Antifungal agents for common outpatient paediatric infections

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The most common fungal infections in infants and children are mucocutaneous candidiasis, pityriasis versicolor, tinea corporis, tinea pedis, and tinea capitis ^[1]. The objective of the present update is to inform clinicians on options for treatment of these symptomatic but non-life-threatening fungal infections in immune-competent hosts, given the wide variety of topical, usually over-the-counter (OTC) (Table 1), and oral prescription (Table 2) drugs available. This update replaces the position statement published in 2007 ^[2].

Mucocutaneous candidiasis

Candida albicans colonization can occur as early as the first week of life. Symptomatic infections such as thrush and Candida diaper dermatitis (CDD) may develop at any age thereafter, particularly following broad-spectrum antibiotic treatment. Systemic candidiasis is rare, but is a particular risk for premature infants ^[3][4].

Although mucocutaneous candidiasis is common, relatively few high-quality randomized control studies of drug therapy in immune competent hosts have been published ^[5][6].

Oropharyngeal candidiasis (thrush)

Oropharyngeal candidiasis (thrush) may start as early as seven days after birth, with an incidence in infants of 5% to 10% depending on the population studied ^[7][8]. Response to antifungal agents is usually good in neonates with no major underlying condition, but a prolonged course may be required and recurrences are common. Colonization of the mother’s nipples in breastfed infants should be considered as a potential mode of transmission. Use of an infant soother increases the incidence of thrush and may make treatment less effective, unless the soother is washed carefully after use ^[9]. In older children, use of antibiotics or inhaled glucocorticoids is a predisposing factor for infection. Patients with severe or recurrent thrush should be investigated for congenital or acquired immune deficiency.

Nystatin suspension has been used since the 1950s ^[10]. It is well tolerated and remains the most frequently prescribed agent for mild thrush in immune-competent hosts. The usual dosage is highly effective, curing 80% of newborns after 2 weeks of treatment ^[5][11]. It should be administered after feeds.

First-generation imidazoles, such as miconazole and clotrimazole, are more effective than nystatin ^[12]. In children 3 years of age or older, mild disease or chronic oral candidiasis may be treated with clotrimazole troches ^[5][13]. Miconazole gel is not licensed in Canada. There is also anecdotal experience that clotrimazole suppositories in a pacifier or clotrimazole vaginal cream applied to the oral mucosa after feedings are effective against thrush ^[14][15]. Because these therapeutic approaches have not been evaluated in controlled trials, they are not recommended as first-line therapies.

Table 1. Selected topical antifungal agents for children
Drug	Formulation	Trade name	Dose	Activity against fungal agent			Indication
				Candida	Dermatophyte	Malassezia
Ciclopirox*	1% cream/lotion	Loprox	Twice daily	+	+	+	Tinea (corporis, pedis, cruris, ungium) Pityriasis versicolor
	Shampoo	Stieprox	Twice weekly	+	+	+	Tinea (corporis, pedis, cruris) Pityriasis versicolor
	8% nail lacquer	Penlac	Once daily  x 4 to 8 wks Approved for children >12 yrs	+	+	+	Onychomycosis
Clotrimoxazole	1% cream troches	Canesten Clotrimaderm	Twice daily x 2 to 3 weeks	+	+	+	Cutaneous candidiasis (e.g., diaper candidiasis);    Pityriasis versicolor; Tinea corporis, pedis, NOT capitis
Ketoconazole	2% cream	Nizoral	Once daily	+	+	+	Cutaneous candidiasis Tinea corporis NOT capitis
	shampoo		Once 2 to 3 times weekly	+	+	+	Pityriasis versicolor Tinea capitis (shampoo may be used only as an adjunct to oral therapy)
Miconazole	2% cream	Micatin Monistat	One to two times daily	+	+	+	Cutaneous candidiasis Tinea (corporis, cruris, pedis) Pityriasis versicolor
Nystatin	Cream/ointment 100,000 units/g	Flagystatin Nyaderm	Two to three times daily	+	-	-	Oral candidiasis
Terbinafine*	1% cream or spray	Lamisil	One to two times daily	-	+	+	Tinea (corporis, pedis, cruris) Pityriasis versicolor
Tolnaftate	1% cream, powder or spray	Tinactin	Two times daily	-	+	-	Tinea (pedis, cruris, corporis)
Selenium sulfide	2.5% lotion	Versel/Selsun	Once daily  x 3 to 7 days	-	sporicidal	+	Pityriasis versicolor
	1% shampoo	Selsun blue	Once daily	-		+	Pityriasis versicolor Seborrheic dermatitis Tinea capitis: used as adjunct to oral therapy
Zinc pyrithione	shampoo		Twice weekly			+	Pityriasis versicolor Seborrheic dermatitis
*Available by prescription only

Second-generation imidazoles, such as oral fluconazole, may be considered if conventional topical treatments fail, or in moderate to severe cases. Although fluconazole is effective, it is not recommended for first-line management of thrush in immune-competent children because of limited paediatric data, potentially significant adverse effects, higher cost, and risk for promoting antifungal resistance.

In cases of refractory thrush, consultation with an infectious disease specialist is recommended for additional investigations of immune function (e.g., human immunodeficiency virus infection) and fungal susceptibility ^[5][16].

Candida diaper dermatitis (CDD)

CDD is common during the second to fourth months of life in healthy infants ^[8][9]. Candida albicans is present in the feces of 90% of such infants ^[13][17]. Treatment should include decreasing maceration of the skin by eliminating impervious diaper covers, changing diapers frequently, and leaving diapers off for long periods of time. Topical antifungal therapy is also recommended. In one randomized, double-blind, controlled trial ^[18] comparing miconazole ointment with zinc oxide petroleum base, miconazole was safe and more effective, particularly in moderate to severe cases. Ointments, creams and powders of nystatin, miconazole, and clotrimazole are available (Table 1). Oral antifungal therapy is not recommended in immune-competent hosts with diaper dermatitis because it can promote colonization with fluconazole-resistant Candida species. In two studies which used concomitant oral therapy ^[19][20], no difference in the initial clinical responses was found.

There are no well-designed trials to assess the efficacy of adding a topical anti-inflammatory agent in treatment of CDD. Potent anti-inflammatory preparations, such as those with high concentrations of steroids, may impair the response to antifungal agents and should be avoided. The role for low potency steroids (e.g., 1% hydrocortisone) is unclear. Although some experts never use steroids with antifungal agents, others advocate them in CDD.

Pityriasis versicolor is a mild, chronic condition characterized by scaly hypo- or hyperpigmented lesions on the trunk. Infection often occurs in adolescents when the sebaceous glands are active. Malassezia, an organism restricted to invading the stratum corneum ^[21], causes the infection ^[22]. Antifungal preparations can be effective, but recurrences are common ^[23].

Topical ketoconazole, selenium sulfide, and clotrimazole are the most common treatments ^[24]. Treatment usually consists of applying shampoo preparations, such as ketoconazole 2% or selenium sulfide as a 2.5% lotion or 1% shampoo, to the affected area for 15 min to 30 min nightly for one to two weeks, and then once a month for three months to avoid recurrences ^[25]. In one randomized trial ^[26] using ketoconazole shampoo for three days versus one day versus placebo, the responses were 73%, 69% and 5%, respectively.

Tinea corporis

Tinea corporis (ringworm) is a superficial infection of the skin that is not covered by hair. It can occur at any age. Lesions are circular (thus the name ringworm). Common causes in Canada include Trichophyton rubrum, Trichophyton mentagrophytes and Microsporum species (especially Microsporum canis), and Epidermophyton floccosum). These are transmitted by direct contact with infected humans, animals (usually dogs and cats) or (rarely) by fomites ^[27].There is little difference in efficacy among clotrimazole, ketoconazole, miconazole, or terbinafine. A good response usually occurs when any of these agents are applied topically, once or twice daily for 14 to 21 days. Continuing topical applications for at least 14 days beyond clinical resolution is recommended to reduce likelihood of relapse. Topical agents mixed with corticosteroids should be avoided ^[25].

Tinea pedis and onychomycosis

Tinea pedis (athlete’s foot) is a common superficial fungal infection of the foot. Causes include T rubrum, T mentagrophytes and E floccosum. Although tinea pedis often spreads among household members, it is uncommon in young children ^[27][28]. Individuals with Trisomy 21 or immune compromise have an increased susceptibility to dermatophyte infections. Onychomycosis (fungal infections of fingernails and toenails) may be caused by dermatophytes and (less likely) by non-dermatophytes (e.g., Candida spp, Scytalidium) ^[29].

Many topical antifungals are effective against tinea pedis. Drying agents, such as Burow’s solution, may be a useful adjunct for macerated or vesicular lesions. Recurrence of the infection can be prevented with good foot hygiene. For infections involving the toenails (onychomycosis), topical antifungal lacquers (e.g., ciclopirox nail laquer) are an effective first-line therapy. However, oral therapy with terbinafine is indicated for refractory cases. A prolonged course of oral therapy of at least 6 weeks (for fingernail infections) and 12 weeks (for toenail infections) is needed for cases where the nail matrix is involved. Treatment may sometimes be required for months to a year. Terbinafine has excellent action against dermatophytes, but is less effective for Candida onychomycosis, and these cases are best treated with azoles. Nail clippings sent for culture allow differentiation between dermatophyte and non-dermatophytic fungal nail infections. In difficult-to-clear infections, referral to an infectious diseases specialist is highly recommended. There are no established paediatric dosing guidelines for oral itraconazole to manage superficial mycoses ^[30]-[32].

Tinea capitis and seborrheic dermatitis

Tinea capitis (fungal infection of the scalp) is the most common paediatric superficial dermatophyte infection. The causative species vary geographically; M canis predominates in Europe, whereas Trichophyton tonsurans predominates in North America. Because the fungal elements are within the hair shaft or follicle, tinea capitis does not respond well to topical therapy alone. Systemic therapy is required, with terbinafine considered first-line therapy (Table 2) ^[27][29]. A boggy or fluctuant round area with associated hair loss, known as a kerion, responds to terbinafine and usually does not require antibiotics or surgical drainage ^[33][34]. Rarely, other dermatophyte species may cause disease in children exposed to infected household pets or farm animals, or living in immigrant populations. In such cases, consideration should be given to obtaining cultures early, and early referral to an infectious diseases specialist may also be beneficial.

Table 2. Selected oral antifungal agents for children
Drug	Formulation	Dose	Duration	Indication
Clotrimazole	10 mg troches	One 5 times daily For children ≥3 years	7 to 10 days	Oral candidiasis
Fluconazole*	10 mg/mL liquid 50 mg tablets 100 mg tablets	3 to 6 mg/kg/d	7 to 14 days	Oral candidiasis  In moderate to severe cases (>50%  of oral mucosa affected or erosive lesions)
		6 mg/kg/d (max 400 mg/d)	3 to 6 weeks	Tinea capitis (2nd-line treatment)
Itraconazole* ¥	100 mg capsule 10 mg/mL liquid	Dose not well established 2 to 5 mg/kg/d in 1 to 2 divided doses (max dose 400 mg/day) Should only be used on ID recommendation	6 weeks 12 weeks	-Onychomycosis     Fingernails Toenails
			2 to3 weeks 2 to 6 weeks	Tinea capitis  Trichophyton spp  Microsporum spp
Nystatin	(100,000 units/mL)	1 to 4 mLs every 6 h	7 to 14 days	Oral candidiasis (Mild) Excellent efficacy in mild disease
Terbinafine*	250 mg tablet	4 to 6 mg/kg/d (max 250 mg) OR 10 kg to 20 kg: 62.5 mg 20 kg to 40 kg: 125 mg >40 kg: max 250 mg	2 to 6 weeks 8 to 12 weeks	Tinea capitis (1st-line treatment) Trichophyton spp Microsporum  spp
			6 weeks 12 weeks	Onychomycosis (1st-line treatment for children <12 years who cannot use nail lacquers) Fingernails Toenails
*These drugs can be hepatotoxic. Some experts recommend baseline, then periodic testing of transaminases, especially when a therapy course exceeding 4 to 6 weeks is anticipated [31]. †Azoles (fluconazole and itraconazole) may interfere with metabolism of other drugs (see Drug Interactions, below). Prescription is required for all the agents in this table. ¥ Itraconazole is not considered first-line therapy for either indication (tinea capitis or onychomycosis). Data are also limited regarding use as alternate agent in tinea capitis. Itraconazole may  be considered for cases of onychomycosis when first-line agents have failed or are unavailable [34].

Cases due to T tonsurans respond well to 4- to 6-week courses of terbinafine, while Microsporum species usually require 8- to 12-week courses ^[29]. The latter may be associated with terbinafine treatment failures, and may require alternate second-line systemic antifungal therapy ^[33][34] and consultation with an infectious diseases specialist. Dermatophyte cultures of scalp scrapings allow identification of the causative agent and are strongly recommended for persistent or recurrent infections. In addition to systemic therapy, ketoconazole or selenium sulfide shampoos may be applied 2 to 3 times weekly to help lower the carriage of viable fungal elements. These shampoos should only be used in conjunction with systemic therapy, however ^[29].

Seborrheic dermatitis and pityriasis capitis (cradle cap) are common, but usually mild, scalp infections caused by Malassezia species (e.g., Malassezia furfur). The condition often resolves with mild soap application. Shampoos containing selenium sulfide or an azole are useful in severe forms.

Oral antifungal agents absorbed systemically

Fluconazole

Fluconazole is a triazole with activity against Candida species, some dermatophytes, and many systemic mycoses. The drug is hydrophilic and, thus, present mainly in bodily fluids rather than in keratin or lipids ^[35]. It is, therefore, not useful for routine treatment of most superficial fungal infections ^[36][37]. Although fluconazole is not considered first-line therapy, it is reasonably effective in treating tinea capitis caused both Trichophyton and Microsporum spp ^[29][34] and therefore may be considered as an alternate option when first-line therapy fails. Hepatic enzymes must be monitored if therapy is prolonged.

Griseofulvin

Griseofulvin has excellent efficacy in tinea capitis caused by Microsporum spp but is no longer commercially available in Canada. Griseofulvin may be available at specialized compounding pharmacies, however.

Itraconazole

Itraconazole is an azole with activity against many dermatophytes, Candida species, M furfur, and some moulds. Despite this activity, itraconazole is still not considered a first-line agent for cutaneous fungal infections in children, because data on safety and efficacy are lacking ^[29]. Itraconazole has a long half-life in the skin and nails, an affinity for both lipids and keratin, and reaches the skin primarily through sebum. The drug may be excreted in sebum for one month after therapy has been discontinued. Itraconazole is available in tablet and liquid formats. Limited data suggest equivalent efficacy to fluconazole in treating tinea capitis, and good efficacy in treating onychomycosis. However, itraconazole use should be limited to cases where first-line therapy has failed, and hepatic enzymes require monitoring during extended use.

Ketoconazole

Ketoconazole was the first azole evaluated for efficacy in the treatment of resistant superficial fungal infections such as tinea capitis. In 2013, Health Canada released an advisory that ketoconazole had been associated with reports of serious hepatotoxicity and death. Ketoconazole is no longer recommended for the treatment of mild to moderate fungal infections.  

Terbinafine

Terbinafine is a lipophilic and keratinophilic fungicidal agent, active in vitro against dermatophytes and some moulds. It diffuses into keratinocytes from the bloodstream to reach the stratum corneum and hair follicles ^[38]. Because terbinafine is not metabolized through cytochrome P-450, many of the drug interactions seen with the azoles do not occur. Terbinafine is well tolerated, with gastrointestinal and skin reactions in only 2% to 7% of patients. Loss of the sense of taste has been reported, but resolves after therapy has ended. Similar to ketoconazole, Health Canada has cautioned prescribers that terbinafine may cause serious hepatotoxicity. Caution should be exercised, especially in patients with risk factors for or pre-existing hepatic disease. Liver enzymes should be monitored periodically, especially in patients who go on to require therapy beyond 4 to 6 weeks ^[29].

Oral terbinafine is effective in the treatment of relatively resistant superficial dermatophyte infections, including tinea ungium (onychomycosis), tinea pedis, and tinea corporis or tinea cruris, achieving mycological cure in over 80% of adult patients ^[39]. Terbinafine is effective for children with tinea capitis caused byTrichophyton spp ^[29][40-44], but may be associated with treatment failures in children’s Microsporum infections. One study ^[45] concluded that terbinafine may be the drug of choice for superficial fungal infections in children. Terbinafine is available in Canada as a topical 1% cream and orally as a 250 mg tablet. No liquid formulation is available.

Drug interactions

Azole antifungals have a good safety profile on their own, but they are known to cause a number of clinically significant drug interactions ^[46]. Azoles co-administered with some drugs can either increase co-administered drug levels and produce toxicity (e.g., immunosuppressive agents, chemotherapy agents, phenytoin, midazolam), or the co-administered drug can reduce azole levels, thus lowering efficacy. Azoles may also prolong the QT-interval, and they potentiate this effect when used along with other medications also known to do so (e.g., azythromycin). Terbinafine is not an azole, but it is hepatically metabolized. Consultation with a clinical pharmacist is recommended when patients are receiving other drugs or have liver disorders.

INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE (2007)

Members: Robert Bortolussi MD (past-Chair); Natalie A Bridger MD; Jane C Finlay MD; Susanna Martin MD (Board Representative); Jane C McDonald MD; Heather Onyett MD; Joan Louise Robinson MD (Chair)

Liaisons: Upton D Allen MD, Canadian Pediatrics AIDS Research Group; Janet Dollin MD, The College of Family Physicians of Canada; Charles PS Hui MD, Health Canada, Committee to Advise on Tropical Medicine and Travel; Nicole Le Saux MD, Canadian Immunization Monitoring Program, ACTive; Dorothy L Moore MD, National Advisory Committee on Immunization; Larry Pickering MD, American Academy of Pediatrics, Committee on Infectious Diseases; John S Spika MD, Public Health Agency of Canada

Consultant: Noni E MacDonald MD

Updated in 2019 by: Tobey Audcent MD, Michelle Barton MD, Karina Top MD

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References

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Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.