Antifungal therapy can be divided into two categories; treatment of serious systemic (deep) mycosis and superficial mycosis involving skin and mucous membranes. The superficial mycoses may be subdivided into dermatophytic infections and Candidosis. Dermatophytic infections, which affect the skin, hair, and nails, are caused by such organisms as Epidermophyton sppi, Trichophyton spp., and Microsporum spp.\i. Candidosis, which affects moist skin and mucous membranes (e.g., gastrointestinal tract and vagina), is usually associated with Candida albicans.
Key characteristics of is ergosterol. Vertebrates are also eukaryotic, but they do not have cell walls. Their major membrane lipid is cholesterol. It is apparent that drugs that affect synthesis and function of cell walls or of hydroxylated glycerols and ergosterol might be more damaging to bacteria and/or fungi than to vertebrates. Examples of these can be found among the antifungals.
Sytemic mycoses tend to be serious and chronic
Many effective drugs are extremely toxic
Major drugs come primarily from one of three families: polyenes; imidazoles; and antimetabolites. Amphotericin B [Fungizone] is a polyene (so is nystatin, but it is not used for systemic infections). Ketoconazole and miconazole are imidazoles. Thiabendazole, the anthelmintic that has antifungal activity is also a member of this group. Flucytosine is an antimetabolite.
Typical infections and drugs frequently used are as follows: (key = amphotericin B, Amph; flucytosine, Flu; ketoconazole, Keto; and miconazole, Mic.)
Systemic candidiasis -- Amph and/or Flu, Keto, Mic, Fluconazole
Cryptococcosis (meningitis) -- Amph + Flu, Mic, Fluconazole better
Systemic aspergillosis -- Amph and/or Flu
Aspergillosis -- sinusitis in dogs -- Emlkonazole (Bowersock95)
Blastomycosis -- Amph, Keto, Itraconazole
Histoplasmosis -- Amph, Keto, Fluconazole
Coccidioidomycosis - Amph, Keto, Itraconazole
Paracoccidioidomycosis -- Ampho, Keto, Itraconazole
Other drugs that have been used are iodides and hydroxystilbamidine isethionate.
From USPDI95 plus others
Amphotericin B is a polyene antibiotic isolated from Streptomyces nodosus. It contains a macrolide ring and an aminosugar, mycosamine.
It is poorly water soluble, but is sufficiently soluble that it is administered by IV infusion (0.1 mg/ml) or (0.3 mg/ml) in 5% dextrose. It is extremely unstable in solution, particularly in normal saline.
Apparently has an affinity for membranes that have higher content of ERGOSTEROL. It forms a channel through the membrane that allows the passage of potassium and other small molecules. The fungus is unable to maintain its internal environment.
Resistance is rare and slow to develop.
The drug crosses cell membranes very poorly, therefore, it is poorly absorbed from the gut and has poor penetration into the eye, CSF, and joint capsules. For treatment of meningitis, it must be given intrathecally.
It is given only via IV injection or intrathecally. Some authorities feel its topical use is no longer justified because of the availability of superior products.
The drug has MANY adverse effects, some serious. It must be given in a hospital setting.
It is noted for its renal toxicity that is both predictable and dose related. Fortunately it is usually reversible. Renal function must be monitored and the drug is usually given in cycles or courses of therapy, e.g., 7 days on, 7 days off. Treatment may last for 6 to more than 24 weeks.
Flucytosine is a synthetic agent chemically related to fluorouracil and floxuridine, both anticancer drugs. It is an antimetabolite.
It is converted to 5-fluorouracil (5-FU) which inhibits thymidylate synthetase. Thymidine is required for DNA synthesis. Vertebrate cells have little of the enzyme required to convert flucytosine to the active antimetabolite, 5-FU. It may be noted that 5-FU is an anticancer drug, therefore, the toxicity of flucytosine could be expected to be similar to that of antimetabolite anticancer drugs. Pharmacokinetics
A major characteristic of this drug is its rapid and complete absorption after oral administration. It distributes widely throughout the body fluids, including the CSF. As a result it is included in therapy of meningitis caused by susceptible organisms, usually Candida and Cryptococcus species..
Half-life in humans is 2.5 to 6.0 hours, but this is extended to 12 to 250 hours if renal function is impaired. This is consistent with the fact that 80 to 90% of the drug is eliminated in the urine unchanged.
This drug is much less toxic than amphotericin B. Nonetheless, as might be expected from a drug that can be converted to 5-FU, it causes bone marrow depression and gastrointestinal disturbances Bone marrow depression includes leukopenia, anemia, and thrombocytopenia. Gastrointestinal disturbances include nausea, vomiting, and diarrhea.
Flucytosine also causes CNS toxicity that may be manifest as headache, drowsiness, confusion, vertigo, and hallucinations.
In addition to being used to treat meninigitis caused by susceptible Candida and Cryptococcus species, it is also used to treat pneumonia, septicemia, and urinary tract infections caused by susceptible organisms. It is also recommended for systemic candidiasis & aspergillosis.
A major drawback to this drug is the high proportion of strains that are resistant to the drug and the rapid development of resistance during therapy. It IS NOT used as a single agent because of this.
The azole derivatives can be subdivided into two categories: imidazoles and triazoles. Ketoconazole and miconazole are the imidazoles used to treat systemic fungal infections. Itraconazole and Fluconazole are triazoles.
Ketoconazole was the first of these drugs to be used widely to treat systemic fungal infections. It was a major step forward in decreasing dependence on amphotericin B. Miconazole offered some useful systemic antifungal activity with less desirable pharmacokinetic properties. Itraconazole and econazole cause fewer side effects and have better pharmacokinetic properties.
The azoles inhibit cytochrome-P450 activity which has many ramifications. With respect to antifungal activity, this decreases conversion of 14-alpha-methylsterols to ergosterol, an important membrane component in fungi. Failure of ergosterol synthesis causes altered membrane permeability leading to loss of ability to maintain a normal intracellular environment.
The azole antifungals inhibit transformation of blastospores into invasive mycelial form in Candida albicans.
The inhibition of cytochrome function may also be the basis of their interference with steroid biosynthesis. Ketoconazole is particularly noted for inhibition of adrenal corticosteroid and testosterone synthesis. At higher doses, this can result in hypoadrenal cortical activity and reduced libido. In fact, the effect has been used therapeutically at doses higher than those used to treat fungal diseases. Adrenal hyperplasia and cancer have been treated with high dose ketoconazole. The effects are reversible. Testosterone and adrenal corticosteroid concentrations in plasma return to normal upon cessation of therapy
Itraconazole and fluconazole have a very weak, non-competitive inhibitory effect on liver (and presumably adrenal cortical and testicular) cytochrome-P450 activity, but retain high affinity for the fungal cytochrome-P450. This difference gives these drugs a greater margin of safety. However, reduction of cortisol concentration was associated with a daily dose of 600 mg of itraconazole (normal dose is 200 to 400 mg/day).
This is a relatively new drug and offers the promise that it is much less toxic than amphotericin B. It can also be used orally as well as parenterally for systemic infections.
This weakly dibasic drug is best absorbed from solutions that have low pH. Note that this is opposite from what one would expect from the "Law of Non-ionic Diffusion." The effect is caused by the increased rate of dissolution of the dose form in the acidic solutions. Once in solution, the drug is rapidly absorbed and distributed uniformly throughout the body.
The drug shows interesting dose-related kinetics consistent with transient saturation of its biotransforming enzymes. The half-lives after administration of varying oral doses are as follows: 100 mg tablet - 6.5 h; 200 mg tablet - 8.1 h; and 300 mg table - 9.6 h.
The list of precautions that should be observed with the use of ketoconazole is quite lengthy and includes, especially concurrent use of other potentially hepatotoxic drugs or alcohol.
Hepatocellular type, has been reported in 1 of 10,000 patients. It is usually reversible.
With high doses, an unintended side effect may be depression of adrenocortical function. Conversely, one may actually use the drug for this purpose. Serum testosterone levels may also decrease during therapy. No specific mention of effect on estrogen or progesterone synthesis, although menstrual irregularities would be consistent with this. Depression of testosterone and adrenal steroid synthesis in males may lead to gynecomastia.
Is similar to ketoconzole, but less able to cross membranes and more toxic. Heavily advertized as a topical antifungal.
Must be used by infusion for systemic effects. Apparently does not cause hepatotoxicity, but is associated with frequent occurrence of hypersensitivity (fever and chills, skin rash or itching), and phlebitis (redness, swelling, or pain at injection site).
is another imidazole that has been introduced recently for use in human medicine. It has also been used in veterinary medicine (Dallman et. al., 1992)
Potassium iodide is an old drug that is still the drug of choice for cutaneous-lymphatic sporotrichosis. (AMADE2:12). Veterinarians also use the drug for actinomycosis. It may be used p.o. as a saturated solution (1 mg/ml). Most textbooks classify KI as an expectorant. It increases secretions in the respiratory tract in approximately 30 min. Adverse effects include hypothyroidism and Iodism. Signs include brassy taste, rhinitis, coryza, salivation, lacrimation, sneezing, burning of mouth and throat, ocular irritation, sialadenitis, and dermal lesions.
Superficial fungal infections are treated either orally (for effect in the gastrointestinal tract) or topically. Drugs include imidazoles mentioned earlier plus clotrimazole and econazole. In fact, there are a whole host of new imidazoles intended for use against topical fungal infections, e.g., butaconazole nitrate [Femstat], econazole nitrate Spectazole], oxiconazole [Oxistat], and Sulconazole [Exelderm]. Thiabendazole is a benzimidazole anthelmintic that has some antifungal activity. It is used in some veterinary otic preparations. A new class of compounds include the Triazoles typified by Terconazole [Terazol 3, Terazol 7]. Tolnaftate and desenex are used topically for dermatophytes (athletes foot and jock itch). Miconazole, too. Amphotericin B and nystatin [Mycostatin] are polyene antibiotics that are used topically. Haloprogin [Halotex] is used for superficial dermatophytic infections and candidal infections. Another new antifungal class, the synthetic allylamines, is represented by naftifine hydrochloride [Naftin].
Griseofulvin is interesting in that it is a systemic antifungal used to treat Topical ringworm infections, e.g., onychomycosis, Tinea capitis, Tinea pedis, etc. Many Trichophyton spp., Microsporum spp. and Epidermophyton spp. are susceptible.
Griseofulvin is derived from Penicillium griseofulvum. It is poorly water soluble and requires bile salts for solubiliization in the gut.
Griseofulin disrupts mitotic spindle structure to lead to metaphase arrest. It concentrates in newly formed cells of skin, hair, and nails and is carried with them as they continue their life history into keratinized structures. This concentration is sufficient to inhibit growth of fungi (drug is static), preventing them from invading. As the skin, hair, or nail is replaced, the fungus is shed.
As a result of the mechanism of action, it is apparent that very long courses of therapy may be required: hair covered skin -- 3 to 4 weeks; nails -- 3 to 4 months.
Used orally. Absorption is best with high fat meals to aid in solubilizing the drug. Unabsorbed drug is eliminated in the feces. Most absorbed drug is biotransformed. A small amount is shed in dead skin and hair.
Griseofulvin causes hepatomas in mice and thyroid tumors rats, but there is no direct evidence of tumorigenic activity in other species. Nonetheless, casual use should be avoided.
Adverse effects are not common, but include confusion, hypersensitivity (skin rash, hives, or itching), oral thrush (soreness or irritation of mouth or tongue), and photosenstivity.
Rare effects seen more with high doses or prolonged therapy include hepatitis, granulocytopenia or leukopenia, and peripheral neuritis (numbness, tingling, pain, or weakness in hands or feet).
Ciclopirox is a broad-spectrum antifungal with a spectru similar to that of the imidazoles. Its use is indicated for topical candidiasis and various ringworms as mentioned above.
Only rarely are adverse efects asociated with its topical use. These include local iritation (burning, itching, rednes, sweling).
This synthetic drug was developed in the 1970s. It is poorly soluble in dipolar solvents. It is effective topically against Trichophyton, Microsporum, and Epidermophyton spp. It is not useful for bacterial and candidal infections. Chronic, hyperkeratotic lesions may not respond well. Use of a keratolytic (e.g., Whitfield's ointment) may help. One may also combine local tolnaftate treatment with orally administered griseofulvin in refractory cases. Treatment of susceptible cases may require 1 to 10 weeks for cure. Affected areas must be kept clean and rug. Tolnaftate is "cidal" as opposed to undecylenic acid [Desenex], another widely used OTC drug that is "static".
Tolnaftate is not significantly absorbed from topical applications and no confirmed adverse systemic reactions have been reported. Cream or liquid should be used for active infections; powders for maintenance of remission. Must apply treatment q12h.
Clotrimazole is a heavily advertised imidazole antifungal intended for topical use. It is toxic when given systemically. It is useful for dermatophytic infections, cutaneous candidiasis, and candidal infections of mucous membranes and mucocutaneous junctions (i.e., perianal, intertriginous, and vulvovaginal areas. Treatment may require two to four weeks. For vaginal candidiasis poor compliance with complex, long regimens has led to using very high doses for one to three treatments. Erythema, urticaria, pruritus, stinging, and blistering may be seen. Use of the Troche form may require monitoring of hepatic function.
Whitfield's ointment represents keratolytic agents which are often important in treatment of topical fungal infections. Whitfield's ointment consists of 3% salicylic acid plus 6% benzoic acid. It has no significant antifungal activity, but helps remove keratinous layer to aid penetration of antifungals.