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SUPERFICIAL FUNGAL INFECTIONS

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					                      SUPERFICIAL FUNGAL INFECTIONS
                            Pinar Oray-Schrom, MD
                                   Week 14


Educational Objectives:

    1. Understand the indications for treatment in onychomycosis and know the
       limitations of available treatments
    2. Describe how to differentiate tinea cruris from other rashes in the groin area
    3. Review the management of tinea versicolor


CASE ONE:


Mr. B. is a 67-year-old male, who has well-controlled type II DM, HTN and
hyperlipidemia. He comes for a routine visit after being lost to follow-up for the last
year. His diabetes has been well-controlled on metformin and glyburide. He also
takes lisinopril and pravastatin. He smokes one pack of cigarettes a day and he
admits to drinking alcohol once in a while. He has not seen a podiatrist for the last
few years. His main complaint is cramping in his legs for the last two months. He
denies any paresthesias. He states that he has always had ugly toenails due to severe
and repetitive trauma in his younger years when he used to be an athlete. He noticed
that his toenails have become thicker and crumbly over the years.

On examination you notice that both of his great toe nails and the fourth and fifth
toenails on the right foot look distorted. They are yellow brownish in color, thick
with some cracks on the surface. There is friable debris visible underneath the distal
edges of the nails. The skin in the web spaces between his toes is macerated with
erythema and scaling. His dorsalis pedal pulse is not palpable bilaterally, there is no
leg edema, and his calves are nontender.

You suspect onychomycosis and discuss initiation of treatment with him.
He states that it doesn’t bother him that his toenails are ugly and that he doesn’t
want to be on any more medications unless absolutely necessary. His brother took
medication for nail fungus for almost a year, and the fungus came back anyway. He
wants to know how effective your treatment will be.




Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
Questions:

    1. Regarding his toenails, what are some important aspects of diagnosis and
       treatment you have to consider and discuss with this patient before initiating
       therapy ?
       This patient most likely has tinea unguium and tinea pedis. Onychomycosis is the
       most prevalent nail disease, accounting for up to 50-60 % of all abnormal
       appearing nails. In North America 90% of toenail onychomycosis is caused by
       dermatophytes (Trichophyton species). There are four clinical types of
       onychomycosis.
           1. Distal -lateral subungual onychomycosis: This is the most common
              clinical presentation and is usually caused by T. rubrum invasion of the
              hyponchium. The nails are yellow with thick subungual hyperkeratosis and
              onycholysis.
           2. Superficial white onychomycosis: This is usually caused by T.
              mentagrophytes. It is an infection of the nail plate and appears as a chalky
              white plaque on the dorsal surface of the nail.
           3. Proximal subungal onychomycosis: This is usually caused by T. rubrum
              infection underneath the cuticle at the proximal nail fold. It can also be
              caused by Candida or nondermatophyte molds. It appears as white
              discoloration of the proximal nail plate. This type is often seen in patients
              with AIDS or in the immunosuppressed, although it may also be present in
              the immunocompetent patient.
           4. Candida: This type is most often caused by C. albicans, a common cause
              of fingernail onychomycosis, particularly in previously damaged nails.
              The clinical features of this type are not as characteristic but can include
              onycholysis, thickening, and yellow or brown discoloration.

        Presence of dystrophic nails alone is not sensitive or specific for onychomycosis.
        Nail dystrophies can occur with trauma, eczematous conditions, psoriasis,
        peripheral vascular disease, and lichen planus. Thus, laboratory studies are
        essential to making the correct diagnosis. Many health insurance companies in
        the U.S. require confirmation of the diagnosis by laboratory testing before
        approving reimbursement for systemic antifungal agents. Periodic acid-schiff
        staining with histological examination of the clipped, distal free edge of the nail,
        and attached subungual debris is the most sensitive diagnostic method (90-95%),
        followed by KOH 20 % microscopy (50-60 %). Fungal culture is the least
        sensitive, and most expensive test.

        After obtaining laboratory confirmation, an important question to answer is: Why
        treat? In many patients, onychomycosis is asymptomatic and goes unnoticed. It is
        not life- threatening and in most cases does not interfere with activities of daily
        living. Not all patients with onychomycosis need to be treated. However, an
        infected toenail might serve as a fungal reservoir that could spread infection to
        other body sites. In patients with diabetes with a history of cellulitis of the lower
        extremity, venous insufficiency or edema, onychomycosis can be a portal of entry

Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
        for secondary bacterial infections, promoting foot ulcers or gangrene. This
        patient population should therefore always be treated unless there is a
        contraindication for antifungal therapy.

        Before selecting a therapy, it is important to assess the patient for predisposing
        factors that contribute to a poor response to therapy. Predictors of poor response
        to oral therapy include lateral onychomycosis , thickened nail plate,
        dermatophytoma, and total nail plate dystrophy. In the elderly population,
        presence of peripheral vascular disease, diabetes, immunosuppression, and
        trauma are factors that contribute to poor response or recurrence, in addition to
        nail matrix involvement and having more than 75% of the nail plate affected.

        Topical agents have low efficacy. The oral therapy regimens for onychomycosis
        are as follows:

                 •   Terbinafine 250 mg daily for 12 weeks (toenails) or six weeks
                     (fingernails)
                 •   Itraconazole 200 mg daily for 12 weeks (toenails)
                 •   Itraconazole pulse therapy 200 mg twice daily for one week followed
                     by three weeks without medication (three pulses for toenails)

        Please also discuss relative costs of therapy (which is likely prohibitive if not
        covered by insurance)

            •    Terbinafine: $390/month (for 250 mg daily)
            •    Itraconazole: $480/month (200 mg daily)
            •    Ciclopirox 8% nail laquer: $210/ 6ml bottle

        Ketoconazole is not recommended due to potential hepatotoxicity. Terbinafine has
        better long-term cure rates and less drug-drug interactions when compared to
        Itraconazole and should be the treatment of choice nowadays. Long-term efficacy
        of oral antifungal therapy has been reported to be in the range of 29-81%.

        All oral antifungals can cause hepatotoxicity. Serum transaminase tests (AST and
        ALT) are suggested prior to beginning oral antifungal treatment and periodically
        during therapy if other conditions that might affect the liver coexist. The
        manufacturers of terbinafine do not recommended terbinafine for patients with
        existing liver disease. Adverse reactions associated with oral antifungal agents
        are usually mild, transient, and reversible after discontinuation of therapy. The
        most frequently reported adverse effects are associated with the GI system,
        followed by skin complaints and headaches.

        Topical therapy can be used in mild to moderate infections (<50 % of distal end
        affected) where the matrix is not involved, and few (<3-4) nails are affected. It
        can be used in combination with oral treatment or alone if oral agents can’t be
        used.

Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
            •    Ciclopirox nail lacquer 8% solution should be applied once daily for 48
                 weeks and removed weekly with alcohol.

            Ciclopirox nail laquer should be used with routine nail debridement to
            provide effective delivery of drug to the infected area and to reduce the
            burden of fungal material. The mycological cure rates at week 48 were 33%
            in the pivotal US clinical trials (Gupta, 2008). Other trials which were mostly
            open label showed mycological cure rates of 47-67% (Gupta, 2008). Though
            mycological cure rates are reasonable, overall success rates may be much
            lower. In a small randomized trial of 80 patients with dermatophyte
            onychomycosis without lunula involvement, comparison of terbinafine 250
            mg/day for 16 weeks with terbinafine plus ciclopirox applied once daily for 9
            months, showed mycological cure rates of 64.7% and 88.2% (p < 0.05)
            respectively. No significant difference was noted in the global cure rates,
            50 % and 67.6 % respectively (Loo, 2007). Combination therapy requires
            further study to determine efficacy.

    2. What about the problem between his toes?
       Tinea pedis (athlete’s foot) has three common presentations:

                     1) The interdigital form is the most common
                     2) A second form has a moccasin-like distribution pattern in which
                        the plantar skin becomes chronically scaly and thickened, with
                        erythema and hyperkeratosis of the soles, heels, and sides of the
                        feet
                     3) The vesiculobullous form is characterized by the development of
                        vesicles and pustules in an inflammatory pattern, usually on the
                        soles

        The differential diagnosis includes contact dermatitis, eczema, and pustular
        psoriasis. Although the history and clinical picture might be characteristic, a
        study performed in dermatologists’ offices revealed that amongst 874 foot rashes
        clinically diagnosed as tinea pedis, only 32% were confirmed to be tinea by
        culture. The remaining 68% of patients either had a nonfungal foot dermatitis or
        tinea pedis with false negative cultures (Fuchs, 2004). Therefore, the diagnosis
        should be confirmed by KOH examination of scrapings from the lesion.
        Streptococcal cellulitis is a potential complication of all three forms of tinea
        pedis.

        Treatment of tinea pedis consists of application of an antifungal cream to the
        infected area. It should be applied 2 cm beyond the active margin. Infrequently,
        systemic therapy is used for refractory infections. Several studies have shown that
        the twice daily application of the allylamine terbinafine resulted in a higher cure
        rate than twice daily application of the imidazole clotrimazole. Please refer to
        Table 2 in the American Family Physician article. Patients should be instructed to
        disinfect footwear to reduce factors contributing to hyperhidrosis. They should

Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
        avoid walking barefoot in public areas such as locker rooms. Using antifungal
        powders to prevent recurrences have not been shown to be effective.

        Considering all of the above, you should discuss the patient’s increased risk for
        bacterial cellulitis due to his underlying diabetes mellitus and peripheral vascular
        disease. A work-up for peripheral vascular disease should be initiated.

        The potential for a cure of his onychomycosis is decreased due to the fact that he
        has lateral onychomycosis, thickened nail plate, presence of DM and PVD.

        In summary, for this patient, because of extensive fungal disease he would require
        oral antifungal treatment. Since the treatment is costly and has potential side
        effects, the diagnosis should be confirmed prior initiation of treatment.
        Terbinafine 250 mg daily therapy for 12 weeks would be a good choice for him.
        Although Ciclopirox nail lacquer treatment has been shown to achieve
        mycological cure rates of 33%, there is not good data on the added clinical
        benefit of using it in combination with oral treatment at this time.
        Because hepatotoxicity is a side effect of terbinafine, and because the patient is on
        other medications that can affect his liver he should have his AST and ALT
        evaluated at baseline. You should also discuss his ETOH use in detail and advise
        him to abstain from alcohol during the course of the treatment. Periodic
        monitoring of his transaminases should be considered.


CASE ONE CONTINUED:


After confirming the diagnosis for onychomycosis and tinea pedis by KOH
microscopic examination, you have a lengthy discussion with him about possible
complications of these infections, treatment options, and side effects. He agrees to
start oral terbinafine for 12 weeks for his onychomycosis (after having his LFTs
checked) and tinea pedis. Since oral terbinafine will be effective against his tinea
pedis he does not require additional topical therapy for it. He doesn’t want to deal
with a nail lacquer at this point. He states that he will abstain from ETOH as he
wanted to quit anyway. You refer him for ABIs.

As he is walking out the door he says, “ By the way doc, I have been having this jock
itch, I tried some OTC creams, but they didn’t help. Can I use this cream you
prescribed for my feet?”

You inspect his groin area, which reveals a bilateral sharply marginated, brownish-
red macular patch on the inguinal areas and medial thighs. There is a collarette-like
scale, but you don’t appreciate central clearing or raised margins.




Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
    3. How do you make the diagnosis?
       The differential diagnosis for a rash of this description in the groin area includes:

            •    Tinea cruris
            •    Erythrasma
            •    Intertrigo
            •    Candidal intertrigo
            •    Inverse pattern psoriasis
            •    Pityriasis versicolor
            •    Seborrheic dermatitis
            •    Langerhans cell histiocytosis

        The patient has onychomycosis and tinea pedis, and because tinea cruris is very
        frequently associated with those two conditions, a diagnosis of tinea cruris would
        be very likely. Tinea rashes usually have an elevated margin or “active edge” and
        central clearing. This characteristic appearance can be altered by topical
        corticosteroid use, where the active edge might not be as prominent and the rash
        can become more uniform without central clearing. This altered tinea rash is
        frequently referred to as “Tinea incognito.” In this case the diagnosis can be
        made by direct microscopy or Wood’s lamp examination. Tinea cruris, candidal
        intertrigo and pityriasis versicolor can be diagnosed by visualizing the
        corresponding fungal structures under direct microscopy on a KOH preparation.
        Although Wood’s lamp examination has become less useful in making the
        diagnosis of tinea infections due to nonfluorescence of most tinea species, it is a
        very useful tool in distinguishing rashes due to other causative organisms. Tinea
        and Candida do not fluoresce, whereas Erythrasma has a typical coral red
        fluorescence (can be absent if the patient bathed recently). Most cases of tinea
        versicolor don’t fluoresce unless they are caused by the species Malassezia furfur,
        in which case it fluoresces yellow-green or blue-green. The wood’s lamp
        examination is useful in ruling in Erythrasma, if fungi were absent on direct
        microscopy.


CASE ONE CONTINUED:


Wood’s lamp examination shows red-coral fluorescence, upon which you make the
diagnosis of Erythrasma.



    4. What is your recommendation to the patient ?
       Erythrasma is a chronic bacterial infection caused by Corynebacterium
       minutissimum. It is part of the normal skin flora which can cause superficial
       infections under certain conditions. Predisposing factors are warm and humid
       climate, prolonged occlusion of skin, macerations, and diabetes. It affects the
       intertriginous areas of the toes, groins, axilla, and the inframammary area.
Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
        Erythrasma mimics epidermal fungal infections, and can cause burning or
        itching.

        Evidence based medicine does not offer clear-cut therapeutic recommendations.
        Topical erythromycin solution twice a day for seven days, benzoyl peroxide gel
        daily for seven days, topical 2% clindamycin up to three times a day for 14 days
        are mentioned in the literature. Oral erythromycin 250 mg qid for 14 days as well
        as other oral antibiotics are reported to be very effective in erradiacting disease.
        Since there is not good data comparing oral and topical treatment, side effects of
        systemic therapy should be reviewed carefully before prescribing such. Further
        infections can be prevented by using daily benzoylperoxide washes. Terbinafine
        cream would not be effective against erythrasma. The patient should avoid tight
        clothing and use absorbent powders in his groin if hyperhidrosis is a problem.


CASE TWO:


P.V. is a 23-year-old Caucasian female complaining of a rash on her chest and back,
which she has had on and off since she was a teenager. Over the years she received
many different “creams” for it, which helped somewhat, but then in the summers
the rash came back! She just returned from a trip to Florida, and after being to the
beach only twice, she, again, noticed the white spots on her chest and back. Her
grandmother advised her to apply cocoa butter, which made it worse. She denies
any itching or pain. She is embarrassed to wear tank tops, her fiancée is worried
that he might “catch the rash.” She just wants to get rid of this for good! She is
otherwise healthy and does not take any medications. On exam you notice multiple
oval to round macular lesions, which are hypopigmented but sharply marginated.
There is superficial scaling. She has the rash on her chest, back, and neck, where it
is most prominent.



    5. What is your differential diagnosis? What are your treatment options,
       knowing that this has been a recurrent problem?
       The patient has tinea versicolor also known as pityriasis versicolor. It is caused
       by yeast of the genus malassezia, which is part of the normal skin flora. The
       clinical disease appears when the normal saprophytic form converts into a
       pathogenic mycelial form. Factors that trigger this conversion include hot and
       humid climate, high rate of sebum production, hyperhidrosis, application of oils
       and high levels of cortisol (prolonged administration of corticosteroids or high
       serum cortisol levels). The infection is frequently seen in adolescents and young
       adults where sebum production is abundant. It is not contagious. It typically
       appears in the summertime and fades during cooler months. Lesions appear in
       regions of the body that have a high sebum production like the head, neck, trunk,
       upper back and upper arms. The disease manifests itself by irregularly shaped,
       round or oval macules that have a fine scale. “Versicolor” refers to the various

Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
        colors of the macular lesions. On untanned skin they can be light yellow-brown,
        pale yellow, dark brown, pink, or reddish. On tanned skin they appear white or
        hypopigmented. In dark skinned individuals they are dark brown macules. At
        times papular or annular plaques may arise. Mild pruritis can be present.
        The differential diagnosis includes:
        - tinea corporis
        - seborrheic dermatitis
        - guttate psoriasis
        - nummular eczema
         -pityriasis rosea
        These other lesions usually have more scaling.

        Also in the differential are:
        - vitiligo
        - postinflammatory hypopigmentation
        - erythrasma
        - secondary syphilis

        The diagnosis is best made by direct microscopic examination. Skin scale can be
        obtained by using microscope slides, using one to raise the scale and move it onto
        the other. Alternatively, transparent tape can be used to strip off the scale. The
        harvested scale is moved into a small pile in the center of the slide and covered
        with a coverslip. 10-20 % KOH solution is added at the edge of the cover slip.
        Examination under the light microscope reveals mounds of round large budding
        cells and short multibranching hyphae, in a pattern resembling “spaghetti and
        meatballs.”

        Wood’s lamp examination typically demonstrates yellow to yellow-green
        fluorescence. Fluorescence can only be seen in less than half of the cases because
        not all Malessezia species have been linked to fluorescence. Wood’s lamp
        examination might be useful in detecting subclinical patches in skin areas that
        don’t tan or in assessing cure after treatment in fluorescent cases. Although the
        infection does not pose a significant health risk to the affected individual, the
        psychological and social implications can be profound. Spontaneous remission is
        generally rare.

        TREATMENT:
        Topical treatment as a first line intervention can be curative. Commonly used
        topical treatments are:
        Selenium sulfide 2.5 % lotion or shampoo: apply 10-15 minutes daily and then
        wash off for one week. Application should be continued once or twice a month for
        six months to prevent recurrences.
        Ketoconazole 2% shampoo: One RCT showed a clinical response rate of 73 %
        with daily applications for three consecutive days only (Table III in Schwartz,
        2002).



Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
        Other topical azoles such as Clotrimazole 1% or Ketoconazole 2% are effective
        as well. Topical Terbinafine 1% cream can be used twice daily for one week.
        Patients should be advised that resumption of pigmentation might take months
        after the completion of treatment. They should avoid skin oils and sun tanning
        which will make the rash more apparent.

        For recurrent cases or extensive disease oral treatment is more convenient and
        more effective. Ketoconazole, itraconazole and fluconazole all can be used.
        However these medications have rare but important side-effects and should be
        used with caution. There is little consensus regarding the optimal dosing regimen
        and duration of treatment with systemic antifungal medications for this condition.
        Ketoconazole can either be given as 200 mg daily for 7-10 days or as a single
        dose of 400 mg. Itraconazole can be used as 200 mg daily for 5-7 days.
        Fluconazole 400 mg as a single dose was found to be as effective as a four-week
        course with lower doses with regard to clinical cure.

        PREVENTION:
        The recurrence rate of tinea versicolor after treatment cessation is as high as
        60% in the first year and 80 % in the second year. The recommended regimen for
        prophylaxis is Selenium sulfide 2.5 % shampoo applied to the whole body for 10
        minutes on the first and third days of the month for six months. Alternative oral
        prophylactic regimens are Ketoconazole 400 mg once a month or Itraconazole
        200 mg twice daily on one day a month for six months.



Primary References:

    1. Hainer BL. Dermatophyte infections. American Family Physician.
       2003;67(1):101-108. http://www.aafp.org/afp/20030101/101.html
    2. Schwartz RA. Superficial fungal infections. Lancet. 2004;364 (9440):1173-76.
       (first 4 pages, section on tinea versicolor only) http://dx.doi.org/10.1016/S0140-
        6736(04)17107-9


Additional References:

    1. Gupta AK, Cooper EA. Update in antifungal therapy of dermatophytosis.
       Mycopathologia. 2008;166(5-6):353-367
    2. Loo DS. Drugs Aging. Onychomycosis in the elderly : drug treatment options.
       2007;24(4):293-302. Review.
    3. Gupta AK, Cooper EA, Ryder JE, Nicol KA, Chow M, Chaudhry MM. Optimal
       management of fungal infections of the skin, hair, and nails. Am J Clin Dermatol.
       2004;5(4):225-237.
    4. Chang CH, Young-Xu Y, Kurth T, Orav JE, Chan AK. The safety of oral
       antifungal treatments for superficial dermatophytosis and onychomycosis: a meta-
       analysis. American Journal of Medicine.. 2007;120(9):791-798.

Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.
    5. Fuchs A, Fiedler J, Lebwohl M, Sapadin A, Rudikoff D, Lefkovits A, Schultz N,
       Khorenian S, Kakita L. Frequency of culture-proven dermatophyte infection in
       patients with suspected tinea pedis. Am J Med Sci. 2004;327(2):77-78.
    6. Pantazidou A, Tebruegge M. Recurrent tinea versicolor: treatment with
       itraconazole or fluconazole? Arch Dis Child. 2007;92(11):1040-1042.
    7. Andrews MD, Burns M. Common tinea infections in children. American Family
       Physician. 2008;77(10):1415-1420.
    8. Color Atlas and Synopsis of Clinical Dermatology. Thomas B. Fitzpatrick …[et
       al.]. – 3rd ed.
    9. Holdiness MR. Management of cutanous erythrasma. Drugs. 2002;62(8):1131-41.




      Pinar Oray-Schrom is a graduate of the Medical School at the University of Vienna
      in Austria. She completed her combined Internal Medicine/Pediatrics residency at
      Bridgeport Hospital in Connecticut. She has worked in private practice and at a
      community health center for several years. Currently she is Assistant Professor
      of Medicine at Yale and works at the Primary Care Center of Yale New Haven
      Hospital.




Superficial Fungal Infections. Yale Office-based Medicine Curriculum, Seventh Edition, Volume 1, 2009.

				
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