Antifungal agents for common paediatric infections

Oropharyngeal candidiasis Oropharyngeal candidiasis (thrush) is usually observed six to 10 days after birth, with the reported incidence ranging from 1% to 37% (1-3). Nonabsorbable agents have been used to treat oropharyngeal candidiasis in neonates without major underlying conditions; response rates in open trials have been up to 80% to 90%. Gentian violet: Gentian violet is the oldest, nonabsorbable agent. Clinical experience has shown it to be moderately effective against oropharyngeal candidiasis, but it can lead to irritation and ulceration with prolonged use (4). Gentian violet stains tissues and clothing, making an assessment of response to treatment difficult for the physician and a mess that is poorly accepted by parents. Nystatin suspension: Nystatin suspension has been used to treat thrush since the 1950s (5). The usual dosage is 200,000 units qid. Nystatin has been found to provide a cure in 53% of newborns at one week and 80% of newborns at two weeks (6). This dose is very well tolerated, and nystatin suspension is, therefore, the most frequently prescribed agent to treat thrush in healthy newborns. However, nystatin suspension should not be given to premature infants because of its high osmolality (up to 2800 mOsm/L). In most commercial preparations, the high osmolality is due to the large amount of sucrose that is used to mask the bitter taste of nystatin. Miconazole: Miconazole is a first generation imidazole that is more active in vitro than nystatin. Miconazole gel is not licensed in Canada, but it has been shown to be more effective than nystatin suspension in controlled trials. In the largest of three studies, 183 ambulatory infants with oropharyngeal candidiasis but without any underlying disease were randomly assigned to receive either nystatin suspension 100,000 units qid or miconazole gel 25 mg qid for five to 12 days (7). By day 5, 84.7% of 98 of the infants treated with miconazole and 21.2% of 85 of the infants treated with nystatin (P<0.0001) were cured. By day 12, 99% of the miconazole group and 54.1% of the nystatin group were cured (P<0.0001). The frequency of clinical relapses and side effects were similar in both groups. Clotrimazole: Clotrimazole is another first-generation imidazole with in vitro activity similar to that of miconazole. No oral preparation of clotrimazole is licensed in Canada. There is anecdotal experience that the use of clotrimazole suppositories in a pacifier or clotrimazole vaginal cream applied to the oral mucosa three or four times daily after feedings is effective against oropharyngeal candidiasis (8,9). However, because these approaches have not been evaluated in controlled trials, they cannot be recommended as first-line therapy. Fluconazole: Fluconazole is an oral, absorbable agent. Although this drug is highly effective for treating oropharyngeal candidiasis, an absorbable agent with potential significant adverse effects is not recommended for the management of oropharyngeal candidiasis in immunocompetent newborns. ID 2000-03


Amphotericin B suspension: Amphotericin B suspension is available in the United States but not in Canada.
Although it is more active in vitro than nystatin against Candida albicans, the clinical response using amphotericin B suspension 100 mg qid was similar to that of nystatin suspension 100,000 to 400,000 units qid in small trials (5,10).
In summary, although nystatin suspension 200,000 units qid is the standard treatment for oropharyngeal candidiasis in healthy newborns, the evidence to support this treatment is weak. Good evidence shows that miconazole gel 25 mg qid is more effective for this condition, but this agent is not yet licensed in Canada.

Candidal diaper dermatitis
Candidal diaper dermatitis (CDD) may develop in the first month of a child's life, but it occurs most commonly during the second to fourth months, with a reported incidence of 3% in healthy infants (2,3). C albicans is detected in the feces of approximately 90% of infants with CDD (11). Treatment of CDD includes measures to decrease maceration of the skin, such as eliminating impervious diaper covers, changing diapers frequently and leaving diapers off for long periods each day. In addition to these measures, topical antifungal therapy is necessary. Ointments, creams and powders of nystatin, amphotericin B, miconazole and clotrimazole are the agents available (Table 1). Evidence from small trials has not shown significant differences among these topical agents for CDD. It is still not clear whether concomitant oral antifungal therapy should be recommended in addition to topical antifungal therapy. In two studies that compared concomitant oral and topical nystatin with topical nystatin alone, there was no significant difference between groups in the initial clinical responses (12,13). But in one study, the relapse rate was decreased by 50% when oral and topical nystatin were used together versus topical nystatin alone (33% versus 16%, respectively) (12).
There are no well designed trials evaluating the role of steroids in CDD. The hypothesis is that when a mild antiinflammatory agent is combined with an antifungal agent, the response will improve. The counter argument is that steroids impair the response to the antifungal agent. There is agreement that potent steroids must be avoided. However, some experts never use steroids with antifungal agents, and others use 1% hydrocortisone with antifungal agents to treat CDD.
In summary, there is no evidence to indicate the superiority of one topical agent over another to treat CDD, and although the evidence is weak, there may be a benefit to using concomitant oral and topical nystatin.

PITYRIASIS VERSICOLOR (TINEA VERSICOLOR)
Pityriasis versicolor (tinea versicolor) is a common superficial disorder of the skin that usually affects the face, neck, trunk and arms. It is more common in adolescents than in prepubertal children and occurs more commonly in tropical climates. Malassezia furfur is the causative agent (14).
Treatment consists of applying selenium sulfide as a 2.5% lotion or 1% shampoo to the affected area for 15 to 30 min nightly for one to two weeks, and then once a month for three months to avoid recurrences (15). Ketoconazole 2% shampoo has been shown to be effective. In one randomized, controlled trial, the response rates of ketoconazole shampoo used for three days compared with the use of the shampoo for one day or placebo were 73%, 69% and 5%, respectively (16). Oral agents may be used for extensive involvement or infections that are unresponsive to topical therapy. In adults, a single dose of ketoconazole (400 mg) has been effective. Little information is available about the use of oral agents for this Paediatr Child Health  indication in children. Some experts recommend ketoconazole 5 to 10 mg/kg/day once daily for three to seven days (14).

TINEA CORPORIS
Tinea corporis (ringworm) is a superficial infection of skin that is not covered by hair. It occurs worldwide in all age groups. The lesions are generally circular (hence the term ringworm). The most common causes of tinea corporis in North America are Trichophyton species (especially Trichophyton rubrum and Trichophyton mentagrophytes) and Microsporum species (especially Microsporum canis and Epidermophyton floccosum). These fungi are transmitted by direct contact with infected humans, animals (primarily domestic dogs and cats) and, less commonly, by fomites (17).
With the exception of patients with widespread lesions, most lesions can be treated with topical antifungal agents once or twice daily for 14 to 21 days. No evidence is available from controlled trials, but there appears to be little difference in response between agents. Topical agents mixed with corticosteroids should not be used for this indication (15).

TINEA PEDIS
Tinea pedis (athlete's foot) is a superficial fungal infection of the foot that frequently presents with lesions between the toes. Although it is common in adolescents, it is not common in younger children. The most common causes are T rubrum, T mentagrophytes and E floccosum. Tinea pedis tends to spread to other household members (17). Involvement of the toenail is not common in children (18).
Any topical antifungal agent is effective against most forms of tinea pedis. Drying agents, such as Burow solution, may be a helpful adjunctive treatment for macerated or vesicular lesions. Recurrence of the infection is prevented by good foot hygiene. Oral therapy is indicated for treatment of nail infections. Clinical studies in children are limited, but they suggest that newer agents, such as fluconazole, itraconazole and terbinafine, are effective (19,20). Itraconazole has been shown to be effective in adults using dosing schedules of 200 mg/day for 12 weeks or 200 mg twice daily for one week on and three weeks off for three to four months. Terbinafine has been used in adults with a dosage of 250 mg/day for two weeks or 500 mg daily for one week on and three weeks off for three to four months.

TINEA CAPITIS
Tinea capitis is a superficial fungal infection of the scalp, and it is the most common paediatric dermatophyte infection. Although the predominant causative species of tinea capitis vary geographically, they fall into the genera of Trichophyton and Microspora. M canis predominates in Europe, while Trichophyton tonsurans predominates in North America. Because tinea capitis does not respond adequately to topical therapy alone, oral therapy is usually necessary (

Griseofulvin
Griseofulvin has been the drug of choice for tinea capitis since the 1950s. Griseofulvin has a good safety profile, and it is available in both tablet and suspension formats. Its most frequent side effects are headaches and gastrointestinal complaints. Griseofulvin is a photosensitizing drug. Its bioavailability is enhanced when it is consumed with a fatty meal. Griseofulvin is fungistatic and requires long courses of therapy (ie, a minimum of eight weeks for tinea capitis). Until recently, griseofulvin was the only treatment available, but a variety of oral antifungal agents are now available.

Ketoconazole
Ketoconazole was the first azole evaluated for efficacy in the treatment of tinea capitis (21)(22)(23)(24). In the studies that evaluated its efficacy (21-24), ketoconazole did not  improve outcome or shorten the duration of therapy, and relapse rates were not reported. Considering the higher cost and risk of hepatotoxicity associated with the long term use of ketoconazole, it should not be used as a firstline agent for the treatment of tinea capitis. Fluconazole is a triazole with activity against Candida species, some dermatophytes and many systemic mycoses. The drug is hydrophilic and, thus, it is present mainly in bodily fluids rather than in keratin or lipids (25). It is, therefore, not useful for routine treatment of tinea capitis although there are case reports of its use to manage this condition (26,27).

Itraconazole
Itraconazole is an azole with activity against many dermatophytes, Candida species, Malassezia furfur and some moulds. It has a long half-life in the skin and nails. It has a strong affinity for both lipids and keratin, and reaches the skin primarily through sebum. Sebum may continue to deliver itraconazole to the skin three to four weeks after ther-apy has stopped. Itraconazole is available in tablet and liquid formats. Clinical trials and case series using itraconazole for the treatment of tinea capitis suggest that it is effective for infection caused by both Trichophyton and Microspora species (28)(29)(30)(31)(32). The dosages used vary in studies, but the majority of participants received 3 to 5 mg/kg/day of itraconazole for four to six weeks, with clinical response rates of about 90%. The drug was well tolerated with few side effects. Although better evidence is required to support the use of itraconazole, it is, potentially, a good first-line agent for the treatment of tinea capitis.

Terbinafine
Terbinafine is an allylamine that has in vitro activity against dermatophytes and some moulds. Because it is lipophilic and keratinophilic, it diffuses to the keratinocytes from the blood stream, and reaches the stratum corneum and hair follicles (33). Similar to the action of azoles, terbinafine inhibits fungal ergosterol synthesis; however, this occurs at a different stage in the synthesis  Reduced antifungal efficacy pathway. Terbinafine inhibits squalene epoxydation. Because it is not metabolized through cytochrome P-450, it avoids many of the drug interactions seen with the azoles. Terbinafine is well tolerated, with gastrointestinal upset and skin reactions occurring in only 2% to 7% of patients. Loss of the sense of taste has been reported, but this side effect resolves several weeks after therapy has ended. Terbinafine has a long half-life and it is fungicidal (34).
Terbinafine is available in Canada as a 250 mg scored tablet, but a liquid formulation is not available. Oral terbinafine has been studied in clinical trials for the treatment of tinea capitis in children (35)(36)(37)(38)(39). In one controlled, comparative trial (34), four weeks of treatment with terbinafine was as effective as eight weeks of therapy using griseofulvin (cure rate 93% versus 88%, respectively). In two controlled trials that compared one, two and four weeks of terbinafine, one trial (n=161) did not show a difference among groups and the other (n=82) showed a higher cure rate at 12 weeks in the group treated for four weeks (P<0.05). The predominant causative agent in these studies was Trichophyton species. The evidence from these studies and from an open clinical trial for the treatment of tinea capitis caused by M canis suggests that four to six weeks of oral terbinafine may be less effective for tinea capitis due to M canis than for tinea capitis due to Trichophyton species (40).

Adjunctive therapy
Although topical monotherapy is not effective treatment for tinea capitis, it is often used adjunctively to decrease the shedding of viable organisms. Topical selenium sulfide has been shown to improve the cure rate when it is used in combination with oral griseofulvin (41).
No difference in efficacy was found between the 1% selenium shampoo (available without a prescription) and the 2.5% prescription preparation (42). Ketoconazole shampoo has not been shown to be useful for the treatment of tinea capitis.
In summary, daily oral griseofulvin used in conjunction with 1% selenium sulfide shampoo two to three times per week remains the first-line therapy for tinea capitis. Several months of treatment with griseofulvin are often required. Both itraconazole and terbinafine, which have shown equal efficacy to that of griseofulvin, are options that should be considered because of the need for the shorter course of therapy with these agents.

DRUG INTERACTIONS AND ORAL ANTIFUNGAL AGENTS
The extent to which an antifungal agent interacts with the hepatic P-450 enzyme system has profound implications on its potential for clinically significant drug interactions (43). Azoles are metabolized by cytochrome P-450 3A (CYP 3A) and may inhibit by competition the elimination of other drugs that are also metabolized by CYP 3A. Other drugs metabolized by CYP 3A include astemizole, antiarrhythmics, cortisol, cyclosporin, estradiol and tacrolimus. Griseofulvin is an inducer of CYP 3A, and it may decrease the concentration of drugs, such as anticoagulants, oral contraceptives and salicylates. Terbinafine is an allylamine and not an azole; it does not affect CYP 3A and it has few drug interactions. Table 3 lists the clinically significant drug interactions of the azoles.
For a good review of antifungal agents for common paediatric infections, see "Dermatophyte infections in children" (44).