Jpn. J. Med. Mycol.
`Vol. 36, 7-12, 1995
`ISSN 0916-4804
`
`Review
`
`Trends in the Management of Cutaneous
`Fungal Infections
`
`Boni E. Elewski, M.D.
`
`Associate Professor of Dermatology University Hospitals of Cleveland
`Case Western Reserve University
`
`11100 Euclid Avenue Cleveland, Ohio 44106
`
`Abstract
`
`The modern antimycotic era began with the introduction of griseofulvin in the 1950’s, which had
`
`a tremendous impact on the management of dermatophytoses. Subsequent advances in therapy have
`
`lowered our threshold to treat recalcitrant cutaneous mycoses, such as onychomycosls. Newer generation
`
`antifungals including the triazoles, itraconazole and fluconazole, as well as the allylamine, terbinafine,
`
`may significantly reduce the prevalence of onychomycosis, as fungal nails are no longer incurable.
`
`The AIDS epidemic has been associated with an increase in the number of cutaneous and systemic
`
`mycotic infections. In spite of recent advances, organisms recalcitrant or resistant to therapy are common.
`
`Newer antifungal agents, improved diagnostic techniques, and standardization of fungal susceptibility
`
`testing are required to adequately treat patients with systemic and cutaneous mycoses.
`
`Historical perspective
`
`The past few decades have realized major
`advances in antifungal therapy for cutaneous
`mycoses~,z). The first oral agent for dermato-
`phytoses, griseofulvin, which was initially used
`to treat fungal diseases in plants, was introduced
`for human use in 1958~-~). Prior to this, only
`relatively non-speclfic and ineffective topical com-
`pounds such as Whitfield’s ointment, Gastellani’s
`paint and potassium permanganate were available
`for superficial fungal infections. Most patients
`were inadequately treated and certain dermato-
`phytoses, such as tinea capitis flourished into
`epidemic proportion.
`Historically, griseofulvin had a dramatic, but
`limited, impact on the management of cutaneous
`mycoses. Its narrow spectrum of activity includes
`the genera Microst~orum, Trichophyton, and Epider-
`mophyton. It is not effective against Candida,
`Malassezia and non-dermatophyte moulds3). Griseo-
`fulvln probably made its largest contribution in
`the management of tinea capltis, which was a
`major public health dilemma of the tlme~,z,4,5).
`Indeed in the early 20th century the presence of
`tinea capitis would prohibit entry or emigration
`into many countries. Prior to griseofulvin, there
`was no adequate therapy for patients with tlnea
`capitis, and some infections persisted for years.
`The subsequent eradication of the M. audouinii
`
`tinea capitis epidemic best exemplifies griseofulvin’s
`role in history.
`Griseofulvin is a fungistatic drug and must be
`given until the patient is clinically and mycologically
`cured. It is delivered via the eccrine sweat, and
`is not bound to the stratum corneum after admi-
`nistration6). Although effective in tinea capltis,
`particularly when caused by Microsporum spp, it
`has been of limited benefit in onychomycosis and
`other dermatophytoses caused predominantly by
`T. rubrum. Treatment failures with Trichoph.yton
`rubrum have correlated with in vitro resistance7-~°).
`Since the introduction of griseofulvin almost four
`decades ago, there has been a surge in tinea
`capitls infections by the genera Trichophyton such
`
`as T. tonsurans in the United States, and now
`recently Europe, as well as T. violaceum in Europe.
`Onychomycosis caused by T. rubrum has also
`shown an increased incidence, and has generally
`been regarded as incurable5,~1-~3).
`Although not useful in cutaneous mycoses,
`amphoterlcin B became the first available anti-
`mycotic for systemic mycoses in the late 1950’s
`1.2). Due to poor oral absorption, it must be
`
`administered intravenously or intrathecally. More
`than 90% of the drug is bound to proteins,
`resulting in poor penetration into body fluids and
`stratum corneum. Although available in topical
`formulations, it has no activity against dermato-
`phytic fungi. These factors account for the ineffec-
`
`Page 1 of 6
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1502
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`tiveness of amphotericin B in treating cutaneous
`dermatomycoses~). However, the drug is effective
`in many systemic mycoses, including disseminated
`candidiasis, aspergillosis and the dimorphic orga-
`nismsl,Z, 14. ,5). It is still the most effective antifungal
`
`drug available, yet one of the most toxic antimicro-
`bics in clinical use. In many instances ampho-
`tericin B is given in conjunction with 5 fluorocy-
`tosine. Fungal susceptibility testing can guide the
`selection of antimycotics.
`The 1960’s and 1970’s witnessed the discovery
`of the topical azole family including clotrimazole,
`miconazole, econazole and ketoconazole. With the
`exception of tlnea capitis and onychomycosls
`which usually require systemic therapy, topical
`azoles are effective in eradicating most dermatomy-
`coses of the stratum corneum. More importantly,
`however, this family of antimycotics heralded a
`new generation of oral azoles and triazoles. Oral
`ketoconazole was introduced two decades after
`griseofulvin, and was the first orally administered
`member of the azole family. The spectrum of
`oral ketoconazole includes the dermatophyte fungi,
`Candida, plus a variety ef nondermatophyte moulds
`and yeasts1, 2,16 2°). Ketoconazole is more effective
`
`in vitro than griseofulvin on fungi in the genera
`Trichoph.yton9). Ketoconazole was the first orally
`delivered antimycotic with activity against Candida,
`and significant improvement occurred in those
`patients with chronic mucocutaneous candidiasis,
`who had previously endured disfiguring cutaneous
`lesions. Further, many patients with systemic
`mycoses could also be treated with an oral, rather
`than intravenous, agent 1~. ~9). Unfortunately, the
`potential of hepatotoxicity has limited its use ~, 2, 21).
`The triazoles, fluconazole and itraconazole,
`became available in the 1990’s and immediately
`
`a vitally important resource for the management
`of HIV infected patients, and other patients with
`other primary or secondary immunodeficiencies
`~,2.~,~.~). The triazole ring may be responsible
`
`for increased potency, decreased toxicity, and a
`wider spectrum of action than the azoles1’~,22).
`Fluconazole is effective against the dermatophyte
`fungi, Candida, Malassezia, Cr2ptococeus and other
`organisms~2). Itraconazole has a similar spectrum
`of activity, but is more effective against Aspergillus
`spp. and dematiaceous fungi22, 2~). Fluconazole is
`available in an oral and parenteral form; itracon-
`azole is available only in an oral form. Itraconazole
`has been particularly helpful in cutaneous mycoses
`such as chronic tinea manuum, tinea pedis and
`onychomycosis due to the "reservoir" effect of
`persisting in the stratum corneum for weeks to
`months after administration6,2a,~7). Being lipophilic,
`it binds to the keratinocytes and is incorporated
`
`into the epidermal basal layer where it may
`persist for weeks after therapy is discontinued~).
`Both itraconazole and fluconazole are fungistatic.
`Fluconazole is delivered to the outer integument
`via eccrine sweat; itraconazole is transported in
`the sebum~>.
`The inadvertent discovery of the allylamine
`family in the mid 1970’s led to the recent intro-
`duction of oral terbinafine, which has proven to
`be a valuable resource in the management of
`traditionally recalcitrant cutaneous infections such
`as onychomycosis and tinea capitis ’, t). Terbinafine
`is fungicidal in vitro, and like itraconazole, is
`lipophilic with a "reservoir" effect of persisting in
`keratinized tissue after discontinuation of therapy
`2s). It apparently binds to the lipophilic keratin-
`
`ocytes and is delivered to the outer integument
`via the sebum. The combination of its fungicidal
`activity, and persistence in the stratum corneum
`permit short courses of therapy in even tradi-
`tionally recalcitrant tinea capitis and onychomy-
`cosis. Although its in vitro activity is broad
`spectrum including most yeasts, nondermatophyte
`moulds and the dermatophyte fungi, in therapeutic
`concentrations, it is primarily used for the
`dermatophytoses. Higher doses may be needed
`for other mycoses~).
`
`Onychomycosis
`
`Onychomycosis, rare until the later part of the
`20th century, is now in epidemic proportion.
`Although predominantly caused by dermatophyte
`fungi, other yeasts and nondermatophyte moulds
`can occasionally cause fungal hall infection (Table
`1).
`Due to the funglstatic mode of action, lack of
`nail plate adhesion, the inherent slow growth of
`the nail, the need to administer until the nail
`has grown out, and potential adverse events,
`griseofulvin has proven to be an inadequate agent
`for fungal nail infection28-~2). Further, the dominant
`
`Table 1. Common etiologic agents of
`onychomycosis
`
`Dermatophyte fungi
`
`Trichophyton mbrum
`
`Trichophyton mentagrophytes
`
`Epidermophyton flo~cosum
`
`Yeasts
`Candida albicans
`
`Non-dermatophyte moulds
`Sco~ulariopsis brevicaulis
`
`Scytalidium dimidiatum
`Scytalidium hyalinum
`Fusarium spp,
`
`Aspergillus spp,
`
`Page 2 of 6
`
`

`

`Jpn. J. Med. Mycol. Vol. 36 (No. 1), 1995
`
`9
`
`organism in many countries is T. rubrum, and there
`are reports of in vitro resistance to griseofulvin7).
`Moreover, some patients with onychomycosis may
`have mixed infection with a dermatophyte and
`non-dermatophyte pathogen, and griseofulvin would
`therefore be ineffective. Systemic ketoconazole,
`although broad spectrum and more effective than
`griseofulvin against T. rubrum, is limited by hepato-
`toxicity. However, the newer oral antimycotics
`(fluconazole, itraconazole and terbinafine) and to-
`pical (amorolfine, ticonazole, ciclopirox olamine)
`
`antifungals formulated for onychomycosis, have
`excellent safety profiles and have greatly improved
`the prognosis of onychomycosis. Due to these
`agents, onychomycosis is no longer considered
`incurable ~. 2.
`There is currently no multicenter clinical trial
`comparing the efficacy of the various topical and
`oral agent in onychomycosis. Further, there is no
`single best agent because patients have different
`tolerances to medication, not all antimycotics are
`available in every country, nor is the dominant
`pathogen the same in each country. For [hese
`reasons, the selection of an appropriate antimycotlc
`for onychomycosis can be derived from a combina-
`tion of factors, including determination of MIC’s
`of organisms cultured from nail infections, as
`well as considering potential adverse events, drug
`interactions, therapy schedules, amount of nall
`
`involvement, and cost. Cost would include that
`of treating recurrent infections.
`Unlike griseofulvin, the newer antimycotics,
`terbinafine and itraconazole, are generally not
`dosed daily until the nail is clinically and mycolo-
`gically normal. Due to its fungicidal activity and
`persistence in the nail plate, terbinafine is effective
`at 250 mg administered daily for only 6 weeks in
`fingernail and 12 weeks for toenail infections l,
`
`Cure rates are over 80%, and best results occur
`if a dermatophyte is the primary pathogen. In
`
`Candida albicans nail infections, fluconazole or itra-
`conazole is probably a better choice. Based on
`its pharmacokinetics, itraconazole can be given
`in two dosage schedules referred to as either the
`"fixed course" or the "pulse dosage’’2La4,~5). Par-
`ticularly pivotal on determination of these dosage
`
`schedules were studies showing that if itraconazole
`is doubled from 100 mg to 200 mg daily, the
`level in the nail rises ten fold. Furthermore, as
`with terbinafine, a "reservoir" effect occurs with
`itraconazole persisting in the hall after therapy is
`discontinued. Itraconazole persists 6-9 months, and
`terbinafine about 4 months in the nail following
`termination of therapy. In the fixed dosage
`schedule, 200 mg of itraconazole is administered
`
`daily for 6 weeks in fingernail disease and 12
`weeks in toenail disease. The nail is not normal at
`the time of discontinuation, but grows out normal.
`The pulse dosage or interrupted therapy is 4,00
`mg daily for 1 week, administered one week
`per month for 1-2 months in fingernail and 3-4
`months in toenail disease. The cure rates of both
`these regimens are about 130%. Although the
`pharmacokinetics of fluconazole have not been
`well studied, preliminary data suggest it to be a
`safe and effective agent in onychomycosis. A dose
`of 150 mg administered once weekly until the
`nail is clinically and mycologically normal has
`been an effective regimen in clinical studiess6).
`
`The AIDS epidemic
`
`Patients with Acquired Immunodeficiency
`Syndrome (AIDS) frequently develop a variety
`of superficial cutaneous and systemic mycoses37-s9).
`The superficial cutaneous fungal infections include
`oral and genital Candida, and extensive and rapidly
`spreading dermatophytoses. Additionally, conditions
`associated with the yeast Malassezia occur, including
`severe seborrheic dermatitis and pityriasis (tinea)
`versicolor4°,4J). The systemic mycoses common in
`
`AIDS include disseminated cryptococcosis, and the
`dimorphic infections: histoplasmosis, coccidioido-
`mycosis, sporotrichosis, and the emerging pathogen,
`
`Penicillium marneffei (Table 2). Cutaneous involve-
`ment occurs in many systemic fungal infections.
`The newer triazoles have been invaluable in the
`management of many mycoses in the HIV infected
`person4~-44). However, drug resistance can develop
`
`and new organisms which are nonresponsive to the
`current assortment of antimycotics are emerging.
`New and more potent antifungals are needed to
`cope with the AIDS epidemic.
`
`Table 2.
`
`Mycotic infections in AIDS patients
`
`Superficial cutaneous mycoses
`
`Systemic mycoses
`
`Chronic oral/genltal candldiasls
`
`Cryptococcosls
`
`Extensive dermatophytoses
`
`Dimorphic infections
`
`Malassezia furfur
`
`Extensive seborrhelc dermatitis
`Extensive pityriasis (tinea) versicolor
`
`Malassezia folliculitis
`
`Histoplasmosis
`Coccidioidomycosis
`Sporotrichosis
`
`Penicillium marneffd
`
`Page 3 of 6
`
`

`

`infection occurs, and dissemination is rare. Oral
`candidiasis occurs in up to 45% of patients with
`HIV; women frequently manifest recalcitrant
`candidal vulvovaginitis. The newer triazoles have
`proven to be invaluable in the management of
`mucocutaneous candidiasis.
`Extensive and unusual presentations of dermato-
`phytoses are common in HIV infected persons4~,
`
`Although not considered serious or life threatening,
`extensive dermatophytosls may be cosmetically
`disfiguring and cause severe pruritus. Nail deformi-
`ties from onychomycosis is also common. Proximal
`white subungual onyehomycosis
`is considered
`pathonumonic for AIDS~. Also, pityriasis ver-
`sicolor and seborrheic dermatitis are typically
`more extensive in patients with AIDS, and may
`also cause in severe prurltus4°,~). Systemic anti-
`fungal therapy is often required in the management
`of superficial and cutaneous mycotic infection in
`the AIDS patient.
`Pseudallescheria boydii has recently been reported
`to disseminate in patients with AIDS, and is an
`example of an emerging mycotic pathogen recal-
`citrant to therapy57). Amphotericin B is generally
`
`not effective, neither are the azoles and triazoles.
`Fungal susceptibility testing is generally required.
`
`Future trends
`
`Prior to the introduction of griseofi~lvin, deter-
`mination of the causative cutaneous fungal
`p~thogen was often an academic exercise as there
`was no available effective antimycotic. Given the
`
`recent advances in cutaneous antifungal therapy,
`the correct determination of fungal pathogen is
`now critical. Onychomycosis best illustrates
`the problem. Fungal nail disease can be caused
`by dermatophyte fungi, Candida, and several
`nondermatophyte moulds including Scytalidium
`dimidiatura, S. hyalinura, and. Scopulari~sis brevicaulis.
`No systemic or topical agent is effective against
`all these organisms and therefore thngal culture
`will determine the causative pathogen, and provide
`data for rational selection of appropriate therapy.
`The introduction of new antimycotics and the
`study of their pharmacokinetic profile in the
`integument, are recent advances in cutaneous
`mycology. In many instances, it is no longer
`necessary to treat until the patient is clinically
`and mycologically cured. This is again best
`depicted in the therapy of onychomycosis. Short
`term treatment schedules with itraconazole and
`terbinafine were based upon pharnaacokinetic data
`and in vitro activity.
`
`Greater choices of antimycotics mear~s more
`difficult decisions in the selection of an appropriate
`agent~). However, determination of MIC’s tbr
`
`Fig. 1. Umbilieated nodules resembling the viral infec-
`
`tion molluscurn eontagiosum is a typical cutaneous
`presentation in an AIDS patient with either dlsserni-
`hated C~y[otococcus neoformans or Penicillium marnef£ei.
`
`This patient had disseminated cryptococeosis.
`
`Amongst the serious mycoses, the dimorphic
`fungus, Penicillium marneffei, is being reported with
`increasing frequency, and is especially common
`in certain parts of Asia45), A systemic reticuloend-
`otheliosis mimicking histoplasmosis is the usual
`presentation often with cutaneous lesions resem-
`bling molluscum contagiosum. Treatment consists
`of amphotericin B or itraconazole, and a relapse
`or resistance is common.
`Cr~ptococaus neoformans is the most common life
`threatening fungal infection in AIDS patients,
`occurring in 5-10% of patients. Dissemination
`occurs in half of HIV infected persons, and skin
`lesions occur in up to 10% of those with dissem-
`
`inated disease~49). Both of the triazoles, fluconazole
`and itraconazole, are useful for the management of
`cryptococcosls, and can be used as prophylactic
`agents against dissemination~°~. Amphoterlcin B
`
`can also be useful.
`Histoplasrnosis is also common in many AIDS
`patients, and is due to reactivation of old disease
`or to primary infection. Treatment is with ampho-
`terlcin B, fluconazole or itraconazole5’~. Dissemi-
`nated sporotrichosis in the HIV patient can also
`
`be due to reactivation of old disease or via primary
`inhalation. Cutaneous presentation is atypical, and
`generalized nodules are common, rather than
`lymphocutaneous spread. Itraconazole and ampho-
`tericin B are useful therapies.
`Coccidioidomycosis occurs in 3% of HIV positive
`patients in endemic areas and occurs as a result
`of reactivation or primary infection~,~). Cutaneous
`lesions are uncommon. Amphotericin B and itra-
`conazole are options in therapy, but even with
`treatment, prognosis is poor.
`Candidiasis is the most common mycotic infec-
`
`tion in AIDS~,4~. Generally, mucous membrane
`
`Page 4 of 6
`
`

`

`Jpn. J. Med. Mycol. Vol. 36 (No. 1), 1995
`
`11
`
`fungal pathogens may provide clinicians a scientific
`rationale for selection of antimycotics. Worldwide
`standardization of fungal susceptibility tests for
`moulds and yeasts is desperately needed. Also
`required are new antifungal drugs to cope with
`the recent surge of mycotic infections occurring
`
`due to the AIDS epidemic, new transplant
`techniques and to the rise in immunocompromlsed
`patients. Recalcitrant organisms including Pseu-
`dallescheria boydii, Penicillium marneffei and Fusarium
`
`spp. are becoming more common, and are diffi-
`cult to manage, underscoring the need for new
`developments in mycology, and more effective
`antimycotic therapy.
`
`References
`
`1) Gupta AK, Sauder DN, Shear NH:Antifungal
`
`Agents: An Overview. Part
`
`I J Am Acad
`
`Dermatol 30: 677-698, 1994.
`
`2) Gupta AK, Sauder DN, Shear NH ~Antifungal
`
`Agents: An Overview. Part
`
`]1 J Am Acad
`
`Dermatol 30: 911-933, 1994.
`
`3) Blank H, Roth FJ:The treatment of dermato-
`mycoses with orally administered griseofulvin.
`
`Arch Dermatol 79 : 259-266, 1959.
`4) Tanz RR, Herbert AA, Esterly NB:Treating
`
`tinea capitis: Should ketoconazole replace
`
`griseofulvin? J Pediatr 12 : 987-991, 1988.
`5) Can VN, Petruska M, C;-insburg CM:Epidemio-
`
`logy and treatment of tinea capitis; ketoconazole
`
`vs. griseofulvin. Pediatr Infect Dis J 6:46-49,
`
`1987.
`6) Elewski BE:Mechanism of action of systemic
`antifungal agents. J Am Acad Dermatol 28 : $28
`
`-$34, 1993.
`7) Artis WM, Odle BM, Jones HE:Criseofulvin-
`
`resistant dcrmatophytosis correlates with in vitro
`
`resistance. Arch Dermatol 117: 16-19, 1981.
`8) Hay RJ:Failure of treatment in chronic derma-
`
`tophyte infections. Postgrad Med J 55:608-610,
`
`1979.
`
`9) Robertson MH, Rich P, Parker F, et al:Ketoco-
`nazole in griseofulvin-resistant dermatophytosis.
`
`J Am Acad Dermatol 6:224-229, 1982.
`10) I.iay RJ, Clayton YM:Treatment of chronic
`dermatophyte infections; the use of ketoconazole
`
`in griseofulvln treatment failures. Clin Exp
`
`Dermatol 27 : 611-612, 1982.
`
`11) Elewski BE, Hazen P : The superficial mycoses
`and dermatophytes. J Am Acad Dermatol 21 :
`
`655-673, 1989.
`12) Hay RJ, BrostoffJ:Immune response in patients
`
`with chronic Trichophyton rubrum infections. Clin
`Exp Dermatol 2 : 373-380, 1977.
`
`13) Legendre R, Steltz M:A multi-center, double-
`
`blind comparison of ketoconazole and grlseo-
`
`fulvin in the treatment of infections due to
`
`dermatophytes. Rev Infect Dis 2:586-591, 1980.
`14) Walsh TJ, Pizzo A : Treatment of systemic fungal
`infections. Eur J Clin Microblol Infect Dis 7:
`
`460-475, 1988.
`15) Atkinson AJ, Bennett JE : Amphoterlcln B
`pharmacokinetlcs in humans. J Antimicrob
`Chemother 13: 271-376, 1978.
`16) Graybill JR, Craven PC:Antifungal agents used
`in systemic mycoses. Drugs 25:41-62, 1983:
`17) Heeres J, Backx LJJ, Mostmans JH, et al:
`Antimycotic imidazoles 4. Synthesis and anti-
`fungal activity of ketoconazole, a new potent
`orally active broad spectrum antifungal agent.
`J Med Chem 22: 1003-1005, 1979.
`18) Borgers M: Mechanism of action of antifungal
`drugs, with special reference to the imidazole
`derivatives. Rev Infect Dis 2:520-534, 1980.
`19) Brass C, Galgiani JN, Campbell SC, et al:
`Therapy of disseminated or pulmonary cocci-
`dioidomycosis with ketoconazole. Rev Infect Dis
`2 : 656-660, 1980.
`20) Cohen J : Antifungal chemotherapy. Lancet 2 :
`532-537, 1982.
`21) Graybill JR:Summary: potential and problems
`with ketoconazole. Am J Med 74 : 86-90, 1983.
`22) Saag MS, Dismukes WE : Azole antifungal agents;
`emphasis on triazoles. Antimicrob Agents Chem-
`other 32 : 1-8, 1988.
`23) Hay RJ, Clayton YM, Moore MK, et al : Itracona-
`zole in the management of chronic dermatophy-
`tosis. J Am Acad Dermatol 23: 561-564, 1990.
`24) Sugar AM:Empiric treatment of fungal infec-
`tions in the neutropenic host: review of literature
`and guidelines for use. Arch Intern Med 150:
`2258-2264, 1990.
`25) Negroni R, Palmierei O, Koren F, et al:Oral
`treatment of paracoccldioidomycosls and histopl-
`asmosis with itraconazole in humans. Rev Infect
`Dis 9 (suppl) : $47-$50, 1987.
`26) Denning DW, Stevens DA:New drugs for
`systemic fungal infections: greater choice means
`more difficult decisions. Br Med J 299:407-408,
`1989.
`27) Hay RJ, Clayton YM, Moore MK, et al: An
`evaluation of itraconazole in the management
`ofonychomycosis. Br J Dermatol 119 : 359-366,
`1988.
`28) Kortlng HD, Schafer-Korting M : Is tlnea unguium
`still widely incurable? Arch Dermatol 128:243-
`248, 1992.
`29) Faergemann J, Zehender H, Hones T, et al:
`Terbinafine levels in serum, stratum corneum,
`dermis-epidermis (without stratum corneum),
`hair, sebum, and eccrine sweat. Acta Derm
`Venereol (Stockh) 71:322-326, 1990.
`30) Miyagawa S, Sakamoto K :Adverse reactions
`to griseofulvin in patients with circulating anti-
`SSA/Ro and SSB!La autoantibodies. Am J
`Med 87 : 100-102, 1989.
`31) Madhok R, Zoma A, Capell H:Fatal exacerba-
`tion of systemic lupus erythematosus after
`treatment with griseofulvin. Br Med J 291 : 249
`-250, 1985.
`32) Van Dijke CPH, Weber JCP : Interaction between
`
`Page 5 of 6
`
`

`

`oral contraceptives and griseofulvin. BMJ 288:
`
`patients during the last 54 years compared to
`
`1125-1126, 1984.
`33) Finlay AY:Pharmacokinetics of terbinafine in
`the nail. Br J of Dermatol 126:39 (suppl) : 28-
`
`32, 1992.
`34) Roseuw D, DeDoncker P:New approaches to
`the treatment of onychomycnsis. J Am Acad
`
`Derm 29: 545-550, 1993.
`
`44 cases on non AIDS patients reported over 4
`
`years. J Myeol Med 4: 194-224, 1993.
`
`46) Kovacs JA: Cryptococcosis in the Acquired
`Immunodeficiency Syndrome. Ann Int Med 103:
`
`533-538, 1985.
`47) Piton ~ Cuteneous Cryptococcosis Resembling
`Molluscum Contagiosum: A First Manifestation
`
`35) Willemsen M, DeDoncker P, Willems ~’, et al:
`
`Post treatment itraconazole levels in the nail. J
`
`of AIDS. Acta Dermatol Venereol 61 : 365-367,
`1989.
`
`Am Acad Derm 26: 731-735, 1992.
`
`36) Kuokkanen K, Alava S:Fluconazole in the
`
`treatment of onychomycosis caused by dermato-
`phytes. J Derm Treat 3: 115-117, 1992.
`37) Stevens DA :Fungal Infections in AIDS patients.
`
`Brit J Clin Practice 71 : 11-22, 1990.
`38) Viviani MA:Opportunistic Fungal Infections in
`Patients with Acquired Immune Deficiency
`
`48) Rico MJ, Penneys NS:Cutenous Cryptococcosls
`Resembling Mollnscum Contagiosum in a Patient
`
`with AIDS. Arch Dermatol 121:901-902, 1985.
`49) Chuck SL, Sande MA:Infections with Crypto-
`coccus neoformans in the Acquired Immuno-
`
`deficiency Syndrome. NEJM 321:794-799, 1989.
`
`50) Durden F, Elewski BE:Cutaneous Involvement
`with Ctyptococcus neoformans in AIDS. J Am Acad
`
`Syndrome. Chemotherapy 38 (suppl) : 35-42,
`
`Dermatol 30 : 844-848, 1994.
`
`1992.
`
`39) Armstrong D : Life-Threatening Opportunistic
`Fungal Infections in Patients with the Acquired
`
`Immunodeficiency Syndrome. Ann NYAS 544:
`
`443 -450.
`40) Mathes B, Douglass M:Seborrheic Dermatitis
`in Patients with Acquired Immunodeficiency
`
`Syndrome. JAAD 13 : 947-951, 1985.
`
`41) Sindrup JH, Lisby G, Weismann K, et al:Skin
`Manifestations in AIDS, ttIV Infection, and
`AIDS-Related Complex. In J Dermatol 26:267-
`
`272, 1987.
`42) Sugar AM, Saunders C:Oral Fluconazole as
`Suppressive Therapy of Disseminated Cryptoco-
`
`51) Minamoto G, Armstrong D:Fungal Infections in
`AIDS: Histoplasmosis and Coccidioidomycosis.
`
`Infect Dis Clin N Amer 2:447-456, 1988.
`
`52) Hazelhurst JA, Vismer HE: Histoplasmosis
`Presenting with Unusual Skin Lesions in Acquired
`
`Immunodeficiency Syndrome
`
`( AIDS ) . Br J
`
`Dermatol 113: 345-348, 1985.
`53) Huang CT, McGarry T, Cooper S, et al:Disse-
`minated I-Iistoplasmosis in the Acquired Immuno-
`
`deficiency Syndrome. Report of Five Cases from
`
`a Non-Endemlc Area. Arch Intern Med 147:
`
`1181, 1987.
`
`54) Prltchard JG, Sorotzkin RA, James RE : Cutane-
`ous Manifestations of Disseminated Coccidioido-
`
`ccosis in Patients with Acquired Immunodefi-
`
`mycosis in the Acquired Immunodeficlency
`
`ciency Syndrome. AJM 85:481-489, 1988.
`
`Syndrome. Cuds 39 : 203-205, 1987.
`
`43) Denning DW:Itraconazole Therapy for Crypto-
`
`coccal Meningitis and Cryptococcnsis. Arch Intern
`
`Med 149 : 2301-2308, 1989.
`44) Powderly WCt:A controlled trial of Fluconazole
`
`or Amphoterlcin B to Prevent Relapse of Crypto-
`
`coccal Meningitis in Patients with the Acquired
`
`Immunodeficiency Syndrome. NEJM 326: 793-
`
`798, 1992.
`45) Drouhet E : Penicilllosis Due to Penicilliurn
`marneffei: A New Emerging Systemic Mycosis in
`
`55) Bronninman DA, Adam RD, Galgiani JN, et
`al:Coccidioidomycosis in the Acquired Immuno-
`
`deficiency Syndrome. Arm Intern Med 372-379,
`
`1987.
`
`56) Elewski BE: Proximal white subungual onycho-
`mycosis in acquired immunodeficiency syndrome.
`
`J Am Acad Dermatol 29:631-632, 1993.
`57) Scherr OR, Evans SO, Kiyabu MT, et al:
`Pseudallescheria boydii Infection in the Acquired
`
`Immunodeficiency Syndrome. Arch Pathol Lab
`
`AIDS Patients Traveling or Living in Southeast
`
`Med 116 : 535-536, 1992.
`
`Asia: l~eview of 44 cases reported in HIV infected
`
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