaemia are further problems.
Intravenous infusions sometimes cause thrombophlebitis (because amphotericin is irritant) and intra-thecal injections cause neurotoxicity. Topical applications also cause skin rash. Though the liposome-encapsulated and lipid-complexed preparations have fewer side effects, they are considerably more expensive.
Griseofulvin:
Griseofulvin is a narrow-spectrum fungi static agent isolated from Penicillium griseofulvum. It is used to treat dermatophyte infections of skin or nails, but treatments needs to be prolonged, usually 6-9 months. It is given orally and is concentrated in keratinised tissue.
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Mode of action:
Griseofulvin interacts with microtubules and interferes with mitosis.
Unwanted effects:
Infrequent, but can cause gastrointestinal upsets, headache and photosensitivity.
Allergic reactions also occur.
Synthetic antifungal agents:
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Azoles:
This group of broad spectrum fungistatic agents include fluconazole, ketoconazole, miconazole and econazole.
Mode of action:
They inhibit lanasine 14α-demethylase which is the fungal cytochrome P450 3A(CYP3A) enzyme responsible for converting lanosterol to ergosterol, the main sterol in the fungal cell membrane. As a result fungal replication is inhibited.
Ketoconazole:
Ketoconazole was the first azole to be used orally to treat systemic fungal infections. It is, however, toxic and relapse is common even after successful treatment.
Unwanted effects:
Though rare, the main hazard is liver toxicity and can prove fatal. The liver toxicity may occur without clinical evidence and may progress even after discontinuation of the drug. Other signs are gastrointestinal disturbances and pruritus.
Rifampicin, histamine H2 receptor antagonists and antacids decrease the absorption of ketoconazole.
Fluconazole:
Fluconazole is the drug of first choice for most types of fungal meningitis, because it reaches high concentrations in the CSF and ocular fluids. Vaginal tissue, saliva, skin and nails also achieve fungicidal concentrations of fluconazole. It can be given orally or intravenously.
Unwanted effects:
Unwanted effects are usually mild and include nausea, headache and abdominal pain. Hepatitis is also sometimes reported, but this is rare.
Itraconazole:
Itraconazole is given orally. Its absorption is variable and after absorption the drug undergoes extensive hepatic metabolism. To overcome this problem, itraconazole encapsulated in p*- cyclodextrin is available for administration by intravenous route. It does not penetrate CSF.
Unwanted effects:
Unwanted effects of itraconazole are gastrointestenial disturbances, headache and dizziness.
Hepatitis, hypokalaemia and impotence can also occur, but rare.
Miconazole:
Miconazole is given orally for infections of the gastrointestinal tract. It can also be given topically. It is inactivated in the liver and reaches therapeutic concentrations in bone, joints and lung tissue but not in the CNS.
Unwanted effects:
Relatively infrequent, but most commonly seen unwanted effects are gastrointestinal disturbances, pruritus, blood dyscrasias and hyponatraemia.
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Flucytosine:
Flucytosine is a synthetic antifungal agent. Drug resistance occurs during treatment when given alone and therefore, it is combined with amphotericin for severe infections such as cryptococcal meningitis.
Mode of action:
Flucytosine is converted to 5-fluorouracil (5-FU) in fungal cells. 5-FU is an antimetabolite and inhibits thymidylate synthetase responsible for DNA synthesis.
Terbinafine:
Terbinafine is a fungicidal compound active against a wide range of skin pathogens. It is highly lipophilic and keratinophilic and acts by selectively inhibiting squalene epoxidase, the enzyme involved in the synthesis of ergosterol from squalene in fungal cell wall. Accumulation of squalene within the cell is toxic to the organism.
It is used both orally and topically to treat fungal infections of nails.
Echinocandins:
Echinocandins compromise a ring of six amino acids linked to a lipophilic side- chain. They inhibit the synthesis of 1,3-β-glucan, a glucose polymer that is necessary for maintaining the structure of fungal cell walls. In the absence of this polymer, fungal cells lose integrity followed by immediate cell lysis.
Capsofungin:
It is effective in the treatment of candiasis and forms of invasive aspergillosis that are refractory to amphotericin. Oral absorption is poor and is extensively protein bound.
Micafungin (FK463):
It is under clinical trials. It is effective against Aspergillus and Candida spp.
Amorolfine:
It is effective against fungal infections of the nails. It is given orally and it inhibits fungal sterol synthesis.
