194IS1I97
`ISSN 1018-8665
`DERAEG I 194(suppll) 1-50 (1997)
`
`Supplement for subscribers free of charge
`
`Clinical Dermatology 2000
`
`May 28, 1996 Vancouver, Canada
`
`Topical Lamisil®
`New Indications and Dosage Forms
`
`Co-Chairmen: G. Evans, Leeds, UK and H. Tagami, Sendai, Japan
`
`Oral Lamisil®
`1996 Worldwide Experience Update
`
`Co-Chairmen: R.K. Scher, New York, N.Y., USA and l Nishikawa, Tokyo, Japan
`
`S. Karger
`
`Medical and Scientific KA 1\. G E R.
`
`Publishers
`Basel· Freiburg
`Paris · London
`New York· New Delhi
`Bangkok · Singapore
`Tokyo · Sydney
`
`List of contents and full text are accessible at:
`http://www .karger .chi journals/ der/ dercont.htm
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 1/6
`
`

`
`Dermatology 1997;194(suppl 1):32_:_36
`
`R.C. Summerbell
`
`Mycology, Ontario Ministry of Health,
`Etobicoke, Ont., Canada
`
`Epidemiology and
`nychomycosis
`
`Key Words
`Trichophyton
`Dermatophytes
`Onychomycosis
`Immunocompromised patients
`Age-related susceptibility
`Transmission
`Candida
`N on-dermatophytes
`
`......•..•.•........................•....•.............................................•...
`Abstract
`The epidemiology and ecology of onychomycosis are complex and little under(cid:173)
`stood. Most is known about tinea unguium, dermatophytic nail infection, and its
`causative agents. This is often categorised according to the precise locus on the
`nail of the infection. The principal infectious propagules are thought to be the
`arthroconidia or chlamydospores which form within the solid substratum of in(cid:173)
`vaded nail tissue. The process of infecting new hosts appears to be facilitated by
`abrasion, moistening and scratching. The role of the non-dermatophyte yeast
`Candida as an agent of onychomycosis per se may have been overestimated.
`The range of interactions between dermatophytes and non-dermatophytes in
`nails is complex and poorly understood. There may be at least six distinct eco(cid:173)
`logical categories of non-dermatophyte isolations from nails. It would be of clin(cid:173)
`ical interest to know which species found in mixed infections were never able
`to advance beyond 'secondary colonisation', as they would not require specific
`treatment.
`
`The epidemiology and ecology of onychomycosis are
`surprisingly complex. A number of factors, each simple on
`its own, come together in this area to form a composite of
`overlapping probabilities that few understand well. More(cid:173)
`over, the biology of many organisms in nails is poorly
`known, and theoretically simple methods of clarifying such
`matters are difficult to co-ordinate with clinical realities.
`The best -known aspect of onychomycotic epidemiology
`is that related to tinea unguium, dermatophytic nail infec(cid:173)
`tion, and its causative agents. Less well understood is the
`epidemiology of non-dermatophytes causing nail infections
`of various kinds. Least well known, and often a matter for
`free speculative contention, is the interaction between der(cid:173)
`matophytes and non-dermatophytes in nails. These subjects
`will be addressed in order below.
`
`Dermatophytes as Sole Agents of Tinea unguium
`
`Of the more than 20 dermatophyte species that regularly
`cause human infections, only a few are significant agents of
`onychomycosis. The ability to cause this disease is evi(cid:173)
`dently specialised, since there is no known parallel disease
`affecting keratinous claws or hooves of our non-anthropoid
`mammalian relatives. Dermatophyte species or variants
`competent at causing tinea unguium are obligate human
`pathogens which have lost the ancestral heterothallic sexu(cid:173)
`ality of the dermatophyte group and which, in the 2 most
`common species, often show degenerate asexual reproduc(cid:173)
`tion, with conidia reduced in number or simplified or dis(cid:173)
`torted in form. They exhibit a great deal of variability in
`colony coloration and microscopic morphology, suggestive
`
`KARGER
`
`E-Mail karger@karger.ch
`Fax+41 61 306 12 34
`http://www.karger.ch
`
`© 1997 S. Karger AG, Basel
`I 0 18-8665/9711947-.Q032$12.00/0
`
`This article is also accessible online at:
`http://BioMedNet.com/karger
`
`Richard C. Summerbell, PhD
`Mycology, Ontario Ministry of Health
`81 Resources Road, Etobicoke, Ont. M9P 3Tl (Canada)
`Tel. +I 416 235 5719, Fax +I 416 235 5951
`E-Mail summerdr@epo.gov.on.ca
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 2/6
`
`

`
`of genetic drift in characters rendered insignificant in tran(cid:173)
`sition to a radically altered habitat [ 1].
`The 3 most common species in many parts of Europe
`and North America are Trichophyton rubrum, T. mentagro(cid:173)
`phytes and Epidermophyton jloccosum, with the former 2
`much more common than the last. In areas of the world
`where dermatophytes which are fundamentally endothrix
`tinea capitis agents are overwhelmingly predominant, these
`species spill over into the causation of tinea unguium
`among other secondary dermatophytoses. Thus T. tonsu(cid:173)
`rans, for example, may cause a significant number of nail
`infections in American urban areas.
`Infections caused by the agents of tinea unguium have
`been broken down into three major categories [2]: (a) dis(cid:173)
`tal-subungual onychomycosis, typical of T. rubrum infec(cid:173)
`tions, in which the nail is infected beginning at the under(cid:173)
`side of the distal end and infection progresses toward the
`proximal end of the nail, often with strong involvement of
`one or both sides of the nail; (b) superficial white onycho(cid:173)
`mycosis, generally caused by T. mentagrophytes, in which
`the causative agent initially grows in discrete opaque zones
`in the upper strata of the nail surface, ultimately progress(cid:173)
`ing to extensive colonisation of the nail, and (c) proximal
`onychomycosis, usually caused by T. rubrum in immuno(cid:173)
`compromised patients, in which the nail is infected ini(cid:173)
`tially at the proximal end, and infection progresses distally.
`Proximal infection is particularly frequently seen in HIV
`patients [3].
`Tinea unguium is rare in young persons and is increas(cid:173)
`ingly more prevalent in higher age groups [4]. It is uncer(cid:173)
`tain if this reflects an age-related difference in susceptibility
`or merely the increasing probability of a successful trans(cid:173)
`mission event over the course of years. A general tendency
`of elderly persons to have greater numbers and diversity of
`onychomycoses [5] suggests that both susceptibility differ(cid:173)
`ences and increments in the probability of transmission
`may be reflected in age-related statistics for tinea unguium.
`Transmission is not thought to be mediated by micro(cid:173)
`aleurioconidia and macro-aleurioconidia, although these
`may be formed in cultures in vitro. Instead, the principal in(cid:173)
`fectious propagules are thought to be the arthroconidia or
`chlamydospores which form within the solid substratum of
`invaded nail tissue. These arthro~onidia may have specific
`binding affinity for epithelial cells of particular human
`body sites [6]. It is not dear, however, that it is necessary
`for arthroconidia to be dissociated from the tissue matrix in
`order to be effective in transmission of infection. It is likely
`that infected nails and foot skin shed minute flakes and par(cid:173)
`ticles of infectious material incorporating both host and
`fungal elements, and that these entire composites may be
`
`the actual particles conveying infection to the next host.
`The process of infecting new hosts appears to be facilitated
`by abrasion and moistening of the feet. For this reason, the
`ideal habitat for transmission is a moist or wet surface on
`which a diversity of adults walk or run with bare feet. Typ(cid:173)
`ical areas with high rates of transmission include swimming
`baths and communal showers in schools and workplaces
`[7]. The subsequent use of shoes, especially humid shoes,
`as a moist chamber incubator for fungal growth probably
`aids in the establishment of infection.
`It may be much more common to acquire tinea unguium
`of the toe-nails from pre-existing tinea pedis than to acquire
`it directly from dissociated inoculum. Toe-nails are less
`likely than intertriginous or plantar skin to abrade directly
`on the moist environmental surfaces which bear fomites.
`Likewise, finger-nail infection may be acquired from exist(cid:173)
`ing groin or pedal infection via scratching or acts of hy(cid:173)
`giene, and the combination of infected groin, feet and a
`single hand is not uncommon in chronic T. rubrum patients.
`Certain patients appear to have an otherwise relatively
`inconsequential
`immunodeficiency which conduces
`to
`chronic dermatophytosis, particularly T. rubrum infection.
`If apparently successfully treated, they tend to relapse or
`re-acquire the same species readily. Zaias et al. [8] have
`recently shown that susceptibility to T. rubrum onychomy(cid:173)
`cosis may be genetically transmitted in families as an auto(cid:173)
`somal dominant character.
`
`Non-Dermatophytes as
`Sole Agents of Onychomycosis
`
`Both yeasts and non-dermatophytic filamentous fungi
`have been implicated as sole agents of onychomycosis.
`Candida albicans is the principal yeast isolated, although
`its role as an agent of onychomycosis per se may have been
`overestimated. It may cause extensive degradation of nails,
`especially finger-nails, in rare congenital conditions such as
`chronic mucocutaneous candidiasis and in cases of constant
`occupational contact with water or wet materials, but it is
`much more commonly an agent of paronychia than of ony(cid:173)
`chomycosis. Samples sent for laboratory analysis may in(cid:173)
`clude scrapings - from both nail and peripheral skin, lead(cid:173)
`ing to the inconect impression that invasion of the latter
`canies over into the former.
`The best evidence of true yeast invasion of the nails is
`elucidated in direct microscopy of unadulterated nail ma(cid:173)
`terial and consists of yeast in its pseudomycelial growth
`phase showing moniliform filaments and lateral blasto(cid:173)
`conidia. The presence of budding yeast cells alone, even in
`
`Epidemiology and Ecology of Onychomycosis
`
`Dermatology 1997;194(suppl 1):32-36
`
`33
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 3/6
`
`

`
`abundance, may merely signify pockets of saprobic colo(cid:173)
`nisation in nails split or fissured by an unrelated disease
`process (e.g. dermatophytosis, psoriasis) so that micro(cid:173)
`scopic humid chambers suitable for yeast proliferation have
`been produced. Non-C.-albicans Candida species of the
`normal skin flora may often be isolated in similar circum(cid:173)
`stances and may persist over time in these harmless coloni(cid:173)
`sations. Distinction of these colonisations from genuine
`cases of infection by these fungi (especially Candida para(cid:173)
`psilosis) can best be accomplished by showing microscopi(cid:173)
`cally that some pseudomycelial tissue penetration has been
`accomplished in the purported infection. (If true mycelia
`are seen, the possibility of overgrown or senescent derma(cid:173)
`tophyte material should be strongly considered - see be(cid:173)
`low.)
`Approximately 35 non-dermatophyte filamentous fungal
`species have been shown to be capable of causing or sus(cid:173)
`taining onychomycosis as sole aetiological agents. In addi(cid:173)
`tion, numerous other species have been alleged but not well
`demonstrated to do so. Most virulent among the well-estab(cid:173)
`lished agents are Scytalidiwn dimidiatum (synanamorph
`Nattrassia nwngiferae, formerly Hendersonula toruloidea)
`and S. hyalinum, which appear to be as effective as der(cid:173)
`matophytes in infecting heavily keratinised epidermis and
`nails [9]. These fungi have somewhat distinctive filaments
`in nail tissue and are rarely or never isolated as contami(cid:173)
`nants in temperate areas of the world; thus, isolation usually
`signifies infection, and this can readily be confirmed by
`direct microscopy. Most dermatomycotic agents, however,
`are common contaminants associated with feet and nails
`and only occasionally 'cross over' into aetiological status.
`The events precipitating such a transition are unknown but
`may include attenuation of host defences in age (especially
`in the elderly), nail injury and prior nail infection by a der(cid:173)
`matophyte. When, in any case, they are present in nails as
`sole agents of infection, they may have distinctive elements
`produced in or from host tissue (e.g. unusual filaments,
`conidiophores, conidia), in which case infection is easy to
`confirm, or only indistinctive hyphae in tissue, in which
`case sole infection may be difficult to confirm except by
`repeated sampling (see below). Such difficult-to-confirm
`infections may be seen with selected members of the gen(cid:173)
`era Scopulariopsis, Fusarium, Aspergillus and Alternaria,
`as well as with less common fungi.
`
`Complex Relations between Dermatophytes and
`Non-Dermatophytes, Including Mixed Infections
`
`In an active bacterial infection, it would be almost un(cid:173)
`thinkable to have entire areas of the affected tissue invested
`only with dead bacterial cells and no living inoculum. Fila(cid:173)
`mentous fungal colonies, however, are continuous, modular
`bodies which, like trees with dead limbs, can be seen in the
`space they occupy either as living or dead forms. The study
`of onychomycosis is primarily rendered complex by the
`fact that approximately 20% of all samples from nails in(cid:173)
`vested with dermatophyte filaments happen to include ma(cid:173)
`terial only from the 'dead branches', or senescent growth
`fronts, of the somewhere still active dermatophyte colony.
`(This type of sample yields a negative culture, often mis(cid:173)
`leadingly referred to as 'false-negative' even though the
`culturing technique reflects the condition of the sample ma(cid:173)
`terial with impeccable accuracy.) When these dead der(cid:173)
`matophyte filaments, seen in direct microscopy, coincide
`with cultures positive for a fungus growing from contami(cid:173)
`nating spores or conidia, this is easily misinterpreted as sig(cid:173)
`nifying a non-dermatophyte infection, especially if the con(cid:173)
`taminating inoculum is of a species well known to cause
`occasional onychomycosis. Similarly, when these dead der.:.
`matophyte elements are intermingled with living elements
`of a co-infecting non-dermatophyte, the diagnosis of a pure
`non-de1matophyte infection may be incorrectly made. Con(cid:173)
`versely, the diagnostician may err oppositely when con(cid:173)
`fronted with a genuine non-dermatophyte infection by mis(cid:173)
`interpreting the non-dermatophyte filaments in the nail as
`dead dermatophyte filaments, and misattributing the non(cid:173)
`dermatophyte culture to contamination. A non-dermato(cid:173)
`phyte genuinely participating in a mixed infection may sim(cid:173)
`ilarly be misinterpreted as a contaminant if a dermatophyte
`grows.
`The degree of overlap among these and related possibil(cid:173)
`ities effectively precludes a firm diagnosis of non-delmato(cid:173)
`phytic or mixed onychomycosis from any single specimen
`where: (a) a non-dermatophyte known to cause onychomy(cid:173)
`cosis occasionally is isolated in the presence or absence of
`a dermatophyte and (b) the elements seen in direct mi(cid:173)
`croscopy are generic fungal filaments and do not unequivo(cid:173)
`cally confirm or exclude the non-dermatophyte in question.
`The non-dermatophyte in such cases is an organism only
`tentatively associated with disease, a situation best clarified
`using Koch's first postulate of pathogenicity, namely, con(cid:173)
`sistency of association of the putative aetiological agent
`with the disease [ 1 0]. This consistency is demonstrated by
`examining one or more successive repeat samples from the
`patient's lesion and finding the same non-dermatophyte
`
`34
`
`Dermatology 1997;194(suppl 1):32-36
`
`Summerbell
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 4/6
`
`

`
`again. Such a finding tends to indicate long-term colonisa(cid:173)
`tion of the nail, implying pathogenicity. Examination of
`multiple pieces of the same nail taken on the same single
`occasion, as recommended by Walshe and English [11], is a
`less convincing probe of pathogenicity, since it runs a much
`greater risk of encountering a dispersion of similar con(cid:173)
`taminant spores acquired in contact with mould-colonised
`material.
`The successive repeat sampling demanded by Koch's
`postulate efficiently determines the indigenous culturable
`fungal population of a nail, but is annoying in practice for
`both patient and physician. Both would generally prefer to
`achieve an effective diagnosis and' prescription of treatment
`in a single consultation. Further probing to determine the
`status of an organism of uncertain aetiological potential and
`possibly problematic therapy is most unwanted. The great
`majority of non-dermatophyte and mixed infection cases
`are probably not fully investigated, partly for this reason.
`Another reason why such cases are not fully investigated is
`general uncertainty about the significance even of non-der(cid:173)
`matophytic organisms well demonstrated to persist in nails.
`Although the pathogenicity of the Scytalidium species is
`unlikely to be questioned, other species may be regarded
`with scepticism.
`This situation is best remedied by improving on the pre(cid:173)
`dictive power of establishing that a certain non-derma(cid:173)
`tophyte is definitely established in a nail. Since even the
`dermatophytes regularly involved in onychomycosis are a
`specialised subgroup, it is very likely that the different
`non-dermatophytes isolated from nails differ in pathogenic
`competence. General principles of fungal ecology and ex(cid:173)
`perience with numerous cases suggest that non-dermato(cid:173)
`phytic filamentous fungi occurring in association with nails
`should be analysed in terms of the following categories:
`(1) 'contaminant', i.e. species growing in culture from
`dormant propagules deposited on the nails;
`(2) normal mammalian surface commensal, i.e. species
`ordinarily growing non-invasively on body smfaces or in
`nail cracks and fissures (usually yeasts);
`(3) transient saprobic coloniser, i.e. species briefly col(cid:173)
`onising accessible simple molecules on the nail surface or
`within debris produced by onychomycotic nail degradation
`but not invading keratinised nail material;
`( 4) persistent secondary coloniser, i.e. species continu(cid:173)
`ously colonising nail material conditioned by a primary in(cid:173)
`vader such as a dermatophyte but not able to persist after
`the substrate-conditioning fungus has been eliminated;
`(5) successional invader, i.e. a species which may or
`may not be able to cause a primary infection but is able to
`cause active infection after obtaining entry into a nail dis-
`
`rupted by a primary pathogen and then is able to persist in(cid:173)
`definitely, possibly even competitively eliminating the pri(cid:173)
`mary pathogen;
`(6) primary invader, i.e. a species able to infect and
`cause onychomycosis in a previously uncolonised nail.
`Some of these categories intergrade with one another,
`especially in cases where the immune status of the patient
`changes due to disease or normal ageing.
`Specific treatment is only required for established organ(cid:173)
`isms in category 5 and all organisms in category 6 above.
`In category 4 and any cases of category 3 coincident with
`dermatophytosis, treatment with drugs aimed primarily at
`dermatophytes would be efficacious against the non-der(cid:173)
`matophytes as well. Clearance of the dermatophyte should
`facilitate elimination of degraded nail material, which in
`tum will prevent the growth of secondary colonisers, most
`transient ones and any not yet established successional in(cid:173)
`vaders.
`In light of the practical consequence of such distinctions,
`investigators should strive to clarify which non-dermato(cid:173)
`phytic fungi can be clearly seen to be:
`(1) at least capable of long-term persistence in asso(cid:173)
`ciation with an active dermatophyte infection (i.e. at least
`a competent secondary coloniser if not a successional in(cid:173)
`vader);
`(2) at least capable of long-term persistence when a pre(cid:173)
`viously co-existing dermatophyte is eliminated by treat(cid:173)
`ment (i.e. a good potential successional invader);
`(3) capable of long-term persistence in a nail yielding no
`evidence of dermatophyte infection (e.g. a probable pri(cid:173)
`mary invader or a successional invader sufficiently compet(cid:173)
`itive to spontaneously eliminate a previously established
`dermatophyte), or
`( 4) eliminated secondarily after the discontinuation of
`anti-dermatophyte therapy as a probable ecological conse(cid:173)
`quence of elimination of the primary dermatophyte infec(cid:173)
`tion.
`In particular, it would be of clinical interest to know
`which species found in mixed infections were never able to
`advance beyond secondary colonisation in their inhabita(cid:173)
`tion of onychomycotic nails. Such species could then reli(cid:173)
`ably be predicted not to require specific treatment. This
`would free patients an4 physicians from the uncertainty
`now faced when these organisms are isolated from ony(cid:173)
`chomycotic nails. The information would help to prevent
`undue significance being attached to many non-dermato(cid:173)
`phytes isolated from nails both before and after antifungal
`therapy, and would thus assist the physician in recognising
`the relatively small proportion [12] of true non-dermato(cid:173)
`phytic onychomycoses.
`
`Epidemiology and Ecology of Onychomycosis
`
`Dermatology 1997; 194(suppl I ):32-36
`
`35
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 5/6
`
`

`
`oooooooooooooooooooooooooooooooooooooaoooooooe~eooooooooooooooooooooooooooooooooeeoooooooooooooooooooooooooooooooooooooooooeoeoooooaoooooo
`
`References
`
`Tanaka S, Summerbell RC, Tsuboi R, Kaaman
`T, Sohnle PG, Matsumoto T, Ray TL: Ad(cid:173)
`vances in dermatophytes and non-dermato(cid:173)
`phytosis. J Med Vet My col 1992;30(suppl I):
`29-39.
`2 Zaias N: Onychomycosis. Arch Dermatoll972;
`105:263-274.
`3 Daniel CR III, Norton LA, Scher RK: The
`spectrum of nail disease in patients with human
`immunodeficiency virus infection. J Am Acad
`Derma to! 1992;27 :93-97.
`4 Heikkila H, Stubb S: The prevalence of ony(cid:173)
`chomycosis in Finland. Br J Dermatol 1995;
`133:699-703.
`
`5 English MP, Atkinson R: Onychomycosis in
`elderly chiropody patients. Br J Dermatol 1973;
`91:67-92.
`6 Aljabre SH, Richardson MD, Scott EM,
`Rashid A: Adherence of arthroconidia and
`germlings of anthropophilic varieties of Tri(cid:173)
`chophyton mentagrophytes to human corneo(cid:173)
`cytes as an early event in the pathogenesis of
`dermatophytosis. Clin Exp Dermatol1993;18:
`231-235.
`7 Weitzman I, Summerbell RC: The dermato(cid:173)
`phytes. Clin Microbial Rev 1995;8:240-259.
`8 Zaias N, Tosti A, Rebel! G, Morelli R, Bardazzi
`F, et al: Autosomal dominant pattern of distal
`subungual onychomycosis caused by Tricho(cid:173)
`phyton rubrum. J Am Acad Dermatol 1996;
`34:302-304.
`
`9 Moore MK: Hendersonula toruloidea and Scy(cid:173)
`talidium hyalinum infections in London, E~­
`gland. J Med Vet Mycol 1986;24:219-230.
`10 Stiller MJ, Rosenthal RC, Summerbell J, eta!:
`Onychomycosis of the toenails caused by
`Chaetomium globosum. JAm Acad Dermatol
`1992;26:775-776.
`II Walshe MM, English MP: Fungi in nails. Br J
`Dermatol 1966;78: 198-207.
`12 Summerbell RC, Kane J, Krajden S: Ony(cid:173)
`chomycosis, tinea pedis and tinea manuum
`caused by non-dermatophytic filamentous fun(cid:173)
`gi. Mycoses 1989;32:609-612.
`
`36
`
`Dennatology 1997;194(suppl 1):32-36
`
`Summerbell
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2186 - 6/6