Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter VI.32. Candida and Fungal Infections
Wendy C. Matsuno, MD
May 2002

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This is a 14 year old male who presents to the office with tender, itchy feet. He has been having persistent itchiness of his toes, particularly between the fourth and fifth toes for the last week. He has been otherwise healthy, and even boasts that he is playing for the community football team.

Exam: VS T 37.0, P 74, R 12, BP 118/64. Ht/Wt at the 50th percentile. The patient is alert, active and in no distress. His physical exam is unremarkable except for his feet. The toes on both feet are inflamed and some scaling of the skin is noted. The interdigital space, between the fourth and fifth toes, appears to be the most affected. There is some cracking and thickening of the anterior plantar surfaces.

A culture of the area is taken and he is prescribed topical tolnaftate cream. He is also advised to use slippers when in the locker room showers, and to wash his feet well when he bathes at home. A week later, he returns with some relief of his symptoms. The results of the culture identify Trichophyton rubrum and Candida albicans. His topical therapy is changed to clotrimazole cream (an imidazole) applied twice daily for 3-4 weeks, since tolnaftate does not cover Candida albicans.


Superficial fungal infections of the skin, nails and hair are common (1). The fungi causing these infections are one of three types: dermatophytes, Candida species or Malassezia furfur. The recent increased incidence has been attributed to a greater number of immunocompromised hosts, use of chemotherapeutic agents, lifestyle changes (increased use of health clubs) and the large elderly population (1). Superficial infections can progress to systemic infections, but systemic and disseminated fungal infections are serious infectious which require inpatient care by infectious disease specialists, that are beyond the scope of this chapter.

Dermatophytoses is a common fungal infection caused by three genera of filamentous fungi: Trichophyton, Microsporum, and Epidermophyton. These organisms can infect any keratinized epithelium, nail and hair follicle because they utilize keratin as a nutrient. Trichophyton species infect skin, nails and hair, with T. rubrum the most common organism (2). Microsporum species primarily invade the hair, while Epidermophyton species invade the intertriginous skin.

Dermatophytoses are classified by the natural habitat in which they grow. Anthropophilic dermatophytes are those acquired from humans and can cause chronic low-grade infections to acute inflammatory disease. Geophilic dermatophytes infect humans sporadically causing an inflammatory reaction and are acquired from the soil. Zoophilic dermatophytes are acquired from animals through direct or indirect contact. The name of the infection itself is determined by the word 'tinea' followed the Latin word for the site of involvement.

Tinea capitis is a dermatophyte infection of the scalp (3). Prior to the 1900s, the most common cause of tinea capitis was Microsporum canis (4). In 1900-1940, M. audouinii was found to be the prominent cause of tinea capitis in North America and Western Europe (4). Since 1952, however, the incidence of tinea capitis caused by T. tonsurans has steadily risen and is now the primary cause of tinea capitis in the United States (4).

The presentation of tinea capitis caused by T. tonsurans can be of either the inflammatory or non-inflammatory type. The inflammatory type occurs in about 40% of cases, and can be accompanied with a kerion (edematous boggy nodule) or dermatophytid "id" reaction (fungus-free, papular eruption, usually on the trunk) (5). The non-inflammatory type occurs in the remaining 60% of cases (5). It presents with scaling in a dandruff-like manner or in a "black-dot" pattern with well demarcated areas of hair broken off at the orifice leaving the appearance of black dots. Posterior occipital and cervical adenopathy may be present.

The differential diagnosis of tinea capitis includes seborrheic dermatitis, psoriasis, alopecia areata, trichotillomania and some dystrophic hair disorders. With the presence of a kerion, a bacterial infection must be considered. In high risk individuals, the presence of patchy, moth-eaten alopecia could be a sign of secondary syphilis. Also, in cases with chronic tinea capitis, the diagnosis of discoid lupus and lichen planopilaris is also possible.

The diagnosis of tinea capitis must be done by potassium hydroxide (KOH) preparation or culture. Wood's light examination is not used because T. tonsurans, the most common causal organism in the US, does not fluoresce. In doing a KOH mount, "black dots" or scrapings from scaly areas should be collected, mixed with 10-20% KOH solution, heated and examined under the microscope. A KOH mount may give a false negative in the case of early or inflammatory lesions. Thus, a culture should be done. The most popular method to collect the culture is by the brush technique where a toothbrush is run over the scalp to pick up scales and hair debris. The culture is then plated on Sabouraud's dextrose agar with cycloheximide and chloramphenicol or on dermatophyte test medium. The culture will usually show growth in 7-10 days.

Topical therapy alone is ineffective in the treatment of tinea capitis (3). Topical therapy with 2.5% zinc sulfide or zinc pyrithione shampoo is helpful in decreasing the shedding of spores, but oral therapy is also needed to eradicate the infection. Oral therapy is often done with griseofulvin, which is currently the only drug approved by the U.S. Food and Drug Administration for the treatment of tinea capitis in children (4). In 1997, the recommended dose and duration of treatment with griseofulvin by the Infectious Disease Committee of the American Academy of Pediatrics was 10-20 mg/kg/d (using the microsize formulation of griseofulvin) for 4 to 6 weeks, with the intention of treatment continuing until 2 weeks after clinically asymptomatic (4). If the ultramicrosize formulation of griseofulvin is used, 5-10 mg/kg/day in a single or two divided doses is the recommended dosage (not to be used in children under 2 years of age). However, most experts use a dose of 20 mg/kg/d (microsize). "Microsize" refers to the product formulation of griseofulvin. The other preparation is ultramicrosize. The difference is that microsize has an absorption of 25-75% after an oral dose vs ultramicrosize which is almost completely absorbed. So an oral concentration of 500 mg of microsize griseofulvin produces similar serum concentrations to 250-330mg of ultramicrosize griseofulvin. The Microsporum species that were the primary causes of tinea capitis in past years, are more sensitive to griseofulvin than T. tonsurans, which explains why tinea capitis is currently more difficult to treat.

Three other agents are also being investigated: terbinafine, itraconazole, and fluconazole. Terbinafine at a dose of 5-11 mg/kg (depending on level of involvement) was used for 1, 2 and 4 weeks with an overall cure rate of 44%, 57%, and 78% respectively (1). In a comparison of terbinafine with griseofulvin, the primary response rates in 50 patients treated for 8 weeks were found to be 72% and 76%, respectively (4). However, at 12 weeks, fewer recurrences were seen with terbinafine with an efficacy of 76% as compared to griseofulvin with an efficacy of 64% (4). In cases of tinea capitis caused by Microsporum species, terbinafine was found to be less effective than griseofulvin with only a 32% cure rate 14 weeks after a 6-week course of therapy (4). Disadvantages of terbinafine include its decreased effectiveness against Microsporum species (compared with griseofulvin), gastrointestinal disturbances seen in 5% of patients and the potential for interactions with other drugs, such as rifampin and cimetidine (4).

Studies are also being conducted with itraconazole and fluconazole. The dosing for itraconazole is 5 mg/kg or 100 mg/day for 2-6 weeks (4). A 6-week course of itraconazole was found to be comparable to a 6-week course of griseofulvin (4). For fluconazole, a study of 44 children infected with T. tonsurans, demonstrated that a dose of 6 mg/kg for 20 days was found to be safe with an efficacy of 89% (1). Itraconazole and fluconazole were found to cause minor gastrointestinal side effects in 5% of patients and cause a reversible, asymptomatic elevation in liver function tests in 1 of 17 patients (4).

Tinea pedis, more commonly known as athlete's foot, is the most common fungal infection (1). The usual etiologic agents are T. rubrum (most common), T. mentagrophytes and E. floccosum (1). Non-dermatophytes and candida species can coexist or produce similar infections. Predisposing factors include occlusive footwear, hot, humid weather, and walking barefoot on contaminated floors. Arthrospores are able to survive for 12 months in flakes of human skin cells.

Tinea pedis is usually seen in preadolescent and adolescent males, and less likely in younger children (3). The toe webs and soles of the feet, most commonly the lateral toe webs, are usually affected. Patients often present with severe tenderness, pruritus, foul odor, fissuring, scaling and maceration of the surrounding skin. In some cases, a diffuse hyperkeratosis of the sole of the foot with mild erythema is seen. In infections with T. mentagrophytes, usually in young children, an inflammatory vesicular reaction is seen on the dorsal surface of the foot. Breaks of the skin may occur leaving a pathway for bacterial infection with group A streptococcus or Staphylococcus aureus. The infection may also spread to the inguinal area (tinea cruris), trunk (tinea corporis), hands (tinea manuum), or nails (tinea unguium).

The differential diagnosis includes normal peeling of the interdigital spaces and infection by Candida or other bacterial organism. Contact dermatitis, atopic dermatitis, and dyshidrotic eczema can also mimic tinea pedis (3).

The diagnosis of tinea pedis can be made by KOH slide examination or by culture. On KOH microscopic examination, fungal mycelia or hyphae are seen. Fungal culture can also reveal the diagnosis. The use of a Wood's lamp can demonstrate erythrasma (coral red fluorescence under the Wood's lamp), but does not provide definitive diagnosis of tinea pedis.

The treatment of tinea pedis involves topical and systemic agents to cure and to prevent recurrence. Topical therapy with tolnaftate, imidazoles (e.g., miconazole or clotrimazole), ciclopirox, etc., can be used once or twice daily for 1-4 weeks (1). Tolnaftate, however, can only be used in uncomplicated cases, since it is not effective against Candida species (3).

Systemic therapy with an imidazole (e.g., oral ketoconazole, itraconazole) is usually sufficient. In one study of 484 patients enrolled in 15 different studies, itraconazole, 200mg twice a day for one week, was found to be highly effective with a cure rate of 85% (1). Thus, this is the recommended regimen for plantar type tinea pedis.

Secondary prophylaxis of tinea pedis is important because recurrences are common. Preventive measures include avoidance of occlusive footwear, use of footwear when bathing in public showers, and complete drying of the area between the toes after bathing. The use of absorbent anti-fungal powder, such as zinc undecylenate (Desenex), which does not cover Candida species, is also helpful (3).

The dimorphic yeast of the genus Candida causes candidal infections. Candida is ubiquitous and may be present on the skin. Beyond the neonatal age, however, C. albicans is considered as part of the normal oral and intestinal flora (6). Environmental factors such as elevated temperature and increased humidity, as well as a decrease in the normal bacterial flora (e.g., due to antibiotics use) can lead to the overgrowth of the yeast. Candida albicans is the primary species that causes candidiasis in children (3). Many candidal infections clear spontaneously, and are relatively minor, such as oropharyngeal candidiasis (thrush) and candidal diaper dermatitis; however, systemic candidiasis can occur, which is serious and beyond the scope of this chapter. Chronic mucocutaneous candidiasis is due to a T-cell deficiency and a specific anergy which is also beyond the scope of this chapter.

Oropharyngeal candidiasis, also known as oral thrush, is rare in the first week of life. When it does appear in the neonate, it is most commonly acquired during passage through the birth canal from the mother's infected vaginal mucosa (vaginal candidiasis). In neonates of mothers with vaginal candidiasis, oral thrush was 35 times more common than in those of non-infected mothers (6). It was found that 20% of mothers with positive vaginal cultures had neonates with positive oral cavity cultures and 11% went on to develop oropharyngeal candidiasis (6). It is important to note that approximately 31% of women with positive vaginal cultures for C. albicans do not complain of discharge (6). Oropharyngeal candidiasis in neonates usually develops an average of 8 days after birth (6). The average interval between a positive C. albicans culture to clinical findings is about 3 days (6).

In addition to being transmitted via the birth canal, C. albicans can also be transmitted from incomplete sterilization of babies' bottle feeding or from the mother's breast. The incidence of oral thrush is higher in bottle-fed infants than in breast-fed infants (6). Neonates and young children are often affected because of the immaturity of host defenses and incomplete establishment of the gastrointestinal flora.

Oropharyngeal candidiasis (thrush) often presents as whitish patches on the tongue, gums and buccal mucosa. The soft palate, uvula and tonsils may also be involved. The patches are adherent (but can be removed revealing a erythematous base, unlike leukoplakia which is not able to be removed) and are made of epithelial cells, leukocytes, keratin, food debris and C. albicans in blastospore and pseudohyphae forms. The patient may exhibit decreased appetite and poor nursing due to pain and/or discomfort, but they are often asymptomatic. Patients taking antibiotics are at higher risk of developing thrush.

Treatment varies from no treatment, to absorbed agents and non-absorbed agents. In untreated cases in newborns, oral thrush has been found to clear on its own in 23-59 days (6). Absorbed agents, such as fluconazole and ketoconazole, are effective, but the non-absorbed (topical) agents are preferred because they are equally effective.

The classically used non-absorbed agents are gentian violet and nystatin. Gentian violet is a non-absorbed agent composed of formaldehyde and mercurochrome. It is effective in inhibiting the growth of C. albicans in the mouth, but not in the bowel. This agent is unfavorable because recurrences are common, with the additional adverse effects of ulceration and irritation of the oral mucosa, staining of tissue and clothing, and the possibility of being carcinogenic (6). Nystatin comes as a suspension. It is usually applied topically three times a day. Older children and teens can swish it in their mouth, but it should be applied with a cotton applicator onto the lesions in infants and young children. Nystatin has activity against candida only (i.e., no activity against tinea and other dermatophytes).

Newer non-absorbed agents, miconazole and clotrimazole, have also been studied. Miconazole is a first generation imidazole that has in vitro activity against yeast, dermatophytes and some Gram positive bacteria. Miconazole oral gel has been studied and found to be more effective than nystatin suspension. In a study of 183 ambulatory infants with no other underlying disease, 85% of infants treated with miconazole oral gel and 21% of infants treated with nystatin suspension were cured on day 5 (6). Miconazole has a superior cure rate and a lower rate of recurrence (6).

Candidal diaper dermatitis is a benign condition that often occurs concomitantly with oropharyngeal candidiasis. Since infants with oropharyngeal candidiasis have C. albicans in their gastrointestinal tract, they inevitably excrete it as well. Infants with oropharyngeal candidiasis have been found to have candidal diaper dermatitis in about 57% of cases (6). However, many infants have candida diaper dermatitis without thrush. Patients on antibiotics are at higher risk of developing candidal diaper dermatitis.

Candidal diaper dermatitis often presents in the perianal area as erythematous (classically described as beefy red), confluent plaques with well defined edges and a scalloped border. There are often satellite lesions (red spots), which are the primary lesions, and are considered the hallmark of localized candidal infections. Candidal diaper dermatitis often extends to the perineum, upper thighs, lower abdomen and lower back. The diagnosis of candidal diaper dermatitis can be established by culture of the area. However in most instances, the diagnosis is made clinically by its characteristic appearance. Treatment of candidal diaper dermatitis involves topical therapy such as nystatin, miconazole or clotrimazole. These agents are usually applied with each diaper change or four times a day.

In patients that have frequent recurrences of candidal diaper dermatitis, oral therapy may be used. Since C. albicans is often harbored in the gastrointestinal tract, oral treatment along with topical treatment may be beneficial. In one study of infants less than three months of age with feces positive for C. albicans, oral plus topical nystatin was compared to oral placebo plus topical nystatin. The mycologic cure rates were the same, but oral nystatin reduced the recurrence rate to 16%, compared to 33% for topical nystatin alone (6).

Tinea versicolor is a chronic fungal infection of the stratum corneum. The dimorphic yeast, Malassezia furfur (previously known as Pityrosporum ovale and Pityrosporum orbiculare), is the infecting organism. The yeast form is present as part of the skin's natural flora, but the filamentous form is seen in the disease state. This organism is more commonly seen in areas of the skin with sebum production capabilities and infection is seen more commonly in adolescents and young adults (3). Tinea versicolor presents with a lesion of varying color depending on the individual's skin type. In lighter skinned individuals, the lesions are typically seen as reddish-brown macules with fine scales. In darker skinned individuals, the lesions may appear as hyperpigmented or hypopigmented macules. The lesions usually start in a perifollicular area then coalesce to form the macular, scaly lesions. The common locations are the neck, upper chest, upper back and upper arms. Involved areas are usually not pruritic and they do not darken after sun exposure.

The diagnosis of tinea versicolor is usually made by clinical appearance, but confirmatory evidence can be obtained with a Wood's lamp, KOH preparation, and skin biopsy. Wood's lamp examination reveals a yellowish gold fluorescence. When examining KOH prepared scrapings from the lesion, a "spaghetti and meatballs" appearance is seen. The "spaghetti" are the thick, angular hyphae and the "meatballs" are the spores. Skin biopsy with culture and periodic acid-Schiff staining for fungi may be necessary to diagnose cases with principally follicular involvement. Under examination, M. furfur is seen in the follicle.

The differential diagnosis of tinea versicolor includes dermatophytoses, seborrheic dermatitis, pityriasis alba and secondary syphilis. Post-inflammatory pigment changes, although they usually do not have scales, may mimic tinea versicolor.

The treatment of tinea versicolor involves topical and oral therapy. Topical agents include selenium sulfide suspension, sodium thiosulfate lotion, and 3-6% salicylic acid applied once or twice daily for 2-4 weeks. Imidazoles such as, miconazole, clotrimazole and ketoconazole can be used twice daily for 2-4 weeks. Terbinafine cream is also effective when used for 2-4 weeks twice a day. When topical therapy fails, oral therapy can be used. Ketoconazole, fluconazole and itraconazole are commonly used oral therapy agents.

M. furfur is a normal saprophyte of the human skin, thus it is not eradicated. Tinea versicolor infections can, therefore, recur in susceptible individuals. Some risk factors of developing a tinea versicolor infection include being in a warm, humid environment, immunosuppression, malnourishment, high plasma cortisol levels, genetic predisposition, and poor skin hygiene. In most individuals, good hygiene and a healthy diet can prevent recurrences.

Antifungal agents can be summarized as follows. Tolnaftate covers only tinea. Nystatin covers only candida. Imidazoles (clotrimazole, miconazole, ketoconazole, etc.) cover both tinea and candida. Amphotericin is generally given IV for systemic fungal or candidal sepsis or disseminated infection.


Questions

1. The most common cause of Tinea capitis in the United States is:
. . . . . a. M. canis
. . . . . b. T. tonsurans
. . . . . c. M. audouinii
. . . . . d. T. capitatans

2. True/False: Tinea Capitis, "black dot" pattern, is best diagnosed with Wood's lamp.

3. True/False: Tinea pedis is most commonly seen in infant females.

4. True/False: Oropharyngeal candidiasis and candidal diaper dermatitis often occur together because of C. albicans colonization of the gastrointestinal tract.

5. Tinea versicolor lesions appear as:
. . . . . a. Hyperpigmented macules
. . . . . b. Reddish brown macules
. . . . . c. Hypopigmented macules
. . . . . d. All of the above

6. Indicate whether the following agents are active against tinea, candida or both:
. . . . . a. tolnaftate
. . . . . b. nystatin
. . . . . c. clotrimazole
. . . . . d. miconazole
. . . . . e. amphotericin
. . . . . f. ketoconazole


References

1. Aly R. Skin, hair and nail fungal infections. Current Opinion in Infect Dis 1998;11(2):113-118.

2. Hazen KC, Wu G. Kill power of oral antifungals against dermatophytes. Pediatr Infect Dis J 1999;18(2):200-204.

3. Darmstadt GL, Lane A. Chapter 616 - Cutaneous Fungal Infections. In: Nelson WE, Benrman RE, Kliegman RM, et al (eds). Nelson Textbook of Pediatrics, 15th edition. 1996, Philadelphia: W.B. Saunders, pp. 1896-1901.

4. Chen BK, Friedlander SF. Tinea capitis update: a continuing conflict with an old adversary. Current Opinion Pediatr 2001;13(4):331-335.

5. Aly R. Ecology, epidemiology and diagnosis of tinea capitis. Pediatr Infect Dis J 1999;18(2):180-185.

6. Hoppe JE. Treatment of oropharyngeal candidiasis and candidal diaper dermatitis in neonates and infants: review and reappraisal. Pediatr Infect Dis J 1997;16(9):885-894.


Answers to questions

1. b. T. Tonsurans is the most common cause of tinea capitis in the United States.

2. False. Tinea capitis, "black dot" pattern, is caused by T. tonsurans. This is an endothrix infection, thus would not be visible by Wood's lamp. Diagnosis is best done with KOH prep or culture.

3. False. Tinea pedis is most common in preadolescent and adolescent males.

4. True. C. albicans often colonizes the gastrointestinal tract. In 57% of patients with oropharyngeal candidiasis, candidal diaper dermatitis is also seen (6).

5. d. All of the above. Tinea versicolor lesions present differently depending on the individual's natural skin color. In light skinned individuals they often appear as reddish brown scaly lesions. In darker skinned individuals they can appear as either hyperpigmented or hypopigmented macules.

6a. tinea only.

6b. candida only.

6c. both.

6d. both.

6e. both.

6f. both.


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