Pharmacotherapy of tinea capitis in children

April 2001

Tinea capitis, a fungal infection of the hair follicles of the head, is the most common dermatophyte infection in children. It can vary in severity from a seborrheic type to kerion formation. The pathogen responsible for most t. capitis episodes in the United States is Trichophyton tonsurans. Other pathogens can also produce tinea capitis, but are less common.

Topical therapy is not effective, and thus systemic antifungals are necessary for resolution. Griseofulvin, an antifungal agent that has been available for more than 40 years, is generally still considered first-line therapy. However, because of potential resistance to griseofulvin and because of extended treatment durations with its use, newer agents that have been used mostly in adults for other fungal infections are attracting the attention of pediatric clinicians. This month’s column will review these agents and their usefulness in the treatment of tinea capitis.

Griseofulvin

Griseofulvin has been and largely continues to be the standard of therapy for t. capitis. It works well, it is largely devoid of significant adverse effects, and clinicians have considerable experience with its use. Published controlled trials of griseofulvin reveal success rates of 80% to 90%. Griseofulvin concentrates in skin and contributes to its high efficacy.

Dosing guidelines from the package insert are 7.3 mg/kg/day to 11 mg/kg/day, depending upon the formulation used. Various griseofulvin products are available (tablets, capsules, suspension) and in two pharmaceutical forms – microsize and ultramicrosize. These dosage forms serve to decrease particle size and increase surface area of the product to enhance dissolution in the gastrointestinal (GI) tract, thus promoting absorption.

Griseofulvin should be taken with a fatty meal (eg, peanut butter or ice cream) to increase absorption, for it is largely insoluble in the aqueous media of the upper GI tract. The ultramicrosize products (tablets only) further decrease particle size, increasing absorption, allowing use of a smaller dose (7.26 mg/kg/day). The clinical benefits of this reduced dose, if any, are not clear. The liquid form, perhaps most useful to a pediatrician treating a young child, is composed of the microsize particles. The current primary literature indicates, however, that many experts are recommending higher doses – 15 mg/kg/day to 25 mg/kg/day (microsize formulation). The American Academy of Pediatrics’ 2000 Red Book: Report of the Committee on Infectious Diseases states that doses of 20 mg/kg/day to 25 mg/kg/day may be necessary.

Treatment durations of 4-6 weeks are usually recommended, although some experts are recommending that 8-week treatment durations may be necessary, or that retreatment may be needed in some patients.

Doses and treatment durations have risen because of increases in treatment failures as noted in several published reports. It is certainly possible that resistance to griseofulvin is responsible, although this is speculative, as resistance guidelines have not been well defined or standardized (eg, as with bacteria and antibiotics) for many fungal organisms.

Generally, griseofulvin continues to be recommended as first-line therapy for t. capitis, for it is effective and has a good safety record. Although other drugs have been explored as treatment alternatives, griseofulvin is the only systemic agent currently approved by the FDA for pediatric t. capitis treatment. (One must, of course, keep this in perspective, as many drugs commonly used in children are not officially approved by the FDA for pediatric uses).

The most common adverse effects of griseofulvin include headache (which can diminish with continued use) and GI (eg, nausea/vomiting), and these are generally infrequent. There is no need to monitor hepatic transaminase enzymes, as with the newer treatments. Additionally, griseofulvin adversely interacts with relatively few other drugs. As explained below, some of the newer agents can interact with numerous other medications. The absorption of griseofulvin can widely vary (25% to 70% absorption rate), which may also explain treatment failures. When efficacy is less than desired for a specific patient, clinicians can consider increasing the dose, as the patient may not be absorbing the drug well. One should verify that each dose of griseofulvin was administered with a fatty meal. Because of a long treatment duration, continued compliance with therapy should be stressed.

Ketoconazole

Ketoconazole (Nizoral, Janssen), an imidzole antifungal agent, is approved for use in adults for various fungal infections, including severe, recalcitrant cutaneous dermatophyte infections unresponsive to griseofulvin. Package labeling indicates that data with children are limited.

Of the newer antifungals, ketoconazole is the least useful in children because of its potential to cause hepatotoxicity. Although not common, hepatotoxicity from ketoconazole use may be fatal. An estimated incidence of hepatotoxicity occurrence is 1:10,000, although this estimate mostly likely is higher, as underreporting probably occurs. Several fatal cases have been reported in children. Because of its potential to inhibit an important enzyme of the hepatic drug metabolizing cytochrome P450 system (3A4 isoenzyme), numerous drug interactions exist with ketoconazole use. Because of these concerns, ketoconazole has essentially no role in the treatment of pediatric t. capitis.

---Tinea capitis
SOURCE: PATRICIA TREADWELL, MD

Itraconazole (Sporanox, Janssen), a trizole antifungal, is not approved for use in t. capitis treatment, nor does it have any pediatric indications. Pediatric efficacy and pharmacokinetic data are limited. Itraconzole also inhibits the hepatic drug metabolizing 3A4 isoenzyme and numerous drugs may be affected (eg, midazolam, cyclosporine, others). The potential for these interactions to occur should always be verified in patients prescribed itraconzole, by soliciting a drug history of other concomitant drug therapies the patient may be currently receiving. Itraconazole use also has been reported to result in hepatotoxicity. Although generally reversible, some fatalities have occurred. Cases have primarily occurred in patients with significant concomitant comorbidities.

When itraconazole is prescribed, hepatic transaminases should be taken at baseline and during therapy (eg, at 2-3 weeks). Patients should be told about symptoms of potential hepatoxicity (eg, jaundiced appearance, dark urine, anorexia and malaise). More common adverse effects include nausea and vomiting, although they are not usually limiting.

Fluconazole

Fluconazole (Diflucan, Pfizer), a triazole antifungal, is indicated for use in children (>6 months) for oropharyngeal candidiasis (and may be useful for other indications), but is not approved for t. capitis. Similar to itraconazole, fluconazole inhibits the hepatic cytochrome P450 drug metabolizing system (3A4), resulting in the potential for numerous drug-drug interactions (eg, midazolam, cyclosporine, phenytoin, corticosteroids, etc.).

The patient’s other concomitant drug therapies should be reviewed prior to fluconazole use. Patients should be counseled on the potential for these interactions to occur, if any new therapies are begun while fluconazole is administered. The hepatotoxicity profile of fluconazole is not unlike itraconazole, in that this effect is uncommon, and is most likely to occur in patients with significant comorbidities. Fatalities have also been reported. Hepatic transaminase and clinical monitoring should proceed as with itraconazole. GI adverse effects (nausea, vomiting) are more common, but most are usually mild. Fluconazole is available as a liquid formulation (orange-flavored, in two concentrations).

---Tinea capitis
SOURCE: PATRICIA TREADWELL, MD

Terbinafine (Lamisil, Novartis), an allyamine agent, is approved for onychomycosis of the fingers or toes. It has no pediatric labeling, although some pediatric pharmacokinetic studies have been published. A potential benefit of terbinafine includes a shorter treatment duration – 2-4 weeks vs. 4-6 weeks for fluconazole and itraconazole. Terbinafine may rarely result in hepatobiliary dysfunction, or cholestatic hepatitis. It is generally recommended that monitoring of hepatic transaminases proceed with treatment courses of 6 weeks or longer, which is greater than the 2-4 week duration recommended for t. capitis treatment. Adverse effects most common with terbinafine therapy, although usually mild, include mainly gastrointestinal effects. Terbinafine does not exhibit the degree of potential drug interactions as do itraconazole and fluconazole. However, because it does interact with the hepatic cytochrome P450 system, concomitant drug therapies of the patient and their potential for interaction should be reviewed prior to use. Unlike itraconazole or fluconazole, terbinafine is not available as an oral solution.

Efficacy

As stated above, griseofulvin is effective for the treatment of pediatric t. capitis and is generally considered first-line therapy. Published controlled trials indicate 80% to 90% efficacy. However, recent reports suggest efficacy rates that are significantly lower. Whether this is secondary to fungal resistance or other factors is not yet clear. When griseofulvin is used, clinicians should consider prescribing higher doses (see table), as is currently recommended by some experts. The newer agents described above have not been well studied for t. capitis treatment, although limited data for this use and data on their use in other fungal infections, together with their pharmacokinetic advantages of good distribution and sustained concentration at the site of infection, suggest that their role may be important. The 2000 Red Book states that itraconzole, fluconazole and terbinafine are all effective therapies for t. capitis.

Conclusion

Griseofulvin should continue to be first-line therapy for pediatric t. capitis. Because of fungal resistance, it is reasonable to begin therapy with doses higher than stated in the package labeling. It is also reasonable to extended treatment durations to 6-8 weeks.

Griseofulvin has a good safety profile, which is advantageous when compared with the adverse effect profiles of the newer agents. When used, patients should be counseled about administration of griseofulvin with a fatty meal and the importance of compliance with the extended treatment duration. The newer agents should be reserved for patients not adequately responding to griseofulvin, for even though they may be as or more effective than griseofulvin, their relative lack of pediatric experience, potential for significant hepatic toxicity, and drug-drug interactions are reason for cautious use. Clinicians should also consider obtaining cultures of infecting pathogens, for sensitivities of the various fungi to the antifungal agents could differ.

For more information:

• Elewski BE. Tinea capitis: a current perspective. Journal of the American Academy of Dermatology. 2000;42:1-20.
• Abdel-Rahman SM. Response to initial griseofulvin therapy in pediatric patients with tinea capitis. Annals of Pharmacotherapy. 1997;31:406-410.
• Caceres-Rios H. Comparison of terbinafine and griseofulvin in the treatment of tinea capitis. Journal of the American Academy of Dermatology. 2000;42:80-84.
• Abdel-Rahman SM. Oral terbinafine: a new antifungal agent. Annals of Pharmacotherapy. 1997;31:445-456.