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`[‘ “itish Journal of Dermatology
`
`Th,
`
`_3!‘lIl'Sl1 journal of l)ermatology is Owned by and is the official organ of the British Association of Dermatologists.
`
`EDITOR
`
`DR JULIAN VERBOV
`Consultants’ Suite, Broaclgreen Hospital NHS Trust, Thomas Drive, Liverpool L14 SLB
`
`EDITOR—ELECT
`
`DR D.].GAWKRODGER
`Department of Derintitology. Royal Hallamshire Hospital, Glossop Road, Shefiield S10 2]F
`
`EDITORIAL ADVISORY BOARD
`
`PROF. M.W.GREAVES. London
`
`PROF. W.C.NOBLE, London
`
`PROF. C.E.M.GRIFFITHS, Manchester
`
`DR W.E.PAR1Sl-1, Sliarnbrook
`
`PROF. R.M.l\/IACKIE. Glasgow
`
`ASSOCIATE EDIToRs
`
`DR ].N.W.N.BARKER, London
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`DR A.G.MESSENGER, Sliefficld
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`DR S.M.BREATHNACH, London
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`DR D.N.SLATER, Rotherham
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`DR M.DAVIES, Plymouth
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`DR F.WOJNARO\A/SKA, Oxford
`
`BOOK REVIEW EDITOR
`
`PROF. RMMACKIE
`
`Department of Dermatology, University of Glasgow G12 8QQ
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`British Journal of Dermatology
`
`Volume 136, Number 4, April 1997
`
`CONTENTS
`
`Original articles
`Cutaneous tuberculosis in Blackburn district (U.K.): a
`1 5-year prospective series, 1981-9 5
`V.M.YATES AND L.P.ORMEROD
`
`Non—dcrrnatophytes in onychomycosis of the toenails
`D.H.EI.I.IS, A.r3.wArso\I. ].E.MARLEY AND T.G.WILLIAMS
`A possible explanation for the increased referral of
`atopie dermatitis from tl1e Asian community in
`Leicester
`SGEORGE. J.BERTH—]ONES AM) K.A.C.(jRAl-1AM-BROWN
`
`Predictors of atopic dermatitis in Leicester children
`].Bi:‘R'J‘H—]ONES, S.Gl-JORGE Ai\D R,A.C.GRAIIAM—BROWN
`
`Measurement of quality of life in atopic dermatitis:
`correlation and validation of two different methods
`R.MiI-LFRD, M.I.TIDMAN, D.A.RUTA AND J.A.A.HUN'1'ER
`The basement membrane zone in lichen sclerosus: an
`
`immunohistochemical study
`PMARREN, DDDAN, M.CI—IARNOCK A\'D F.WO]\iAROWSKA
`
`A prospective study ol'Mohs" micrographic surgery in
`two English centres
`c.c..JLnAN AND P.W.B()WERS
`
`Cyelosporin inhibits intercellular adhesion molecule-1
`expression and reduces mast cell numbers in the
`nsebia mouse model of chronic skin inllammation
`A.oRAN, 1.s._~1ARsnALL. S.KONDO. DPAGLIA AND R.C.MCKENZIE
`
`Treatment of psoriasis with intermittent short course
`cyclosporin (Neoralgf). A multieentre study
`1.BERrH—ioNEs. C.A.1-ii:'NL)i:'RSON. C.S.MUNR(), S.R0(5ERS.
`R.1.c.cHArMriRs. M.inorF.A. i>c.NoRRis, P.s.rRiEDMANN.
`i<.A.c.eaAaAM-si<owN.
`i’.M.D()WDi RMARKS AND M.].SUi\/[NPR
`
`Renal biopsy findings in long-term cyclosporin
`treatment of psoriasis
`HZACHARIAE,
`i<.i<RAcsALLi3, H.E.HANSEN‘ N.MARcusssN AND
`S.()LSEN
`
`Effect of calcitriol on the production of T—cell—derived
`cytokines in psoriasis
`M.BARNA. ].D.BOS. I\/i.L.i‘xAPSE.\1BEK(j AND r.e.M.sNuDsw1Nr
`Anthralin (dithranoi) in vitro inhibits human
`
`monoeytes to secrete IL-6. IL-8 and TNFQ, but not IL-1
`UMROWIETZ. H.]ESSA"l‘, A.scHwA1<z AND ’1'.SCIIWARZ
`Double—blind trial of botulinum. A toxin for the
`treatment of focal hyperhidrosis of the palms
`r.scaNiDsR. MBINDER, r.AUrr. H.KITTT,ER, T.Bl-JRGER AND 1<.woLrr
`
`Persistent pruritus after hydroxyethyl starch infusion
`therapy: a result of long-term storage in cutaneous
`nerves
`DMETZE, s.izsiMANN. Z.S‘ZEPFAI.USI, ssoats D.l<.RAt"l' AND
`T.A.LUGER
`
`The prevalence of epidermolysis bullosa in Scotland
`H.M.HORN. e.c.ri<irs'i'LsY, R.A.i.rADY AND T\/i.].TiT)7\/TAN
`Site. histological type, and thickness of primary
`cutaneous malignant melanoma in western
`Netherlands since 1980
`LM,r.VAN DER SPEI{—KEI]SER. H.].VAN DER RHEE. c.TorH. RA/‘AN
`WESTERING. I.A.BRUUN AND J.W.W.COEBERGU
`
`Concise communications
`Expression of endothelial nitric oxide synthase in
`human eccrine clear cells
`Y.SH1MlZU. M.sAkAi. Y.UMi-LVIURA AND ILUEDA
`
`A multicentre (double—blind) comparative study to
`assess the safety and efficacy of fluconazole and
`griseofulvin in the treatment of tinea corporis and
`tinea cruris
`].FAERGEMANN, N.].MoRK. A.HAGLUNL) A_\'D ’I.ODEGARD ET AL
`
`Case reports
`Carney complex: report of a kindred with
`predominantly cutaneous manifestations
`D.K.B.ARMS1‘l{ONG, A.U.lt{VlNi-J.
`|.M.l-IANDLEY, M.Y.wALsH,
`D.R.nADDi3N AND I-1.A.l3INGHAM
`
`Michelin tyre syndrome: a congenital disorder of
`elastic fibre formation
`l\/i.SA'l'0. o.1sai1<AwA. YMIYACIH. T.Aoi<i, T.TOMOMASA AND
`i<.\'Ac.AsHiMA
`
`A novel human papillomavirus identified in
`
`Blackwell
`science
`
`[Z1IZI7-lZ‘3E3ClE!El7B4)13S:4:1-7
`
`iii
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`

`
`.....
`
`With anti--pruritic lauromacrogols, Balneum Plus
`Cream effectively soothes the itch of eczema
`and dermatitis, reducing the urge to scratch.
`
`
`
`
`
`undesirable aflects: burning sensation,
`BAINEUM PLUS CREAM Presentation:
`E. Merck Pharmaceuticals. (A Division Of
`on the clinical response. Contraindications:
`Merck Ltd), Harrier House, High Street.
`erythema, pruritus orthe formation of pustules.
`Patients with known hypersensitivity to any
`Balneum Plus Cream contains lauromacrogols
`West Drayton, Middlesex UB7 7[1G.
`Contact allergy has also been reported.
`ofthe ingredients. It should not be used to treat
`3% wlw and urea 5% wlw as active ingredients.
`Presentation: Balneum Plus Cream is available
`® Merck and Balneum are registered
`acute erythroderma, acute inflammatory,
`Indications: pruritus, eczema, dermatitis, and
`trademarks.
`in aluminium tubes containing 1009. NHS price
`oozing orinfected skin lesions. Special
`scaling skin conditions where an antipruritic
` _———— —:——
`is £5.53 for 1009 tube. Authorisation Number
`warnings and precautions Ior use: May cause
`and/or hydrating effect is required. Dosage:
`——..—
`
`MBRCK Dermatology IIERIIAI..¢—.——— .-———_
`PLl 1 648/0020. Legal category GSL. Date of
`irritation if applied to broken or inflamed skin.
`Adu|t5,the Elderlyand Children: Balneum Plus
`It should notbe used onthe breast immediately
`preparation: 6 December 1996;
`Cream should be applied to each affected area
`For further information contact:
`~7
`priorto breastfeeding during lactation.
`twice a day. The duration oftreatment depends
`
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`
`epidermodysplasia verruciformis
`A.I.HARRlS. KPURDIE, 1.M.LE1GH. CPROBY AND S.BURGE
`Reversible dilated cardiomyopathy following treatment
`of atopic eczema with Chinese herbal medicine
`].E.FERGUSON. R.].G.CHALMERS AND D.].ROWI.ANDS
`Cutaneous manifestations of fucosidosis
`CFLEMING, ARENNIE. MFALLOWFIIELD AND P.M.MCH_ENRY
`
`Unique digital skin lesions associated with systemic
`sclerosis
`A.V.MARZANO. EBERTI, o.oAsPARiNi, A.vi=.sPAsiAN1. R.SCORZA AND
`R.CAPU'l‘O
`
`Xanthomas due to generalized oedema
`LEECKIIOUT, DVOGELAERS. M.L,GE‘.ERTS AND J.1\/LNAEYAERT
`
`Epidermolysis bullosa acquisita associated with
`epidermal—binding circulating antibodies
`s.H.wAKsL1N, e,BHocAL. M.M.BLACK, LALLEN. RWOINAROWSKA.
`T.HASHiM0'1‘(), P.M.FARR AND A.F.SWAIN
`
`Kikuchi disease (histiocytic necrotizing
`lymphadenitis) in association with HTLV1
`VBATAILLE. C.C.HARLAND. LBEHRENS, M.G.COOK AND C.A.HOLi)E.i\'
`
`Expression of adhesion molecules in pagetoid
`reticulosis (Woringer—Kolopp disease)
`P.DRILLENBL’RG, C.M.BRONKHORST, A.c.vAN DER WAL.
`L.A.NOORDUYN, RHOEKZEMA AND S.T.PALS
`
`Mycosis fungoides palmaris et plantaris: successful
`treatment with the carbon dioxide laser
`D.].GOLDBERG. T.M.STAMPIl-IN AND R.A.SCHWARTZ
`Werner's syndrome — chromosome analyses of
`cultured fibroblasts and mitogen-stimulated
`lymphocytes
`K.M(JRITA, c.N1sa1coR1, M.S.SASAKi. NMATSUYOSHI. KOHTA.
`H.oKAMoTo, K.n<AI AND SJMAMURA
`
`Erythema elevatum diutinum in association with
`coeliac disease
`KTASANEN. R.RAUDAso}A, M.KALL1o1N1~:N AND A.RANKl
`
`Painful piezogenic pedal papules: response to local
`electro—acupuncture
`S.L.WOODROW, CLBRERETON-SMITH AND S.HANDFIELD—]O,\'ES
`
`Treatment of angioma serpiginosum using a pulsed
`tunable dye laser
`C.C.I.()NG AND S.W.LANIGAN
`
`Correspondence
`Persistent telangiectatic erythema associated with an
`automatic implantable cardioverter defibrillator
`K.1<RAsAoAKIs, R.VOGT, arenas AND S.GOERDT
`
`Spontaneous regression in angiocentric T-cell
`lymphoma
`DNSLATER
`
`Reply
`D.DE BERKER AND L.SVILAND
`
`General -practitioner referrals
`H.wILL1AMs
`
`Reply
`RBASSARAB, S.E.MUNN AND ILRUSSELL-JONES
`
`CONTENTS
`
`Alopecia in liver transplant recipients
`G.E.SALE
`
`Reply
`M.MONTI AND MBARBARESCHI
`
`Congenital hypertrophy of the lateral nail folds of the
`hallux in twins
`s.cAMaIAc.H1. (LPISTRITTO AND CGELMETTI
`
`Pyoderma gangrenosum following treatment with
`isotretinoin
`II.B.GANGARAM, L.r.1'AN. A.T.oAN. 1-LHSURAIYA AND
`TGANESAPILLAI
`
`Pyoderma gangrenosum in myelodysplasia
`responding to granulocyte macrophage-colony
`stimulating factor (GM-CSF)
`S.BUL\/IK AND PJACOBS
`
`Local intralesional therapy with rhGM-CSF for a
`large genital ulcer in Behg:et’s disease
`NTALLI, GKARAKAYALI. LKAHRAMAN AND F.AR’I'ilZ
`
`Merkel cell carcinoma of the skin treated by primary
`radiotherapy
`S.K.AI_rGHAZAL AND A.HONG
`
`Bullous pemphigoid associated with eosinophilie
`pustules
`1VL].i-IUETI-IER. ].L.BOLOGN'IA, S.IMAEDA AND I.M.MCNIFF
`Proliferation markers Ki67 and PCNA in cutaneous
`
`squamous cell carcinomas: lack of prognostic value
`].KANITAKIS. DNARVAEZ, S.EUVRARD, MFAURE AND A.CLAUDY
`Cytokine dermatosis: reactivation of eczema during
`interleukin-2 infusion
`M.].CORK, S.G‘KE()l-IANE.
`lJ.I.GAWKRODG1-JR. B.W.HANCOCK.
`ETSHERIDAN AND S.S.BLEi-THEN
`
`Drug-induced hypersensitivity syndrome and toxic
`epidermal necrolysis. Treatment with N-acetylcysteine
`RREDONDO, I.DE FELIPE. A.DE LA PENA. J.M.ARAMHND1A AND
`v.vANAcLocHA
`
`Skin lesions as the only manifestation of the
`hypereosinophilic syndrome
`MBARNA, L.1<EM11:NY AND A.DOBOZY
`Isolated subcutaneous candidal abscess and HIV
`disease
`RMANFREDL A.MAzzoN1, ANANETTI, A.MAsTRo1ANN1,
`O.V.CORONADO AND F.CHIODO
`
`Giant hemifacial angioma and PHACE syndrome
`EQUECEDO. M.P.GTI.-MATEO, V.PONT, M.I.FEBRE‘.R AND A.ALIAGA
`
`Peculiar inflammatory cutaneous metastasis from
`stomach adenocarcinoma
`s.sAH1N. U.H1ND1oGLU, MBENEKLI, B.S1VRl. c.so1<M£NsUER AND
`A.stNcUR
`
`Laboratory abnormalities in granuloma annulare: a
`case-control study
`s.vERALD1, P.L.BENCINI, ETDRUDI AND R.CAPUT()
`
`653
`
`655
`
`655
`
`Book reviews
`
`Historical Vignette
`News and Notices
`
`Information on this journal can be accessed at http://wwwblackwell-science.com/products/journals/bjd.htm
`
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`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`British Journal 0fDermatulogy 199 7; 136: 49(')—493.
`
`Non—dermatophytes in onychomycosis of the toenails
`
`D.H.ELLIS,* A.B.WATSOl\l.f ].E.MARLEY:). AND T.G.W’lLLIAMS§
`*l/Wmil'i1’s and Children's Hospital, Adelaide, SA, Australia
`Tlioyal Newcastle Hospital, Newcastle, NSW Australia
`:,ETl1e University of Adelaide, Adelaide, SA, Australia
`§Sando: Australia Pty l.td. North Ryde. NSW, Australia
`
`Accepted for publication 10 September 1996
`
`Summary
`
`A multicentre trial for the treatment of dermatophyte onychomycosis of the toenails with terbinafine
`was carried out in Australia and New Zealand. Between eight and 12 nail samples were obtained
`from each of the 118 patients in the 48-week trial, and each sample was investigated by direct
`microscopy and culture for dermatophyte and non-dermatophyte fungi. Patients were randomized to
`treatment with terbinafine at 250 mg/ day or placebo for the first 12 weeks of the study, then non-
`responders were offered a 12-week course of terbinafine from week 28. All patients had a
`dermatophyte infection.
`In 42 patients (36%) microscopy and mycological culture identified
`dermatophytes alone. In the remaining 76 patients (6 96), a non—dermatophyte mould or yeast
`was also isolated at some stage during the trial, but in only three patients did the same non-
`dermatophyte persist in two or more successive nail specimens. The presence of a fungal con-
`taminant in addition to a dermatophyte had no apparent effect on the efficacy of treatment with
`terbinafine. We conclude that non—dermatophyte moulds and yeasts are generally found as
`contaminating organisms in dermatoph_vte onychomycosis. secondary to the dermatophytes. and
`that they do not influence the outcome of treatment.
`
`Dermatophytes are the principal cause of onychomycosis,
`accounting for 90% of toenail infections and at least 50%
`of fingernail infections, 90% if paronychia is excluded.
`Trichopliyton rubrum and Trichopliyton nwnt:agropliytes
`var. intcrdigitale are the dominant dermatophyte species
`involved. Candida is mainly associated with paronychia
`affecting the fingernails. The main non-dermatophyte
`moulds involved in onychomycosis as primary pathogens
`appear to be Scopulariopsis and Scytalidium. and such
`infections may account for between 1 - 5% and (7% of nail
`infections.‘l‘3‘ However, there is considerable controversy
`on the significance of non—dermatophyte moulds and
`yeasts when they are identified in the presence of a
`dermatophyte. It has been claimed that these so—called
`mixed infections are increasing in frequency, with impor-
`tant implications for patient management.4 However,
`most information on the mycology of onychomycosis
`has been obtained either from cross—sectional epidemiol-
`
`ogy studies or from investigations of specific organisms
`in patients selected for clinical trials of therapeutic agents.
`There is little information on the complete mycological
`history of infection before, during and after therapy. We
`
`Correspondence: Dr David Ellis, Mycology Unit. Women's and
`Children‘s Ilospital, North Adelaide, South Australia 5006. Australia.
`
`present data from repeated investigations in patients
`with onychomycosis who were treated with the antifungal
`agent terbinalinegs
`
`Methods
`
`Patients were aged from 18 to 70 years with distal or
`total dermatophyte onychomycosis of at least one toe-
`nail, confirmed by mycological culture. They initially
`entered a randomized, double—blind, 12-week compar-
`ison of terbinafine (250 mg once daily) or matching
`placebo. At week 24, after a 12-week wash-out period
`patients were classified as responders or non—respon—
`ders. Non-responders were offered 12 weeks of terbina
`tine (250 mg once daily) from week 28. The trial was
`conducted in 11 centres in Australia and in two centres
`
`New Zealand, and the results have been publisher.
`previously. 2
`Patients were seen at baseline and then at weeks 4, 8.
`
`12, 16 and 24. The most severely affected toenail was
`assessed for efficacy. Response to 12 weeks treatmen’
`with terbinafine or placebo was assessed at week 24.
`Patients were classified as responders if they had
`negative culture for a dermatophyte and the unaffected
`
`490
`
`© 1997 British Association of Dermatologise
`
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`
`NON-DERl\/l/\TOPHY'l‘l:]S IN ON YCHOMYCOSIS
`
`491
`
`"able 1. Mycology of a single toenail with a pure dermatophyte
`infection over 12 months
`
`‘ eel:
`
`Microscopy
`
`Culture
`
`Treatment
`
`Tricliophyton rubrum
`Trirhophyton rubrmn
`Trichophytoii rubrum
`’l'r1'cIiophyt0n rubruni
`Triclwpliyton I‘tllJI‘ltHt
`
`terbinafine 2 50 mg/day
`for 12 weeks
`
`length of the toenail had increased by at least 3 mm
`“om baseline. Responders and non—responders who
`refused a course of terbinafine in the second part of
`L116 trial were seen at weeks 28, 36 and 48. At each
`
`toenail was assessed clinically and
`the target
`isit.
`mycologically by direct microscopy and mycological
`cultures Each patient had between eight and 12 con-
`ecutive nail specimens collected from the same nail
`allowing for an assessment of the fungal nail flora from
`1321 nail specimens.
`For the direct microscopic examination of nail scrapings
`a wet mount was made in 10% potassium hydroxide
`solution with Parker ink or Calcofluor white stain. For
`
`:ulture, specimens were inoculated on to Sabouraud's
`dextrose agar (SDA) containing chloramphenicol, genta—
`miein and cycloheidmide (actidione). Duplicate cultures
`A/CFC also set up on SDA plates without cycloheximidef” All
`cultures were incubated at 26 °C for 4 weeks.
`
`Results
`
`Fhere were 1 18 patients included in the trial, of whom
`111 were available for assessment at week 24. and 107
`
`Table 2. Mycology of a single toenail showing the occurrence of
`Scopulariopsis, Curvularia and Penicillium as incidental contaminants
`of an underlying dermatophyte infection
`
`Week
`
`Microscopy
`
`Culture
`
`Treatment
`
`were available for assessment at week 48. At the start
`
`the trial. 96 ()8 %) patients were infected with
`of
`T. rttbrwn, 19 (16%) with T l7'7(’Hf({gl‘()pl1yI(’.S var. interd1'g1'—
`tale, two (2%) with Trirhophyton tonsurans and one (1%)
`with Fpiclerniophyton floccosum.
`The typical mycological findings from a patient with a
`pure dermatophyte infection are shown in Table 1. The
`nail was initially diagnosed by microscopy and culture as
`being positive for T. rubrmn. The patient was then rando-
`mized to receive terbinafine 250mg/day for 12 weeks.
`Nail culture remained positive for a month after treat-
`ment, and fungal elements remained present for a further
`4 months, although they were 11on—viable. At the end of
`the trial. the nails were clinically and mycologically cured.
`A similar result was recorded in 36% of the 118 patients,
`where a dermatophytc only was isolated. from the com-
`mencement of treatment to either the successful eradica-
`
`tion of infection or the end of the study.
`The other 64% of patients had an underlying dermato-
`phyte infection with at least one non—dermatophyte mould
`or yeast isolated from one or more specimens during the
`study period. For example, the mycological tindings in the
`nail of one of these patients are presented in Table 2. The
`only difference from the previous case is the appearance of
`some non—dermatophyte moulds, such as Scopulariopsis,
`Curvularia and Pmicillizmi, as incidental contaminants.
`
`However, once again the treatment outcome was the
`same and the nail was clinically and myeologically
`cured at 12 months. The non-dermatophyte moulds
`and yeasts isolated as incidental contaminants from a
`study of 174 specimens collected from 76 patients, and
`their relative incidence. are reported in Table 3.
`Significantly, only three (225%) of 118 patients had
`the same species of non—dermatophyt.e mould or yeast
`isolated from two or more consecutive specimens. One
`patient had Scedosporium apiospermum isolated on five
`consecutive occasions (Table 4), another had Scapular-
`iopsis brevieaulis isolated on three consecutive occasions,
`and the third had Candida fcimata isolated of two
`consecutive occasions. It should also be noted that the
`
`fungal elements detected on direct microscopy of the
`nail specimens from these three patients were consistent
`with those of a dermatophyte (Table 4). Once again, the
`treatment outcome was the same and in all cases
`
`Baseline
`4
`8
`12
`1 6
`24
`2 8
`3 6
`
`++
`++
`++
`
`Trirtliophyton rulmun
`Tricliupliytarl rttlmmi
`Trichophyton rubrum
`Tricliopliytan rubrum
`Scopulariopsis
`Curvitlarin and Pmiittillium
`—
`—
`
`terbin afine 2 50 m g/d ay
`for 12 weeks
`
`the nails were clinically and mycologically cured at
`12 months following treatment with terbinatine.
`
`Discussion
`
`Repeated samples of toenails affected by a dermatophyte
`onycliomycosis revealed that a no1i—dermatophyte or
`
`© 1997 British Association of Dermatologists. British lournm‘ ofl)mnatalngy, 136. 490—493
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2067 - 7/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2067 - 7/9
`
`

`
`recognizing that the isolation of an organism does not
`prove it is the causative pathogen. Greer4 claimed there
`is accumulating evidence of mixed infections in onycho—
`mycosis with important implications for the manage-
`ment of the disease. In this study. only three of 1‘ 8
`patients had the same non—dermatophyte isolated from
`two or more consecutive specimens. These three cases
`probably represent secondary colonization where tie
`fungi concerned are utilizing nutrients available from
`the breakdown of keratin by the underlying dermato-
`phyte. The overall mycological cure rate for patie: ts
`treated with terbinafine in this trial was 94°/of This
`
`high cure rate suggests that transient, incidental con-
`tamination or secondary colonization with non—deri7 wa-
`tophytes or yeasts had little impact on the therapeutic
`outcome.
`
`An epidemiological survey in Britain confirmed ti’ at
`most cases of onychomycoses occur in the toenails
`rather than fingernails, and dermatophytes are tne
`most important pathogens. Trichophyton rubrum \/‘-JEIS
`the most common cause, followed by T. mmitagropliytvs
`var. interdigitale and E. floccosumz Our results support
`the predominance of T rubrum and T. mentagrophy 33
`var. intercligitale in toenail onychomycosis.
`remains
`The
`role
`of non—dermatophyte moulds
`controversial. Traditionally they have been regarded ils
`secondary pathogens of nails which are already diseased,
`although they may act as primary pathogens in a small
`number of cases. For example, non-dermatophytes suh
`as Scopulariopsis and Scytcilicliimi can opportunistically
`invade keratin that has already been degraded. When
`they are present it is usually with a dermatophyte and u
`an injured nail. Williamsz stated that non-dermatophytcs
`could account for l-5%—b% of all onychomycoses. but
`their role as a causative agent is still very much a rnati r
`of debate and their interaction with dermatophytes, pre-
`existing disease and nail damage is still unclear. Ccmdiria
`and other yeasts can also be found as saprophytes ..-T1
`nail tissue, directly invading the nail plate only when
`host defences are disturbed, such as in immune suppres-
`sion. The presence of a derrnatophyte on direct mici ;—
`scopy or culture has long been accepted as evidence that
`it is the pathogen responsible for disease, even in mixed
`infections? Weitzman and Surnmerbellf’ supported tips
`View that dermatophytic fungi are still the main aetiola—
`gical agents of onychomycosis and stressed that
`the
`growth of a 11on—dermatophyte on culture following 3
`positive result on direct microscopy is not sufficient 50
`diagnose a non—dermatophyte infection.
`The longitudinal data from our trial, based on at leml
`eight. samples from each patient over 48 weeks, strt)11_f’V
`
`492
`
`D.H.ELLIS et al,
`
`Table 3. lncidencc of non—dermatophyte moulds and yeasts from nails
`of 118 patients with an underlying dermatophyte infection (data from
`1 3 2 1 mail specimens)
`
`Frequency
`
`14%
`14%
`13%
`0-9%
`O-6%
`()-6%
`O-4%
`04%
`04%
`03%
`023%
`02%
`02%
`0’2%
`015%
`0-15%
`0-] 5%
`0-08%
`0-08%
`0-08%
`008%
`07%
`O-2%
`
`U) 00
`
`0OI\J\lOOOO
`
`8 5 55 4 43 3 322 2 l l 11
`
`—I>—-A+—4>—A
`
`1 O
`3
`
`Genus
`
`Cladosporium
`Altermiria
`Epicoccum
`Penicillium
`Aspergillus
`Cu rvulcirioi
`Scopulariopsis
`Chrysosporiurn
`Fusarium
`SCedaspnrium
`Chaetoniium
`Stemphylium
`Scyl:alirlium
`Pciecilamyces
`Drechslera
`Acremanium
`Geotrichum
`Ulocladium
`Beauveria
`Exophiala
`Graphium
`Stachybotrys
`Candida
`Rhodotorula
`
`yeast was isolated on a single occasion in almost two-
`thirds of patients. The occurrence of these organisms
`represent
`incidental contaminants associated with a
`non—sterile specimen. Weitzman and Summerbellf’ have
`also reported that the growth of non—der1natophytes is
`common from nails. but that successive sampling will
`rarely demonstrate the same contaminant. Although
`
`Table 4. Mycology of a single toenail showing the occurrence of
`Scedosporium apiospermum as a secondary colonizer of an underlying
`dermatophyte infection
`
`Week
`
`Microscopy
`
`Culture
`
`Treatment
`
`Baseline
`4
`8
`12
`1 6
`2 4
`
`28
`
`36
`40
`48
`
`'l'rir'h0pl1ytnn rubrlmi
`Srledosporiurn
`Trichophyton rulmmi
`Gmphium sp.
`Scedosporium
`Scedospuriuni
`
`Sccdosporium}
`
`Scedospariimi
`—
`—
`
`placebo
`for 12 weeks
`
`terbinafine 250 mg/day
`for 12 Weflks
`
`© l997 British Association of Dermatologists, British fourmil oflkrlmitology, 136, 49U'*4‘
`
`3
`
`CFAD V. Anacor, |PR20’|5-01776 ANACOR EX. 2067 - 8/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2067 - 8/9
`
`

`
`NON-DERMATOPHYTES IN ONYCHOl\/IYCOSIS
`
`4:93
`
`upport the notion that non-dermatophytes and yeasts
`do not have a significant role in fungal infections of
`the toenail. Mixed infections, involving the persistence
`.
`i‘ a non—dermatophyte in two or more successive speci-
`mens, were very rare and probably represent secondary
`colonization. The fungi
`involved have questionable
`
`i athogenicity and are probably utilizing the products
`of dermatophytic keratin degradation as a nutrient
`source. Non-dermatophyte moulds and, less commonly.
`‘M easts often appeared transiently as incidental contami-
`nants, but they had no impact on the outcome of therapy
`with terbinaline.
`
`Considering the strong evidence of the role of derma-
`fophytes in onychomycosis and the common occurrence
`of
`incidental contaminants,
`it would be useful
`for
`
`linicians if laboratory reports included a comment on
`the likely significance of a culture result, as well as the
`result itself. Repeat collections may also be necessary to
`
`detect the presence of a dermatophyte in nail specimens,
`as most contaminant fungi will ovcrgrow or mask the
`presence of a dermatophyte in culture.
`
`References
`
`1 Roberts DT. Prevalence of dermatopliyte onychomycosis in the
`United Kingdom: results of an omnibus survey. Br I Derrmitol
`1992: 126 (Suppl. 39): 23-7.
`Williams HC. The epidemiology of onyehomycosis in Britain. Br]
`Dernmtul 1993; 129: l0l—9.
`Midgley G. Moore MK, Cook ]C at al. Mycology ofnail disorders. [Am
`Acad Dcrrmztal 1994: 31 (Suppl.): S68—S74.
`4 Greer DL. Evolving role of non—dermatophytes in onychomycosis. Int
`]Dermatal1995: 34: 521-4.
`5 Watson A. Marley J, Ellis D, Williams T. Terbinafine in onycho1ny—
`cosis of the toenail: a novel treatment protocol. ]/im /lead Dermatol
`1995: 33: 77543.
`6 Weitzman L Sumrnerbell RC. The dermatophytes. Clin A/licrabiol Rev
`1995: 8: 240—59.
`
`1997 British Association of Dermatologists. British Iournal 0fDmnrit0l0gy. 1 36. 4904193
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2067 - 9/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2067 - 9/9

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