CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 1/12
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`
`JOURNAL OF THE AMERICAN ACADEMY OF
`
`DERMATOLOGY
`
`VOLUME 50
`
`NUMBERS
`
`‘la
`
`.
`
`,
`
`Cop)/Hg/zt © 2004 by the A nzerlca/2 Academy Q/‘Dennarology. Inc.
`c.“"-*0
`«'2
`.9 *
`3'3
`m
`C
`
`A.
`'.
`
`U
`
`O
`
`l938
`5-7 at ,aiT°\
`
`CONTINUING MEDICAL EDUCATION: CUTAEOUS BIOLOGY
`
`The role of interleukin 10 in the pathogenesis and potential treatment of
`skin diseases
`
`Elliot Wieiss, BA, Adam Joseph Mamelak, MD, Stephania La Morgia, MD,
`Binghe Wang, MD, Claudio Feliciani, MD, Antonio Tulli, MD, and
`Daniel Nathan Saucler, MD Balr‘z'more, Maryland, cmcl Clare/rf amrl Rome, Italy
`
`CME examination
`
`Answers to CME examination (Identification N 0. 804-105), May 2004 issue of
`
`the journal of the American Academy of Derrnatology
`
`REPORTS
`
`Seasonal variations in the diagnosis of cutaneous melanoma
`Monil<a—Hildegarcl Schtnid-\X7'enc1t,net, MD, Jens Battmert, MSC, Gerd Plewig, MD, and
`Matthias Volkenandt, MD M2,r,m‘cla,
`(;"errmr'z/zy
`‘
`
`Addition of dermoscopy to conventional naked-eye examination in
`melanoma screening: A randomized study
`Paolo Carli, MD, Vincenzo de Giorgi, MD, Alessandra Chiarugi, MD,
`Paolo .\'a1‘dim', MD, Martin A. \Weinst.ock, MD, Emanuele Crocctti, MD,
`Marcello Stante, MD, and Benvenuto Giannotti, MD Florence Italy, and
`l’rr)zJz’oler7,ce, Rbocle Islomcl
`
`G A L D E R M A
`—
`
`Complimentary subscriptions to the Journal of the American Academy of Dermatology
`are available to dermatology residents, fellows, and osteopathic trainees in the United
`States and Canada as an educational service by Galderma.
`
`Comfmrrerzl on page 6A
`
`D E R M I ® Complimentary subscriptions to the Journal of the American Academy of Dermatology
`are provided to the Society of Dermatologic Physician Assistants by Dermik Laboratories.
`
`The JournaloftheAmerican Academy ofDermatology (ISSN 0190-9622) is published monthly (six issues pervolume, two volumes peryear) by Elsevier Inc.
`Corporate and editorial offices: 11830 Westline Industrial Dr, St Louis, MO 63146-3318. Accounting and circulation offices: Elsevier |nc., 6277 Sea Harbor
`Dr, Orlando, FL 32887-4800. Periodicals postage paid at Orlando, FL 32862, and additional mailing offices. 2004 Subscription rates: $232.00 for indi-
`viduals, $461.00 for institutions. Prices are subject
`to change without notice. Printed in the U.S.A. © 2004 by the American Academy of
`Dermatology, Inc. POSTMASTER: Send address changes to Journal ofthe American Academy of Dermatology, Elsevier Inc., Periodicals Department, 6277
`Sea Harbor Dr, Orlando, FL 32887-4800.
`
`CFAD v. Anacor, |PR2015—O1776 ANACOR EX. 2059 — 2/12 SA
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 2/12
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`

`
`cormrzr./,ed
`Contents
` m
`
`Genital lentigincs and melanocytic nevi with superimposed lichen sclerosus:
`A diagnostic challenge
`
`Laila El Shabrawi—Caelen, MD, H. Peter Soyer, MD, Hem/‘lg Schaeppi, MD,
`Lorenzo Cerroni, MD, Carl G. Schirren, MD, Christina Rudolph, MD, and
`llelrnut Kerl, MD Gmz mm’ Drirrzbzrn, Arrstrror, and Dm'n’z.s‘mdI, Ge//‘rrmrzy
`
`Number of acquired melanocytic nevi in patients with melanoma and
`control subjects in Japan: Nevus count is a significant risk factor for
`nonacral melanoma but not for acral melanoma
`
`Shiho Rokuhara, MD, Toshiaki Saida, MD, PhD, Misae Oguclii, MD, PhD,
`Kazuhiko l\/latsumoto, MD, PhD, Surnio Murase, MD, PhD, and Shinji Oguchi, MD, PhD
`Moztsmrzo/0 (moi Us‘z.wZa, japan
`
`Cutaneous malignant melanoma in association with mycosis fungoides
`Alun V. Evans, MRCP, Julia _]. Scarisbriclc MRCP, F. J. Child, MRCP,
`Katharine M. Aclancl, MRCP, Sean _l. Whittaker‘, MRCP, and Robin Russell—]ones, FRCP
`lrmdorz, Urzz'zfecr’ Kingdorrr
`
`Sunless tanning
`
`Jennifer M. Fu, BA, Stephen W’. Dusza, MPH, and Allan C. Ilalpern, MD, M8
`New Yor/<2, New Yorle
`
`lmiquimod 5% cream for the treatment of actinic keratosis: Results from two
`
`phase III, randoinized, double~blind, parallel group, vehicle-controlled trials
`Mark Lehwohl, MD, Scott Dinchart, MD, David Whiting, MD, Peter K. Lee, MD, PhD,
`Naji Tawfik, MD, PhD, Joseph Jorizzo, Ml),]a1nes H. Lee, MD, PhD, and
`Terry L. l-‘ox, MS New York, New )"()7‘k,- Little Rock, Ar‘A2cm5c1s',r Dallas, Texas,-
`M1Tm/zer/rpr)Zz'.s mzd St Paul, ll/.fz'm1e.s‘r)Zcr,' lndrfarzapc)/1'5 and Evrmwille,
`/ndz’r/zrza,- orrzci
`Wz'r1sf<)1/z—.S”aler71., Non‘/J Ccrrolrimr
`
`Imiquimod 5% cream for the treatment of superficial basal cell carcinoma:
`Results from two phase HI, randomized, vehicle-controlled studies
`john Geisse, MD, Ivor Caro, MD, Jane Lindholm, MD, Loren Golit’/., MD,
`Patti Stampone, MS, and Mary Owens, MD I/’czZle_%/‘r),
`(7ozlgflm'zz'cr,- Boston, rllor.s's'crc/9u.s‘ez‘Z.s‘,-
`Frrdley, .Wrmesola,- Denver, Colomdo; and St Paul, Mmrzesora.
`
`Narrowband UVB and cream psoralen-UVA combination therapy for plaque-
`type psoriasis
`
`Marcella Grundrnanr1—Kollmann, MD, Ralf Ludwig, MD, Thornas M. Zollner, MD,
`Falk Ochsenclorf, MD, Diamant Thaci, MD, Wolf—l Ienning Boehncke, Ml’),
`jean Krutrnann, MD, Roland Kaufrnann, M D, and Maurizio Podda, MD
`/Jmn/efurt am’! Dz1r'sseZa’orf Germmry
`
`Low-dose UVA1 phototherapy in systemic sclerosis: Effects on acrosclerosis
`Alexander Kreuter, MD, Frank Breuckrnann, MD, Andrea Lfhle, MD,
`Norbert Brocl<rne_Ver_, MD, Gregor Von Kol)yletzl<.i, MD, Marcus Freitag, MD,
`Markus Stuecker, MD, Klaus Hoffmann, MD, Thilo Garnbichler, MD, and
`Peter Altmeyer, MD Bocbum,
`(¥er‘mcln._y
`
`Statements and opinions expressed in the articles and communications herein are those ofthe author(s) and not necessarily those ofthe
`Editorls), publisher, or Academy, and the Editorls), publisher, and Academy disclaim any responsibility or liability for such material. Neither
`the Editor(s), publisher, nor the Academy guarantees, warrants, or endorses any product or service advertised in this publication, nor do
`they guarantee any claim made by the manufacturer of such product or service.
`
`C()I'Zl‘iI'Zli€(A[ on page 10A
`
`6A MAY 2004
`
`CFAD V. Anacor, IPRZO1 5-01 776 ANACOR EX. 2059 - 3/12
`] AM ACAD DERMATOL
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 3/12
`
`

`
`Contents
`
`coizmmed
`
`Epidemiologic surveillance of cutaneous fungal infection in the United States
`from 1999 to 2002
`
`748
`
`K. VY/'ade Foster, MD, PhD, Mahmoud A. Ghannoum, PhD, and Boni E. Elewski, MD
`B1’;/mzfiglvmn, Alabcmm, and Cleve/mzd, O/oio
`
`l DERMATOLOGIC SURGERY !
`
`Keratoacanthoma as a postoperative complication of skin cancer excision
`Leonard l-l. Goldberg, MD, FRCP, Sirunya Silapunt, MD, Kathleen K. Beyrau, MD,
`.8. Ray Peterson, MD, Paul M Friedman, MD, and Murad Alam, MD
`Houston, Texas, Portage, W"z'scomm, and Chicago, Jllmozls‘
`
`['B'ffiMAToPATHoLoGY ]
`
`Standard ijnmunostains for melanoma in sentinel lymph node specirnens:
`Which ones are most useful?
`
`Darius J. Karimlpour, MD, Lori Lowe, MD, Lyndon SL1, MD, Ted Hamilton, MS,
`Vernon Sondak, MD, Timothy M. Johnson, MD, and Douglas Fullen, MD
`Ann Arbor, Michigan
`
`Compound melanocytic nevi with granular cell changes
`l-latem M. El-Gamal, MD, Leslie Robir1son~Bostom, MD, Kirk D. Saddler, MD,
`Teddy Pan, MD, and Martin C. Mihm, MD Indz‘m'1.a,I)o]z'.s', lndicma,
`Pmmdence, R/Jody Island, and Boston, A/Icz.s‘.s‘czcl.msez‘ts
`
`«CLINICAL REVIEW |
`
`Turner’s syndrome in dermatology
`Eve J. Lowenstein, MD, PhD, Karen H. Kim, MD, and Sharon A. Glick, MD
`Broo/eiyn, New York
`
`l
`
`IDEAS I
`
`Pathogenesis of androgenetic alopecia
`Alfredo Rebora, MD Genoa, Italy
`
`F5333
`
`Surgical Pearl: Pinch-punch excisions for scrotal calcinosis
`Ching—I-Lao Chang, MD, Chih—Hsun Yang, MD, and IIong—Shang Hong, MD, PhD
`'/mpez’, Ta/‘wom
`
`Iotaderma #124
`
`Jeffrey D. Bernhard, MD EdlTO1”
`
`Comfmuecz’ on jmge 12A
`
`MAY 2004
`
`CFAD V. Anacor, IPRZO1 5-01 776 ANACOR EX. 2059 - 4/12
`J AM ACAD DERMATUI.
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 4/12
`
`

`
`Contents
`
`C02/zmzueol
`
`T BRJEFREPORTS D
`
`Dacarbazine but not temozolomide induces phototoxic dermatitis in patients
`with malignant melanoma
`
`Regina Trcudler, MD, Juliana Geo1‘gieVa, MD, Christoph C. Geilen, MD, and
`Constantin 1:‘. Orfanos, MD b’e7‘[z'n, Germomy
`
`Pyodermatitis-pyostomatitis Vegetans With circulating autoantihodies to
`bullous pemphigoid antigen 230
`Bong kyun Ahn, MD, and .So0—Chan Kim, MD Seoul, K()I”€6l
`
`—ASEREPRS
`
`A nonepidermal, priinary malignant melanoma arising in a giant congenital
`melanocytic nevus 40 years after partial surgical removal
`Brian N. Streams, MD, Peter A. Lio, MD, Martin C. Mihm, MD, and Arthur _I. Sober, MD
`B05/on, MassczCl.7usel[.s'
`
`Amelanotic lentigo maligna managed with topical imiquixnod as
`immunotherapy
`
`Ann—Marie Powell, MB, MRCPI, and Robin RussCll—_Iones, l\/LA, FRCP, F RCPatl1
`lomion, Umfed Kzngdoriz
`
`I LETTERS: CASE NOTES ’
`
`Papulolinear collagenoma
`
`Ricardo Romiti, MD, and Ney Romiti, MD 5520 Pcmlo and De Smzfos, Bmzz]
`
`SWeet’s syndrome in a patient with entcrococcal subacute bacterial
`endocarditis
`
`Karen P. Gould, MD, Jeremy D. Jones, MD, andjeffiey P. Callen, MD
`Loz.zvz'5z2z'l/e, Kcmtzrcky
`
`Coexistence of acquired localized hypertrichosis and lipoatrophy after
`lupus panniculitis
`
`Ignacio Garcia~DoVal, PhD, Elena Roson, PhD, Maite Abalde, MD, Carlos Peal, MD,
`and Manuel]. Cruces, PhD Pomez/e(;lm, Q/7a1T7'z
`
`ETTERS: NOTES &CMMENTS
`
`On brachioradial pruritus and notalgia paresthctica
`Ekin .§aVl<, MD, and S. Oiiei‘ Savk, MD Aydin, 7‘zu”key
`
`Rifampicin/pyrazinamide therapy should not be used. for latent
`tuberculosis infection
`
`Ignacio Garcia—DOVal, PhD Pomezxedrcz, Sjamn
`
`Reply
`
`Gil Yosipovitch, MD, and Yuin Chew Chan, MD
`W"7“z7st0rz—Sa/971/zy, A/(m‘l7 Carolirzcz, mm’ Smgapore
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2059 - 5/12
`I /\M ACAD DERMATOL
`
`(.‘mz.lz'7~7.zwcl 072 page 74A
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`
`CO7'ZZ‘i11Lt€d
`Contents
`
`
`Melanoma is never “featureless”
`
`Thomas N Helm, MD W/z'Z[z'am5z/z'Zle, New York
`
`Withdrawal of immunosuppressive therapy after developing melanoma
`Steven M. Sotschet, MD Wazwozzt, Wz'sc07'z5zTn
`
`Hypertrichosis surrounding scar of knee replacement surgery
`Somesh Gupta, MD, Sanjeev Gupta, MD, Amrinder J. Kanwar, MD, and
`Bhushan Kumar, MD Cbmzcligarlv and R0/flak, I7/z.dz‘oz
`
`Clinical trial of allogeneic cultured dermal substitute for the treatment
`of intractable skin ulcers in 3 patients with recessive dystrophic
`epidermolysis bullosa
`
`Toshio l-lasegawa, MD, Yasushi Suga, MD, Masayuki Mizoguchi, MD, Shigaku lkeda,
`MD, PhD, Hideoki Ogawa, MD, PhD, Kentaro Kubo, Hiromichi Matsui, Shizuko
`Kagawa, and Yoshimitsu Kuroyanagi, Dr.Eng., Dr.rer.nat., Dr.Med.Sci. To/‘aye, _/Zzprm
`
`BOOK REVIEWS
`
`Dermatology. Jean L. Bolognia, Ronald P. Rapini, and Joseph L. Jorizzo
`Reviewed by Jane M. Grant—Kels, MD Fozrmz‘72gtm'z, Cb7meczfz’cz.¢2*
`
`Interactive atlas of dermoscopy. Giuseppe Argenziano, MD, H. Peter Soyer,
`MD, Vincenzo De Giorgio, MD, Domenico Piccolo, MD, Paolo Carli, MD,
`Mario Delfino, MD, Angela Ferrari, MD, Rainer Hofmann-Wellenhof, MD,
`Daniela Massi, MD, Giampiero Mazzocchetti, MD, Massimiliano Scalvenzi,
`MD, and Ingrid H. Wolf, MD
`
`Reviewed by Peter A. Lio, MD, and Paul Nghiein, MD, PhD Boszfon, Mmxsac/;7z.tsetts
`
`Color atlas of oral diseases. 3rd edition. George Laskaris
`Reviewed by Jeffrey D. Bernhard, MD Ec2’z'z‘or
`
`Dermatologic syndromes card deck. S. B. Mallory and E. Gutierrez
`Reviewed by Suzanne .\'. Granados, MD C/r2ozrZ0ttesm’l[e, V1'rg1'7zz'a
`
`SELFASSSSENT
`
`Self-Assessment examination of the American Academy of Dermatology
`(Identification No. 804-205)
`
`Diminished buccal fat
`
`Melinda Gooderham, MD, MSC, and Nowell Solish, MD, FRCPC
`Toronto, O7zlam'(),, Canada;
`
`Multiple facial papules
`
`Nathaniel Jellinek, MD, Stephen Brady, MD, and Thomas Cropley, MD
`Worcester, Massachusetts
`
`14A MAY 2004
`
`CFAD V. Anacor, |PR201 5-01 776 ANACOR EX. 2059 - 6/“I2
`J AM AeAD DERMATOL
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`(forzliiz 24,951 on page 77A
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 6/12
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`
`
`
`Contents c(m2.‘z'm,/led
`
`Persistent facial plaque
`Nathaniel Jellinek, MD, Stephen Brady, MD, Thomas Cropley, MD, and
`Richard Ellison, MD Worcester, Massczc/Juseffs
`
`Fever and rash
`
`Nathaniel Jellinek, MD, SLephen Brady, MD, and Mark Scharf, MD Worceszfer,
`Molssozc/.7u.setts
`
`Woman with swelling of the lower lip
`Amor Khaehemoune, MD, CW5, Anthony J. Papadopoulos, MD, Eric Ehrsam, MD,
`and C. Lisa Kauffman, MD W/’c1.5bingr()7'z, DC
`
`Dermoscopy challenges
`Robert Johr, MD, and Ralph Braun, MD M11/zm.z', Florida, and Genem, Su/vzfzerlcznd
`
`CORRECTIONS
`
`Correction to De Simone C, Guerriero C, Giampietruzzi AR, Constantini M, Di
`Gregorio F, Amerio P. Achilles tendinitis in psoriasis: Clinical and
`sonographic findings. J Am Acad Dermatol 2003;419:217-22 (August)
`
`Correction to Agelli M, Clegg LX. Epidemiology of primary Merkel cell
`carcinoma in the United States. J A1n Acad Dermatol 2003;49:832-41
`(November)
`
`ANNOUCEMENTS
`
`American Board of Dermatology examination dates
`
`Call for bound volumes
`
`READER SVICES 7
`
`Information for authors
`
`Information for readers
`
`Dermatology opportunities
`
`Instructions for Category I CME credit
`
`www.eblue.org and
`January 2004, pages 25A, 26A, 27A, and 28A
`
`24A
`
`Instructions for Category I CME credit (Self-Assessment)
`
`Statement 011 advertising in the Journal
`
`Change of address
`
`Full-text access to Journal of the American Academy of Dermatology Online is now
`available for Academy members and all print subscribers. To activate your online
`subscription, please visitjournal of the American Academy of Dermatology Online by
`pointing your browser to http://WWw.eblue.org.
`
`I AM Aem) DERMATOL
`
`CFAD V. Anacor, |PR201 5-01 776 ANACOR EX. 2059 - 7/
`MA ' 2004
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`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2059 - 7/12
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`

`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`_:j
`
`Epidemiologic surveillance of cutaneous fungal
`infection in the United States from 1999 to 2002
`
`K. Wade Foster, MD, PhD,“ Mahmoud A. Ghannoum, PhD,“ and
`Boni E. Elewski. MD“
`
`Bz'r1m'nglmm, Alabama, and Cleveland, Ohio
`
`Background: Cutaneous fungal infections are common in the United States, and causative organisms
`include dermatophytes, yeasts, and nondermatophyte molds. These organisms are in constant competition
`for their particular environmental niche, often resulting in the emergence of one or more predominant
`pathogens and displacement of other less competitive species. Changes in the incidence of fungal
`pathogens can be followed from laboratory culture results of infected cutaneous tissues over time. These
`data can be used to ascertain past and present trends in incidence, predict increases in antifungal resistance
`and the adequacy of our current pharmacologic repertoire, and provide insight into future developments.
`
`Objective: This study identifies epidemiologic trends and the predominant organisms causing superficial
`fungal infections in the United States.
`
`Methods: A total of 15,581 specimens were collected from clinically suspected tinea corporis, tinea cruris,
`tinea capitis, tinea faciei, tinea pedis, tinea manuum, and finger and toe onychomycosis from 1999 through
`2002. Specimens were submitted to the Center for Medical Mycology in Cleveland, Ohio, for fungal culture
`and identification, and the incidence of each species was calculated.
`
`Results: Dermatophytes remain the most commonly isolated fungal organisms except from clinically
`suspected finger onychomycosis, in Which case C'cmdi’da species comprise >70% of isolates. Tr‘iir:bopbylo7z
`mbmm remains the most prevalent fungal pathogen, and increased incidence of this species Was observed
`in finger and toe onychornycosis, tinea corporis and tinea cruris, tinea manuum, and tinea pedis. As the
`causal agent of tinea capitis,
`’1'zo7/ztmrmzs continues to increase in incidence, achieving near exclusionary
`proportions in the United States.
`
`Conclusion: Consideration of the current epidemiologic trends in the incidence of cutaneous fungal pathogens
`is of key importance to investigational efforts, diagnosis, and treatment.
`(J Am Acad Dermatol 200/i;50:,748—52.f)
`
`ycotic infection of the skin can be caused
`by dermatophytes, yeasts, and. nonde.r-
`matophyte molds,
`although
`dermato-
`phytes are the most frequently encountered caus-
`ative a gent. Together, these organisms account for a
`high number of office visits and treatment—related
`
`expenses.‘ Superficial fungal infections comprise a
`
`From the Department of Dermatology, University of Alabama at
`Birmingham School of Medicine,“ and University Center for
`Medical Mycology, Cleveland.”
`Funding sources: None.
`Conflicts of interest: None identified.
`Accepted for publication May 12, 2003.
`Reprint requests: M. A. Ghannoum, PhD, University Center for
`Medical Mycology, 1 1 100 Euclid Ave, Cleveland, OH 44106-5028.
`E-mail: mag3@po.cwru.edu.
`Published online February 18, 2004.
`© 2004 by the American Academy of Dermatology, Inc.
`0190-9622/$30.00
`d0i:10.1016/S0l90—9622(O3)O2117-0
`
`complex host—parasite relationship that is in constant
`flux. Species compete to exploit an environmental
`niche within a host population, often resulting in the
`emergence of one or more predominant pathogens
`and displacement of organisms with less adaptive
`qualities.“ Changes in the incidence of a pathogen
`affect the physicians ability to render a diagnosis
`and can change the approach to treatment? Multiple
`factors may affect the incidence of fungal pathogens
`within a population. These include the geographic
`area and climate, immunocompetence of the host, the
`pathogenicity of the infectious agent, and the availabil-
`ity of medical treatment. This study provides insight
`into recent trends in the incidence of fungal species
`isolated from skin infections in the United States.
`
`METHODS
`
`A total of 15,581 patient samples including nail
`clippings, subungual debris, hair, and skin scrapings
`were collected at the Center for Medical Mycology in
`
`743
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`] AM ACAD DERMATOL
`VOLUME 50, NL'Ml3ER S
`
`Foster’; G/aan.nozmz, and Elews/ei 749
`
`A
`Finger onychomycosis
`60’
`52.6
`54-“
`535
`<04
`"
`40 ‘
`30
`20'
`
`Incidence
`
`B
`100’
`80
`
`60
`
`Incidence
`
`10—
`
`Toe onychomycosis
`
`64.4
`
`77.,
`‘
`
`81.4
`
`79.3
`
`9_ 83.
`
`Tinea capitis
`87.4
`3; 3
`I‘
`
`C
`"ml 39-3
`80
`60
`
`wt
`20
`
`Incidence
`
`2001
`2000
`E99
`-& Candida a/bicanx
`Tricnop/iylon rubru/-71
`-I— Candida pa/'apsil05i.s'
`Candida tropical is
`-A-- Fusarium Spp
`
`2002
`
`1999
`
`2000
`
`2001
`
`2002
`
`1999
`
`2000
`
`2001
`
`2002
`
`-0- Tr/‘C/riophylon rubrum
`’/"r/c/10 nylon meniagropliyies
`-I-Fmaripuni spp
`%ACrem0nium spp
`'-A“ Candida parapsi/osis
`
`-0- "1 'ric/10p/iylon l0n.suran.s'
`Microsporuin cams
`1 Tricliophyion rubruin
`Tric/zop/iymn menlagropnyzes
`>A~/llrernaria spp
`
`D Tinea corporis/tinea cruris
`70—‘
`
`Tinea manuum
`86.6
`
`Tinea pedis
`
`76.4
`
`Incidence
`
`Incidence
`
`. ,2’
`
`1999
`
`Incidence
`
`2(I00
`
`2001
`
`200
`
`2000
`
`2001
`
`20402’
`
`% Trichop/iyton rzibrum
`Trichop/aylon tonsurans
`f-Candida albicans
`<1-Microspomm can/'5
`~~A--Microspomm gy,r)semn
`
`% Tricnop/iyton l”llf7I”’llI’I’l
`'' Candida pa/‘ap.~;il0s/‘S
`—I— Candida albicans
`Epiderm op/7yion_floccosum
`~A-- Cladospor/"um spp
`
`% Trichophyion mlirum
`Tr/chop/Iiyton menragrophyres
`-I- Epide rm ophyl on floccosum
`Candida albicans
`--A“ Candida parapsi1031'S
`
`the
`Fig 1. Incidence of cutaneous fungal species from 1999 to 2002. Values represent
`incidence of the 5 most common species isolated from finger onychomycosis (A), toe onych—
`omycosis (B), tinea capitis (C), tinea corporis and tinea cruris (D), tinea manuum (E), and tinea
`pedis (F). Tabular presentation of complete data sets for each body site is available online at
`wvxwv.eblue.org.
`
`Cleveland, Ohio, fromjanuary /1, I999, through Sep-
`tember -/1, 2002. Specimens were obtained from clin-
`ically suspected fungal infections of various body
`sites including fingernail, toenail, body and groin,
`head and scalp, face, hand, and foot by US podia-
`trists, dermatologists, and primary care physicians.
`In all, 11 states were represented in the study: Ala-
`bama, California, Florida,
`Illinois, Michigan, Mis~
`souri, New York, Ohio, Pennsylvania, Tennessee,
`and Texas. Specimens were submitted in a Derma-
`Pak (Microbiological Supply Co, Toddington, Ifnited
`Kingdom) on Mycosel agar (BBL, Cockeysville, Md)
`or on dermatophyte testing agar,
`described.5 Pri-
`mary isolation medium included Mycosel agar and
`potato dextrose agar supplemented with chloram—
`phenicol and gentamycin, as described.“ Cultures
`were incubated at 30°C for 11p to 28 days and
`checked twice weekly for growth. Negative cultures
`were confirmed after 4 weeks of no growth. Identi-
`
`fication of derrnatophyte isolates was on the basis of
`microscopic morphology, urea testing, growth on
`Trz’cbopb_yion. agars, and hair perforation assays.
`Nondermatophyte molds were identified by micro-
`scopic morphology. Recovered yeasts were sub—
`jected to the germ tube testf‘ analyzed using an
`identification system (API 20C, bioMerieux Inc,
`Durham, NC),7 and checked for morphology in
`cornmeal agar (BBL). All specimens were sent
`part of routine medical workup and analyses were
`conducted retrospectively. The incidence of the 5
`most common species from each body site is pre-
`sented graphically (Fig 1). A more detailed analysis
`is presented in a series of tables that can be accessed
`online at wwWv.eblue.org.
`
`RESULTS
`
`From fingernail debris, 674 isolates were ob-
`tained. The incidence of nondermatophy”t.e molds
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`I AM ACAD D E RM ATO t
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`decreased 5-fold from 1999 to 2002, yet the inci-
`dence of Ccmolzfda species remained relatively con-
`stant, ranging from 70.5% to 75.8%. C (1/bicoms was
`tl1e predominant isolate, accounting for 47.9% to
`54% of positive cultures (fig 1, A). Tl1e incidence of
`dermatophytes increased nearly 2-fold during the
`study period, fueled by upward trends in the inci-
`dence of Tmbmm. Tmtlamm was also the predom-
`inant derrnatophyte, accounting for >90% of all fin-
`gernail—deriVed derrnatophyte isolates in each of the
`4 years analyzed.
`From infected toenail debris, 3698 isolates were
`obtained. The fungal isolates were diverse and in-
`cluded 29 species of nonderrnatophyte molds, 8
`species of Ccznolicloz, and 6 species of dermato-
`phytes. As with finger onychomycosis, the incidence
`of nondermatoph_vte molds decreased during the
`study period, with a pronounced decline in the in-
`cidence of Fu.scm'2m2 species. In contrast to finger
`onychomycosis, incidence of Cmzdidoz species was
`low, ranging from only 3.5% to 6.7%. Incidence of
`dermatophytes ranged from 72.4% to 88.2% and
`trended upward during the study period secondary
`to increases in the incidence of T mbrmn, the pre-
`dominant dermatophyte (Fig 1, B). Analysis of com-
`bined (fingernail- and toenail-derived) data identi-
`fied Tmbmm as the predominant causative agent of
`onychomycosis, with incidence ranging from 55.2%
`in 1999 and increasing steadily to 72.8% in 2002.
`Conversely, analysis of combined nail data showed
`that Ccmdida species accounted for a much smaller
`fraction of onychomycosis, and a steady decline in
`incidence from 18.9% in 1999 to 11.5% in 2002 was
`observed.
`
`From hair— and scalp—derived tissues, 775 isolates
`were obtained. Nondermatophyte molds and Com-
`olicioz species were isolated. in low abundance from
`hair and scalp tissues, accounting for <54% and
`<1.6% of
`isolates,
`respectively. Dermatophytes
`comprised the majority of isolates, with incidence
`ranging from 94.6% to 99.7%. T torzsurmzs remains
`
`the most commonly isolated pathogen, with inci-
`dence reaching 95.8% in 2002 (Fig 1, C). As with
`tinea capitis, the predominant isolate from face—de—
`rived tissues was Ttonsuxrmzs, with incidence rang-
`ing from 50% to 100% during the study period.
`From body— and groin-derived tissues, 130 fungal
`isolates were obtained. The incidence of nonder—
`
`matophytes was low, ranging from 0% to 4%. The
`incidence of Cmzciidcz species was higher, but with
`somewhat more erratic fluctuations from year to
`year, ranging from 0% in 2001 to 25.5% in 2002.
`Dermatophytes had the highest incidence through-
`out the study ranging from 76.5% to 96%. Although
`several species of dermatophytes were isolated, the
`
`predominant pathogens were T mbmm and T [012-
`5ZH‘6l7‘lS (Fig 1, D). The incidence of T rubmm in-
`creased during the study period, comprising 32% of
`isolates in 1999 and increasing to 47% in 2002. Con-
`versely, T Z0713?!/”6l7Z5 accounted for 30.1% and only
`17.7% of isolates in 1999 and 2002, respectively.
`A total of 40 isolates were obtained from the
`
`hand. An abrupt decrease in the incidence of non-
`dermatophyte molds from 21.4% in 1999 to 0%
`thereafter was observed. The incidence of (Jmzdida
`
`species was variable, ranging from 6.7% to 35.5%.’/0
`during the study period. Dermatophyte incidence
`trended upward, from 64.4% in 1999 to 80% in 2002,
`secondary to increases in the incidence of Tmbrum,
`the most common isolate (Fig ’l, E).
`isolates
`From foot—derived tissues, 189 fungal
`were obtained. Both nondermatophytes and C6111-
`ciidcz species had relatively low incidence, whereas
`dermatophytes accounted for 86.2% to 100% of iso-
`lates. T mbmm was the most common isolate, and
`the incidence of this species increased steadily dur-
`ing the study period (Fig 1, F).
`
`DISCUSSION
`
`Analysis of finger‘ and toe onychomycosis in this
`study showed an inverse relationship between T
`mbrzmz and Cciizdidcz species. In finger onychomy-
`cosis, Cmadzda species have high incidence and T
`mbrmn has relatively low incidence. In toe onych-
`omycosis, the opposite is true. The high incidence of
`C‘mzcZz'o2’a species in finger onychomycosis has been
`noted previously, albeit not to the degree present in
`this study. Work conducted in The I\'etherlands con-
`firmed analogous roles for T mbmm and C‘arzdz'da
`species in onychomycosis, with C czlbzfcans account-
`ing for 58.5% and 6.4% of finger and toe onychomy-
`cosis, respectively.8 Similarly,
`in the United King-
`dom, Tmbmm and Coznolicia species accounted for
`39% and 58% of fingernail— and 80% and 1% of
`toenail—derived isolates,
`respectively.9 In Canada,
`the organisms causing toe onychomycosis were
`90.5% dermatophyte and 1.7% Candida; species,
`whereas the corresponding organisms causing fin-
`ger onychon1ycosis were 70.8% and 29.2%, respec-
`tively.” The incidence of (kzrzolicia species in finger
`onychomycosis in the current study ranged from
`70.3% to 75.8%, somewhat higher than that noted by
`other groups. Although these observations are in-
`triguing, the data are difficult to interpret for a num-
`ber of reasons, including the lack of clinical corre-
`lation
`and microscopic
`observation
`and
`the
`possibility that the high incidence of Cmzdida ob-
`served in this stud.y represents only secondary infec-
`tion.” Furthermore,
`recent studies have demon-
`
`strated
`
`that Ccmdzda
`
`species,
`
`particularly C
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`] AM ACAD UERMATOL
`VOLUME 50. NUMBER 5
`
`Fosler, C’/ammozmz, arid Elezz,/ski 751
`
`po1m,Ds7TZOsis and C aZbz'Cr/122.5‘, are capable of hand
`colonization without causing apparent disease.”
`Further study of this phenomenon is required before
`definitive conclusions may be drawn.
`The incidence of organisms causing tinea capitis
`varies according to region? Studies conducted in
`The Netherlands identified multiple causative spe-
`cies including Tmbmm and Tmenragr'op/bytes, but
`T z.2e7‘Vuc‘o5um, T scbonlemrfr‘, T vz’oZozcerm'z, and
`
`rW‘l'C7‘()S]307”l//777, Ccmis were most common, accounting
`for 25.3%, 24%, 17.5%, and 14.4‘?/o of infections, re-
`spectively. T to'n.su.mr7,5 was not
`isolated in this
`study.“ in Germany,
`the predominant organism
`causing tinea capi1.is
`is M calms, accounting for
`>54% of infections, and the incidence of T1072-
`swans was <4%."5 in contrast to Western Europe,
`
`T lonsurcms remains the predominant causative
`agent in North America and currently accounts for
`>950/ii of tinea capitis in the United States. The ob-
`servations reported here are in general agreement
`with previous studies conducted in the United States
`and Canada, showing that '1't0n5umrzs accounts for
`88.1% and 76% of tinea capitis, respectively.55 In
`ad.dition to the recent increases in the incidence of
`
`TZ077,sm‘oms in tinea capitis in this country, studies in
`Canada report a more rapidly increasing incidence
`initially observed at only 9% in 1985 but climbing to
`76% in 1996.3 The nearly exclusive role of T Zon-
`sumns in tinea capitis and its increasing incidence in
`tinea faciei in this study highlight the success of this
`organism as a pathogen.
`Of isolates obtained from the groin and body,
`T mbrzmz, TfO77«S1,H‘(xl1’lS, and Cmzdida species ac-
`counted for 32% to 60%,
`'l,7.7°/0 to 54.5%, and <2/1%
`of isolates, respectively. Although these results are in
`general agreement with previous Canadian and US
`studies,55 the incidence gap between T mbmm and
`Tt(m.s'z,n*ozrz.s has widened in the United States since
`
`1999. Compared with previous studies cond.ucted in
`the United States where ’1'mbru.m and C albiccms
`
`accounted for 20.3% and 47.9% of isolates, respec-
`
`tively,5 we observed a decrease in the incidence of
`C albrccms and an increase in the incidence of
`
`'1'mZ9rmn, reaching 47% in 2002. These observations
`taken together indicate an increasingly important
`role for T mbrrmz in tinea corporis and tinea cruris.
`Tmbmm, continues to play a significant role in
`tinea manuurn and tinea pedis as well, accounting
`for 80% and 82.9% of isolates, respectively, in 2002.
`The incidence of T mbmm in tinea manuum and
`
`tinea pedis continues to rise in the United States but
`is still noticeably less than that observed in Canada,
`where it has achieved near exclusionary propor»
`tions.5
`
`This work identifies both annual changes and
`even broader trends in the incidence of cutaneous
`
`fungal pathogens that span or even extend beyond
`the length of this study. Monitoring the incidence of
`these species enables the detection of emerging or-
`ganisms and allows for assessment of the adequacy
`of current pharmacologic regimens. Emerging spe-
`cies with increased resistance to mainstay antifungal
`
`therapeutic
`agents must prompt testing of novel
`drugs or drug combinations. Two t_ypes of resistance
`are currently recognized. The first of these, termed
`“clinical resistance,” denotes a lack of clinical re-
`sponse to an antifungal agent, likely secondary to
`low circulating levels of drug, noncompliance with
`therapeutic regimens, or immunosuppression. The
`other type of antifungal resistance,
`in vitro resis-
`tance, is manifest in organisms with increased min-
`imum inhibitory concentration values and is classi-
`fied as either primary, denoting an innate resistance
`to the pharmacologic agent, or secondary, indicating
`an acquired resistance to a drug.“ Acquired resis»
`tance is becoming more common in individuals who
`are immunosuppressed, lack the ability to effectively
`clear infections, and in whom the selective pressures
`of multiple antifungal agents are at work.” Der-
`matophyte resistance to antifungal agents has been
`previously demonstrated. Specifically, griseofulvin-
`resistant T VI/L/.’)VlH’I'l has been obtained from clinical
`sources and induced in the laboratory setting after
`
`mutagenesis.‘5~“’ Moreover, increased minimum in
`hibitory concentration values for griseofulvin, l<eto—
`conazole, and itraconazole have been observed in
`subsets of T mbrum and T z'nterdr'gz'tale.17 As with
`dermatophytes,
`tria7.ole—resistant Ccmrficla species,
`including C glabmlcl, C czlbiccms, and C /e1'*z.r.sez',“*~"**
`and nondermatophyte molds exhibiting single— or
`multi—drug resistance are becoming increasingly
`prevalent.l9~3“’ These observations taken together
`emphasize the growing problem of antifungal resis-
`tance, predict future increases in severity, and un—
`derscore the importance of continued epidemiologic
`surveillance.
`
`In conclusion, these data reiterate the continued
`predominance of dermatophytes as the principal
`pathogens in cutaneous fungal infections. T mbrum
`remains the most prevalent pathogen, and increased
`incidence of this organism was observed in finger
`and toe onychomycosis,
`tinea corporis and tinea
`cruris, tinea manuum, and tinea pedis. High inci-
`dence of Cmzdzda species was documented in finger
`onychomycosis, but necessitates clinical correlation
`and further study. As the causal agent of tinea capi-
`tis, T Arms/mm/zs continues its expansion to near
`exclusionary proportions in the Linited States and
`exhibits parallel increases in incidence in tinea fa-
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`752 Fosteij. Gbozm/zoimz, and Elewski
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`1 /\M /\C/\D DERMATOL
`MAY 2004
`
`ciei. Diagnosis, treatment, and inyestigational efforts
`should include consideration of these recent data.
`
`We thank Nancy Isham and Debbie Yearick for their
`efforts collecting the d