DERMATOPHYTOSIS
`
`PRESENTED AT THE "INTERNATIONAL SUMMIT ON CUTANEOUS
`ANTIFUNGAL THERAPY," SUPPORTED BY EDUCATIONAL GRANTS
`FROM JANSSEN PHARMACEUTICA; ORTHO PHARMACEUTICAL
`CORPORATION--DERMATOLOGICAL DIVISION; ROERIG--A DIVISION
`OF PFIZER; AND SANDOZ PHARMACEUTICALS CORPORATION,
`
`II
`
`II
`
`I
`
`IIIII I IIIII
`
`I
`
`I
`
`I Ill I I
`
`Ecology and epidemiology of dermatophyte
`infections
`
`Raza Aly, PhD San Francisco, California
`
`Our knowledge of ecology and epidemiology of dermatophytes and the factors influencing
`their transmission has helped us understand better the natural history of derrnatophytoses.
`It seems that the anthropophilic agents of scalp infection are being eradicated in developing
`nations. The exception is Trichophyton tonsurans-related tinea capitis in North America.
`Microsporum canis is a prevalent agent of tinea capitis in many regions of the world, and this
`could be related to close association of humans with their pets. Trichophyton violaceurn is
`endemic in certain parts of Eastern Europe, Africa, Asia, and South America but not in North
`America. Trichophyton rubrurn is the most common cause worldwide of tinea pedis, nail in-
`fection, tinea cruris, and tinea corporis. Although the incidence of tinea capitis is declining
`in developed nations, tinea pedis and onychomycosis are becoming more common. The in-
`creased use of athletic shoes both by men and women and communal bathing could be con-
`tributing factors. Five or six species account for most dermatophytoses globally. (J AM ACAD
`DERMATOL 1994;31:$21-$25.)
`
`The causes of dermatophytoses are classified into
`three anomorphic genera, Trichophyton, Micro-
`sporum, and Epidermophyton, depending on their
`conidial structures. Teleomorphic dermatophytes
`are classified into one genus, Arthroderma. Approx-
`imately 40 species are in the anomorphic genera: 22
`species of Trichophyton, 16 of Microsporum, and
`two of Epidermophyton.
`
`ECOLOGIC CLASSIFICATION
`
`Dermatophytes are frequently divided into three
`major groups on the basis of their natural habitat
`and host preferences: (1) geophilic or soil-inhabiting
`fungi, which occasionally can be pathogenic for hu-
`mans or animals; (2) zoophilic species, which prefer
`animals as hosts but also can infect humans; and (3)
`anthropophilic species, which are typically human
`pathogens (Table I).
`
`From the Department of Dermatology, University of California, San
`Francisco.
`Reprint requests: Raza Aly, PhD, Department of Dermatology, Uni-
`versity of California, San Francisco, San Francisco, CA 94143-0517.
`Copyright ® I994 by the American Academy of Dermatology, Inc.
`0190-9622/94 $3.00 + 0 16/0/57448
`
`The dermatophytes basically are soil saprophytes
`that have acquired the ability to digest keratinous
`debris in soil, thus becoming "keratinophilic fungi."
`A few of these organisms gradually evolved to par-
`asitize keratinous tissues of animals living in close
`proximity with soil, such as Microsporurn nanum in
`pigs and Trichophyton quickeanum in mice. The
`other keratinophilic soil fungi, Chrysosporium
`keratinophilum and Trichophyton terrestre, for in-
`stance, failed to parasitize human or animal keratin
`and remained the link between geophilic dermato-
`phytes and nonkeratinophilic soil fungi. Some of
`these dermatophytes, adapting to cornified substrate
`in living animals, became zoophilic and lost their
`ability to survive in soil. Microsporum canis vat
`distortum (a zoophitic species) survives for only a
`short period when experimentally inoculated into
`soil. l
`Anthropophilic dermatophytes are believed to
`have evolved from zoophilic fungi.2 According to
`this view, some zoophilic dermatophytes adapted to
`human keratin while losing their ability to digest
`animal keratin. The selectivity of Microsporum au-
`douinii and Trichophyton rubrum may have devel-
`oped in this way because they rarely infect animals.
`S21
`
`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1032
`IPR Petition for
`U.S. Patent No. 7,214,506
`
`1 of 3
`
`

`

`Journal of the American Academy of Dermatology
`Volume 3 I, Number 3, Part 2
`
`Table III. Main causal agents for tinea capitis in different geographic areas
`
`Europ~
`
`1
`
`N. An~rica
`
`t
`
`Africa
`
`I Pakistan/lnd|a
`
`M. canis
`
`T. tonsurans
`M. canis
`M. audouinii
`
`7". violaceurn
`
`T. violaceum
`T. soudanense
`M. audouinii
`M. canis
`7". yaoundei
`
`Aly $23
`
`S. America
`
`7". violaceum
`34. canis
`
`rubrum. Data can be validated when the clinical or-
`igin of isolated dermatophytes is taken into consid-
`eration (Table II). In a 20-year survey of the
`Chicago area, Bronson et al.4 reported an epidemic
`of infection with Trichophyton tonsurans. From
`1976 to 1980, 96% of tinea capitis and 76% of tinea
`corporis infections were caused by this fungus. The
`increase in the number of cases of tinea corporis
`caused by 7’. tonsurans has paralleled that seen in
`tinea capitis. Women outnumbered men in a ratio of
`nearly six to one. The high prevalence in women of
`childbearing age may be from their frequent contact
`with infected children. Another important finding in
`this study was that prepubertal infection with Z
`tonsurans does not always resolve at puberty, as do
`infections with Mierosporum species.
`Tinea capitis is a classic example of the changing
`geographic patterns of dermatophytosis in Western
`Europe and much of the rest of the world.
`Microsporum audouinii and M. eanis were the
`causes of scalp infection in the late nineteenth and
`early twentieth centuries in Western and Mediter-
`ranean Europe. In Eastern Europe, T. schoenleinii
`was the predominant cause of the favus type of tinea
`capitis.S, 6 Presently tinea capitis has been disappear-
`ing in Western Europe. This decrease has lead to a
`reduction in infection from the four anthropophilic
`species in this location ( M. audouinii, 7". tonsurans,
`T. violaceum, and T. schoenleinii).7 Sporadic eases
`of tinea capitis still occur but are usually caused by
`M. canis.6 T. violaceum is now the predominant
`agent of scalp infections in Eastern Europe. In the
`Mediterranean, the incidence of M. canis infection
`has been rising steeply in recent years. In Italy and
`Slovenia (Yugoslavia), M. canis is the most fre-
`quently isolated dermatophyte8 in tinea capitis.
`In the United States, M. audouinii and M. canis,
`once the major agents of tinea capitis, have been su-
`perseded by T. tonsurans. Since the 1950s, T. ton-
`surans has advanced from Mexico and the Carib-
`bean and is now the prevalent cause of tinea capitis
`in North America.4, 9, 10 The epidemiology of tinea
`capitis from 7". tonsurans has been studied on several
`
`occasions.t l. t 2 Infections from T. tonsurans are
`transmitted directly or indirectly from person to
`person. Mackenzi03 studied an outbreak of 72. ton-
`surans in a residential school and recovered the fun-
`gus not only from infected children but also from
`hairbrushes, combs, pillowcases, other bedding ma-
`terials, and even dormitory floors.
`In Africalarge-scale epidemics of tinea capitis are
`associated with Trichophyton soudanense, T. vio-
`laceum, 7". schoenleinii, Microsporurn ferrugineum,
`and M. audouinii (Table III).14 Infections with T.
`tonsurans and 7". mentagrophytes are widely dis-
`tributed but are not common. Certain anthro-
`pophilic species (Trichophyton soudanense, T.
`yaoundei, and T. gourvilii) remain geographically
`restricted. There are no established endemic loci in
`the neighboring regions)4 7". soudanense has been
`regularly introduced into Britain by Africans and
`yet the local population rarely became infected.
`Triehophyton megninii is found mainly in North
`Africa and sporadically in Portugal, Spain, and
`Sardinia. In Portugal it accounts for about 4% of
`dermatophytes isolated from scalp and glabrous
`skin.15 Other geographically restricted dermato-
`phytes are T. yaoundei in Cmneroon, Africa, 7".
`concentricum in the Western Pacific, Malaysia, and
`Central and South America, and T. schoenleinii in
`the Appalachian Mountains of the United States. In
`Japan tinea capitis caused by M. ferrugineum has
`been virtually eradicated in recent years because of
`improved hygienic conditions. 16 In the Indian sub-
`continent and Southeast Asia, little tinea capitis ex-
`ists, which has been attributed to the cosmetic use of
`hair oil (mustard seed oil) that may perhaps prevent
`or inhibit colonization by these dermatophytes)7 7".
`viotaceum is the common tinea capitis agent in these
`regions (Table III). In South America M. canis is
`the most common cause of scalp infection in Argen-
`tina, but T. violaceum is more conu’non in Brazil and
`7". tonsurans in Peru. M. canis is also the main cause
`of tinea capitis in Australia and New Zealand, but
`T. tonsurans is endemic in the aborigines of North
`and Central Australia.~7
`
`2 of 3
`
`

`

`Journal of the American Academy of Dermatology
`Volume 31, Number 3, Part 2
`
`Degreef and DeDoncker
`
`about to become a serious dermatological problem? Der-
`matology 1992;184"87-9.
`9. Sinski JT, Flouras K. A survey of dermatophytes isolated
`from human patients in the United States from 1979 to
`1981 with chronological listing of worldwide incidence of
`five dermatophytes often isolated in the United States.
`Mycopathologia 1984;85:97-120.
`10. Aly K. Incidence of dermatophytes in the San Francisco
`Bay area. Dermatologica !980;161:97-100.
`11. Becobo FC, Eadie GA, Miedler LJ. Epidemiologie study of
`tinea capitis caused by 7". tonsurans and M. audouiniL
`Public Health Rep 1952;67:53-6.
`12. Philpot CM. Some aspects of the epidemiology of tinea.
`Mycopathologia 1977;62:3-13.
`13. Mackenzie DWR. The extra human occurrence of T. ton-
`surans (var su~treum). Arch Dermatol 1951;63:493-6.
`14. Verhagen AR. Distribution of dermatophytes causing tinea
`capitis in Africa. Trop Georgr Mud 1974;26:101-20.
`15. Cabretta J, Esteves J, Sequeira H. Dermatophytes in Por-
`tugal ( 1972-I 981 ). Mycopathologia 1984;84:159-64.
`16. Watanabe S, Watanabe SU. Dermatophyte flora in Kan-
`
`sai district of Japan. In: Comptes Renous des Communica-
`tions. Proceedings of Vth Congress International Society of
`Human and Animal Mycology. Paris, France: ISHAM,
`1971.
`17. Rippon TW. The changing epidemiology and emerging
`patterns of dermatophyte species. In: McGinnis MR, ed.
`Current topics in medical mycology. Vol 1. New York:
`Springer-Verlag, 1985:208-34.
`18. Nickerson W J, Irving L, Mehmert HE. Sandals and
`hygiene and infections of the feet. Arch Dermatol Sym-
`philot 1945;52:365-8.
`19. Taplin D. Superficial mycoses. J Invest Dermatol 1976;67:
`177-80.
`20. Taplin D. Fungus and bacterial diseases in the tropic: final
`report to the U.S. Army, R and D Command. Washington,
`D.C.: Contact DADA, 1978;report 17-71-C1084.
`21. Roberts DT. Prevalence of dermatophyte onychomyeosis in
`the United Kingdom: results of an omnibus survey. Br J
`Dermatol 1992;39:23-7.
`22. Prevalence, morbidity, and cost of dermatological diseases.
`J Invest Dermatol 1979;73:395-401.
`
`PRESENTED AT THE "INTERNATIONAL SUMMIT ON CUTANEOUS
`ANTIFUNGAL THERAPY," SUPPORTED BY EDUCATIONAL GRANTS
`FROM JANSSEN PHARMACEUTICA; ORTHO PHARMACEUTICAL
`CORPORATION~DERMATOLOGICAL DIVISION; ROERIG--A DIVISION
`OF PFIZER; AND SANDOZ PHARMACEUTICALS CORPORATION.
`
`IIII I
`
`I
`
`I
`
`II II
`
`Current therapy of dermatophytosis
`
`Hugo J. Degreef, MD,a and Piet R. G. DeDoncker, MScb Leuven and Beerse, Belgium
`
`In the past dermatophytes were treated with topical agents or, in the case of more recalci-
`trant or extensive disease, with oral antifungals (griseofulvin or ketoconazole). Topical ther-
`apies may beeffectivein manycases, but theyhavelimitations.They maybeviewed as inconven-
`ient by the patient, thereby affecting compliance. Therapy with early oral anti£ungals entails
`long treatment periods until complete cure is obtained. For ketoconazole rare but serious side
`effects can occur, particularly with prolonged use. Griseefulvin is still the drug of choice for
`the treatment of tinea capitis of the Microsporum type. In recent years a few new antimy-
`cotic agents have been developed for systemic therapy of superficial fungal infections. Itra-
`conazole is a broad-spectrum triazole. Fluconazole belongs to the same chemical class and
`was used mainly in systemic yeast infections and mucosat candidosis. Terbinafine is an al-
`lylamine and has been found to be effective and safe in brief therapy of dermatophyte infec-
`tions. Short-duration therapy of most dermatophyte infections is also possible with itracon-
`azole. The high and specific activity against the causative agents, together with their phar-
`macokinetie properties, explains the good results obtained with these new drugs and their
`improved safety prone. Their mode of actlon, pharmacokinetics, and treatment schedules will
`be discussed. (J AM ACAD DERMATOL 1994;31:$25-$30.)
`
`From the Department of Dermatology, UZ Saint-Rafa~l Catholic
`University Leuven,~ and The Department of Clinical Research,
`Janssen Research Foundation? Beerse.
`Reprint requests: Hugo Degreef, MD, UZ St. Ra fa~l, Capueienenvoer
`33, 8-3000 Lcaven, Belgium.
`Copyright ~ 1994 by the American Academy of Dermatology, Inc.
`
`0190-9622/94 $3.00+ 0 16/0/57449
`
`Fungal infections of the skin, hair, and nails are
`among the most common skin diseases. In recent
`years the incidence of these infections has been in-
`creasing steadily. Much of this increase has been at-
`tributed to the expanding number of immunocom-
`promised patients and to lifestyle changes. The use
`$25
`
`3 of 3
`
`