Systemic antifungal agents for cutaneous fungal infections

Summary
Cutaneous fungal infections are usually treated topically, but nail and hair infections, widespread dermatophytosis and chronic non-responsive yeast infections are best treated with oral antifungal drugs. The oral drugs currently available in Australia for the treatment of cutaneous fungal infections include griseofulvin, ketoconazole, fluconazole, itraconazole and terbinafine.

Introduction
The cutaneous mycoses are superficial fungal infections of the skin, hair or nails. Essentially no living tissue is invaded; however, a variety of pathological changes occur in the host because of the presence of the fungus and/or its metabolic products. The principal aetiological organisms are:

• dermatophytic moulds belonging to the genera Microsporum, Trichophyton and Epidermophyton which cause ringworm or tinea of the scalp, glabrous (hairless) skin and nails
• Malassezia furfur, a lipophilic yeast responsible for pityriasis versicolor, follicular pityriasis, seborrhoeic dermatitis and pityriasis capitis (severe dandruff)
• Candida albicans and related species, causing candidiasis of skin, mucous membranes and nails

The usual approach to the management of cutaneous infections in immuno competent patients is to treat with topical agents. However, nail and hair infections, widespread dermatophytosis and chronic non-responsive yeast infections are best treated with oral antifungal drugs.

When to use systemic therapy

Dermatophytosis (tinea or ringworm) of the scalp, skin and nails
Most dermatophytic skin infections in their early stages are responsive to topical therapy. Examples are interdigital tinea, tinea cruris and localised tinea on other parts of the body. However, once there is involvement of nails or hair, topical therapy is rarely adequate. The major indications for using oral antifungals are:

• tinea capitis - this never responds adequately to topical therapy
• tinea affecting the nails - sometimes nail removal combined with topical treatment may be effective when one or, at most, two nails are involved, but in most instances, oral therapy will be required for a true cure
• tinea involving more than one body region simultaneously, e.g. tinea cruris and corporis, or tinea cruris and tinea pedis. Patient compliance with topical treatment is rarely adequate enough to treat two body regions effectively at the same time
• tinea corporis where the lesions are particularly extensive
• tinea pedis when there is extensive involvement of the sole, heel or dorsum of the foot or when there is recurring and troublesome blistering
• tinea of a localised body area which is sufficiently annoying and recurrent after topical therapy to justify systemic therapy and its attendant risks

Chronic non-responsive yeast infections
Most Candida infections of the skin or mucosa are due to impaired epithelial barrier functions and respond readily to topical antifungal therapy. Basically, healthy individuals do not get candidiasis; therefore, a key strategy in treatment is to correct the underlying predisposing conditions that allow Candida to colonise the skin or mucosa.

Most cases of pityriasis (tinea) versicolor and seborrhoeic dermatitis, with pityriasis capitis being the mildest manifestation, also readily respond to topical treatment. As the causative yeast Malassezia furfur is part of the normal skin flora, prophylactic treatment is often necessary to avoid recurrences.

The major indications for use of oral antifungals are in cases where topical treatment has failed:

• pityriasis versicolor where the lesions are particularly extensive and resistant to topical treatment
• candidiasis where the lesions are particularly extensive and resistant to topical treatment
• vaginal candidiasis which is sufficiently annoying and recurrent after topical therapy
• candidiasis of the nails

How should the decision to treat be confirmed?
When oral therapy is being contemplated, it is mandatory to confirm that a dermatophyte or yeast infection is present, either by microscopy or culture.

Disadvantages of topical drugs
Although topical drugs can provide an immediate reduction in infectivity, are free of systemic adverse effects and are relatively inexpensive, they have some disadvantages. Local irritation is the most common adverse effect and is easily reversible.

There are major problems with compliance as the patient finds it difficult to continue treatment or to know where to apply the cream once the inflammatory signs have settled. In practice, most topical drugs would need to be continued for some time after disappearance of the symptoms and visible signs. Topical drugs may be difficult to use in certain areas e.g. on the hair and nails, and in some more sensitive areas such as the vagina, groin or the natal cleft.

Advantages and disadvantages of systemic drugs
The advantages of systemic therapy are essentially those of enhanced compliance, particularly in areas where treatment times with topical drugs would need to be long, such as on the foot. Other advantages are the ability to treat several body regions at the same time and areas that are not obviously infected.

The disadvantages are principally those of potential adverse effects. There are also cost considerations, particularly with the newer systemic antifungals.

Oral antifungal drugs

Griseofulvin
This is an oral fungistatic agent derived from a number of Penicillium species. It inhibits cell division and nucleic acid synthesis in fungi. Griseofulvin is active against dermatophytes, but has no effect against yeasts or other fungi. The usual adult dose is 500 mg/day and an ultra micro size formulation of 330 mg/day is also available (not less than 10 mg/kg should be given). However, higher doses of 1000 mg/day are commonly given when treating nail infections. The dose for children under 25 kg is 10 mg/kg and for children over 25 kg is 250-500 mg daily. It is best taken with food to facilitate absorption. The duration of therapy varies from patient to patient and on the site and severity of the infection, with 4-6 weeks required for skin and hair infections and 12 months for nails. Relapse is common, especially for nails where between 40-70% of patients fail treatment.

Griseofulvin is usually well tolerated. Adverse effects include headache, gastrointestinal disturbance and, less commonly, urticaria, diarrhoea and photosensitivity. The drug should be avoided during pregnancy and in patients with liver disease. Griseofulvin can diminish the anticoagulant effect of warfarin and concurrent administration of phenobarbitone may decrease griseofulvin's bioavailability. Griseofulvin may also interact with alcohol, causing a disulfiram type reaction. Therefore, alcohol will be a contraindication to its use in many patients.

Ketoconazole
Ketoconazole is an oral or topical synthetic dioxolane imidazole compound that interferes with the biosynthesis of ergosterol, leading to alterations in certain membrane-associated cell functions. It has a high affinity for keratin and a broad spectrum of activity which includes both dermatophytes and yeasts. The risk of hepatitis, albeit rare (1 in 10 000 to 1 in 15 000 of patients treated with a medium time of onset of one month), makes ketoconazole a secondary choice for dermatophyte infections. However, ketoconazole has become the drug of choice for treating Malassezia infections and is an important adjunct in the treatment of AIDS patients with fluconazole-resistant Candida infections.

Ketoconazole is not absorbed systemically following topical application, but is well absorbed orally under acid conditions. It is poorly absorbed in patients with achlorhydria and in those taking antacids or H2 receptor antagonists. The usual adult dose is 200-400 mg/day depending on the infection being treated. In children, a dose of 3 mg/kg can be used. The duration of treatment will also depend on the nature of the infection.

Liver function must be monitored in patients receiving treatment for more than 30 days. The most common adverse effects are nausea, anorexia and vomiting occurring in about 20% of patients. Adrenal or testicular steroid metabolism may be affected. Co-administration of ketoconazole with either terfenadine or astemizole has been associated with potentially fatal cardiac arrhythmias. Ketoconazole also enhances the effects of warfarin, oral hypoglycaemics and phenytoin.

Fluconazole
Fluconazole is an oral synthetic bis-triazole compound that inhibits the cytochrome P450-dependent 14 alpha-demethylation step in the formation of ergosterol. This leads to alterations in a number of membrane-associated cell functions. Fluconazole has a broad spectrum of activity that includes both dermatophytes and yeasts. The drug is particularly effective in the treatment of mucosal and cutaneous forms of candidiasis. It is currently the drug of choice for controlling oropharyngeal candidiasis in AIDS patients.

Absorption of fluconazole is not dependent on acid conditions and is also unaffected by food intake. The usual adult doses range from 100-400 mg/day, depending on the immune status of the patient, the infecting organism and the patient's response to therapy. With most mucocutaneous diseases in immuno competent patients, the recommended adult dose is 150 mg/week for 4 weeks. Vaginal candidiasis usually responds to a single dose of 150 mg.

Fluconazole is generally well tolerated with minor adverse effects such as nausea and vomiting occurring in a few patients. Unlike ketoconazole and itraconazole, fluconazole has few significant drug interactions. However, the effects of warfarin, oral hypoglycaemics, phenytoin and theophylline may be increased by fluconazole when given in doses of 200mg/day or higher.

Itraconazole
This is an oral synthetic dioxolane triazole compound that functions in much the same way as fluconazole. It has a broad spectrum of activity that includes both dermatophytes and yeasts. Itraconazole can be used to treat various cutaneous infections, including dermatophytosis, pityriasis versicolor and oral and vaginal forms of candidiasis.

Absorption from the gastrointestinal tract is improved if the drug is given with food or under acid conditions. The usual adult dose for cutaneous infections is 100-200 mg/day depending on the infection being treated.

Itraconazole is generally well tolerated with minor adverse effects of nausea, headache and abdominal pain being reported in a few patients. Itraconazole concentrations are reduced following concomitant administration of phenytoin, rifampicin, antacids and H2 antagonists. Co-administration of terfenadine or astemizole with itraconazole is contraindicated and the effects of warfarin, oral hypoglycaemics, phenytoin and digoxin may be enhanced.

Table 1 Oral treatment options for cutaneous fungal infections (In general, the treatment options are listed in order of currently accepted cost-effectiveness, although in some cases those listed as alternatives may be just as or more effective in terms of treatment outcome.)
Infection	Recommended	Alternative
Tinea unguium (Onychomycosis)	Terbinafine 250 mg/day - 6 weeks for finger nails, 12 weeks for toe nails	Itraconazole 200 mg/day/3-5 months or 400 mg/day for one week per month for 3 consecutive months. Griseofulvin 500-1000 mg/day until cure (approximately 12 months)
Tinea capitis	Griseofulvin 500 mg/day (not less than 10 mg/kg/day) until cure (4-6 weeks)	Terbinafine 250 mg/day/4 weeks, Itraconazole 100 mg/day/4 weeks
Tinea corporis	Griseofulvin 500 mg/day until cure (4-6 weeks), often combined with a topical imidazole agent	Terbinafine 250 mg/day/2-4 weeks, Itraconazole 100 mg/day/15 days, Fluconazole 150 mg/week for 4 weeks
Tinea cruris	Griseofulvin 500 mg/day until cure (4-6 weeks)	Terbinafine 250 mg/day/2-4 weeks, Itraconazole 100 mg/day/15 days, Fluconazole 150 mg/week for 4 weeks
Tinea pedis	Griseofulvin 500 mg/day until cure (4-6 weeks)	Terbinafine 250 mg/day/2-6 weeks, Itraconazole 100 mg/day/4 weeks, Fluconazole 150 mg/week for 4 weeks
Chronic and/or widespread non- responsive tinea	Terbinafine 250 mg/day for 4-6 weeks	Itraconazole 200 mg/day/4-6 weeks Griseofulvin 500-1000 mg/day until cure (3-6 months)
Chronic or severe pityriasis versicolor or pityriasis capitis	Ketoconazole 400 mg single dose non-responsive or 200 mg/day for 5-10 days	Itraconazole 200 mg/day/5-7 days, Fluconazole 400 mg single dose, or 150 mg/week for 4 weeks
Chronic/recurrent mucocutaneous candidiasis	Fluconazole 150 mg/week for 4 weeks	Itraconazole 200 mg/day/5-7 days, Ketoconazole 200 mg/day/5-10 days
Recurrent vaginal candidiasis	Fluconazole 150 mg single dose	Itraconazole 400 mg single dose (two 200 mg doses 8 hours apart)
Candidiasis of the nail	Itraconazole 200 mg/day for 3-5 months or 400 mg/day for one week per month for 3 consecutive months	Fluconazole 150 mg/week for 10-12 months
Please consult the relevant product information sheet for prescribing details

Terbinafine
This is an oral or topical synthetic allylamine compound that inhibits the action of squalene epoxidase, a crucial enzyme in the formation of ergosterol, leading to membrane disruption and cell death. It is a fungicidal agent with a limited clinical spectrum of activity primarily against dermatophytes. Oral terbinafine has become the drug of choice for dermatophytosis of nails. It is also the drug of choice for dermatophytosis of the skin and/or scalp where griseofulvin has failed or is contraindicated.

The drug is well absorbed and is strongly lipophilic, being concentrated in the dermis, epidermis and adipose tissue. Terbinafine is metabolised by the liver and the inactive metabolites are excreted in the urine. The usual adult dose is 250 mg/day with the duration of treatment dependent on the site and extent of the infection, ranging from two weeks for inter digital tinea pedis, 4-6 weeks for widespread or chronic non-responsive dermatophytosis of skin and/or scalp, to 12 weeks for nails.

Terbinafine is generally well tolerated with the most common adverse effects being nausea and abdominal pain, and allergic skin reactions, but these are often mild and transient. Taste disturbance and hepatic toxicity have also been reported.

Which drugs should be used when?
The oral treatment options for adults with superficial fungal infections are set out in Table 1.

Conclusion
The treatment of cutaneous fungal infections may require systemic treatment for a number of reasons relating to site, host and invading organism. There is now a large range of therapeutic options available which are, on the whole, safe and effective.

Further reading
Balfour JA, Faulds D. Terbinafine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial mycoses. Drugs 1992;43:259-84.

Elewski BE. Cutaneous fungal infections. Topics Clin Dermatol 1992. (unverified)

Grant SM, Clissold SP. Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 1989;37:310-44.

Grant SM, Clissold SP. Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 1990;39:877-916.

McGrath J, Murphy GM. The control of seborrhoeic dermatitis and dandruff by antipityrosporal drugs. Drugs 1991;41:178-84.