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  • REVIEW ARTICLE

    Toenail onychomycosis: an important global diseaseburden

    J. Thomas* BPharm MPharmSc, G. A. Jacobson* BPharm (Hons) PhD, C. K. Narkowicz* BSc(Hons) PhD, G. M. Peterson* BPharm (Hons) PhD MBA FSHP FACP AACPA MPS, H. BurnetDip App Sc (Pod) and C. Sharpe BPod*School of Pharmacy, University of Tasmania, Hobart, Tasmania and Department of Podiatry, RoyalHobart Hospital, Hobart, Tasmania, Australia

    SUMMARY

    Onychomycosis is a fungal infection of the nail

    plate or nail bed. It does not usually cure itself

    and it can trigger more infectious lesions in other

    parts of the body. The reported prevalence of

    onychomycosis is increasing in Western coun-

    tries, presumably due to lifestyle changes and the

    ageing of the population. Approximately 10% of

    the general population, 20% of the population

    aged >60 years, up to 50% of people aged

    >70 years and up to one-third of diabetic indi-

    viduals have onychomycosis. Care should be

    taken for the accurate diagnosis and timely

    treatment of toenail onychomycosis to prevent

    complications. Current treatment options have

    relatively limited therapeutic success, particularly

    long-term. Oral medications are associated with

    high recurrence rates and treatment failure, and

    are not suitable for many cases due to potential

    adverse effects. Topical medications are recom-

    mended only for mild to moderate cases. The cost

    of therapies may also be prohibitive in some

    cases. In the light of these issues, more research is

    warranted for the investigation and development

    of more effective and economical options for the

    treatment and prophylaxis of toenail onychomy-

    cosis. In patient populations such as diabetic

    individuals, where onychomycosis can provoke

    lower extremity complications, professional

    podiatry care of toenails and feet should be

    encouraged.

    Keywords: dermatophytes, diagnosis, epidemiol-

    ogy, onychomycosis, toenail, treatment

    INTRODUCTION

    Onychomycosis is a fungal infection of the nail

    plate or nail bed, leading to the gradual destruction

    of the nail plate. Onychomycosis has been referred

    to as the most prevalent of the nail ailments and

    accounts for about 50% of all diseased nails and

    about 30% of cutaneous fungal infections (1). It is

    caused by dermatophytes, yeasts or non-dermato-

    phytic moulds (2). The dermatophytes Trichophyton

    rubrum and Trichophyton mentagrophytes are the

    main causative pathogens, responsible for 8090%

    of cases (36). Non-dermatophytic fungi such as

    Acremonium spp., Alternaria spp., Aspergillus spp.,

    Fusarium spp., Scytalidium spp. and Scopulariopsis

    spp. have been found to be involved in 211% of

    the onychomycosis cases reported. Yeasts, inclu-

    ding Candida spp., account for 210% of fungal nail

    infections (5, 711). Dermatophytes are normally

    transmitted through infected moist floor areas and

    are less often transmitted via direct personal con-

    tact. Non-dermatophytic fungi have been fre-

    quently associated with the infection of

    traumatized nails in aged patients (11).

    Onychomycosis is associated with less noticeable

    symptoms than foot ulceration due to tinea pedis,

    and is often considered a cosmetic problem and

    overlooked (12). Tinea pedis can lead to onycho-

    mycosis and has been associated with onychomy-

    cosis in 3059% of cases (13, 14). The secondary

    spread of fungal organisms may lead to the infec-

    tion of web spaces, toes, nail plates, sole, heel and

    across the whole foot (14, 15).

    Received 18 May 2009, Accepted 18 May 2009

    Correspondence: J. Thomas, School of Pharmacy, University of

    Tasmania, Private Bag 26, Hobart, Tasmania, 7001, Australia.

    Tel.: +61 (3) 6226 1069; fax: +61 (3) 6226 2870; e-mail: jackson.

    [email protected]

    Journal of Clinical Pharmacy and Therapeutics (2010) 35, 497519 doi:10.1111/j.1365-2710.2009.01107.x

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd 497

  • HISTORY OF ONYCHOMYCOSIS

    In 1853, onychomycosis was first described and

    reported by Meissner, a German medical student

    (16). The history of onychomycosis is analogous to

    that of T. rubrum, the major causative fungal

    pathogen involved in the pathogenesis of onycho-

    mycosis and tinea pedis (17). T. rubrum was until

    recently, limited to Southeast Asia, Indonesia,

    Northern Australia and West Africa (18). People

    living in these regions are reported to have suffered

    from chronic tinea corporis; however, tinea pedis

    was not found among them. This was presumably

    due to the lack of footwear among the local pop-

    ulation (17, 18). However, the use of occlusive

    footwear by European colonists and soldiers

    provided a highly favourable environment for

    T. rubrum to grow and cause pedal fungal infec-

    tions (17, 18).

    The incidence of tinea pedis was rare in Europe,

    before the arrival of T. rubrum. Increased popula-

    tion mobility that resulted from world wars, mass

    migration and recreational travel led to the trans-

    location and subsequent distribution of T. rubrum

    from its original endemic regions to new ecological

    environments in Europe and America (17, 19). The

    first reported clinical case of tinea pedis in the

    United States was encountered soon after World

    War I. In the same country, the first documented

    case of onychomycosis is said to have been repor-

    ted in 1928 (17, 20). World War II and the Korean

    and Vietnam wars, increased participation in fit-

    ness activities, the use of occlusive footwear and

    periodic and migratory movement of populations,

    have contributed towards the increased prevalence

    of tinea pedis and onychomycosis in the 20th cen-

    tury (21). After the Vietnam War, T. rubrum sur-

    passed T. mentagrophytes as the most commonly

    isolated dermatophyte worldwide (21). In the

    United States, it has been found that dermatophytic

    fungi can be isolated from the plantar surface in

    about 70% of the population (18, 22).

    EPIDEMIOLOGY

    In post-industrialized countries, more than 10% of

    the general population is reported to have ony-

    chomycosis (23). A few other studies reported a

    similar prevalence for onychomycosis worldwide;

    a Finnish study (n = 800) reported a prevalence of

    84% and two large Canadian studies (n = 2001;n = 15 000) reported a prevalence ranging from

    65% to 91% for onychomycosis (2426). Manyauthors believed that onychomycosis started as an

    insignificant medical problem (27, 28). It has been

    suggested that the prevalence of onychomycosis

    has steadily increased over the past few decades

    (17, 27, 28). Results from several population studies

    support this. A 1979 United States study

    (n = 20 000) reported the overall prevalence of

    onychomycosis to be 218% (29). A United Statesstudy in 1997 (n = 1038) revealed a much higher

    prevalence of onychomycosis (87%) (30) and alarge-scale multicentre North American study

    published in 2000 (n = 1832) estimated the preva-

    lence of onychomycosis to be 138% (31).An Indonesian study has demonstrated a similar

    pattern: the study concluded that the average

    incidence of onychomycosis has increased from

    35% in 19971998 to 47% in 2003 (32). A survey(Achilles project, 1999) conducted among the

    general population visiting physicians in Europe

    (Belgium, Netherlands, Luxembourg, Switzerland,

    Hungary, Great Britain, Poland) (n = 22 760) and in

    East Asia (China, South Korea, Taiwan)

    (n = 43 914) demonstrated a substantial onycho-

    mycosis prevalence of 26% and 22%, respectively.

    The Achilles project concluded that 2 out of 10

    patients of the studied population showed signs of

    onychomycosis (33).

    RISK FACTORS

    A summary of various predisposing factors for

    onychomycosis is given in Table 1.

    Age and gender

    Onychomycosis is reported to be more prevalent in

    the elderly and appears to occur more frequently in

    males (21, 30, 31). Early studies have shown that

    there is a correlation between age and onychomy-

    cosis. Approximately 20% of the population aged

    >60 years and up to 50% of the subjects aged

    >70 years are reported to have onychomycosis (5,

    20). The correlation between increasing age and

    onychomycosis may be attributed to reduced

    peripheral circulation, inactivity, suboptimal

    immune status, diabetes, larger and distorted nail

    surfaces, slower growing nails, difficulty in

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    498 J. Thomas et al.

  • grooming the nails and maintaining foot hygiene,

    frequent nail injury and increased exposure to

    disease-causing fungi (2, 5, 11, 34).

    Gupta and colleagues postulated that the gender

    difference may be attributable to the differences in

    hormone levels (progesterone and other related

    hormones) that result in a different capacity to

    inhibit the growth of dermatophytes (24, 35, 36).

    Increased use of occlusive footwear and nail inju-

    ries may also contribute to the higher incidence of

    onychomycosis in males (37). Onychomycosis is

    seen in only a small proportion (approximately

    04%) of children (1, 38). The lower prevalence ofonychomycosis in children compared to adults

    may be due to reduced exposure to infected envi-

    ronments (communal showers, public changing

    rooms and saprophytic fungi), smaller nail surface

    area, faster nail growth and lower prevalence of

    tinea pedis and nail injuries (39).

    Genetics

    Some recent studies suggest a genetic basis for the

    susceptibility to onychomycosis (20, 40). In an

    American study, Zaias and colleagues reported

    familial patterns of distal lateral onychomycosis

    caused by T. rubrum infection that appeared to be

    unrelated to interfamilial transmission (41, 42).

    Several studies have reported the autosomal

    dominant pattern of inheritance associated with

    T. rubrum infection and highlighted the increased

    risk of developing onychomycosis in subjects where

    at least one parent had onychomycosis (34, 42, 43).

    Environmental factors

    Some authors suggest an association between

    onychomycosis and the use of footwear. The

    prevalence of onychomycosis is low in

    regions societies where people do not wear shoes(4446). Perspiration of the foot within a shoe (and

    usually also a sock) can generate a moist warm

    environment that is ideal for fungal growth. Other

    environmental factors said to influence the

    prevalence of onychomycosis include bare-footed

    walking through damp areas, increased usage of

    non-breathing shoes, playing sports (see below),

    use of community bathing facilities and injuries

    (20, 34, 47, 48).

    Frequent contact with source(s) of infection can

    also instigate disease onset. For example, cases of

    fingernail onychomycosis were reported in tealeaf

    pluckers due to the geophilic dematiaceous non-

    dermatophytic mould, Scytalidium dimidiatum. In

    addition, increased risk of onychomycosis is repor-

    ted in individuals who are exposed to saprophytic

    fungi (4, 34, 49, 50). It has been proposed that the

    high prevalence of onychomycosis in the commu-

    nity has resulted in the heavy contamination of

    swimming pools, public toilets and communal

    bathing facilities with fungal hyphae and this may

    have further increased the risk of developing the

    infection (5153). The incidence of onychomycosis

    has been shown to be three times more prevalent in

    swimmers compared with non-swimmers (34, 54).

    Sports

    A Brazilian study reported a higher prevalence of

    onychomycosis (2-fold) and concomitant onycho-

    mycosis-tinea pedis infections (25-fold) in athletes,compared with non-athletes (48, 55). Onychomy-

    cosis is often found in conjunction with tinea pedis.

    Moreover, the presence of one infection can

    increase the risk of the other occurring (48). The

    key predisposing factors contributing to infection

    Table 1. Predisposing factors for onychomycosis

    Subject characteristics

    Advancing age

    Gender

    Sub-optimal health

    Inability to maintain foot hygiene

    Genetic factors

    Family history

    Smoking

    Systemic conditions

    Immune deficiency

    Diabetes

    Peripheral vascular disease

    Immunosuppressive medications

    Environmental factors

    Shared bathing facilities

    Occlusive footwear

    Sporting activities

    Frequent nail trauma

    Other

    Concomitant fungal infections (e.g. tinea pedis)

    Psoriasis

    Modified from (2, 47).

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    Toenail onychomycosis: an important global disease burden 499

  • in sports persons are the speed intensity involvedwith sport (runners), the sudden starting and

    stopping nature of the sport (e.g. tennis, squash,

    soccer and cricket), practising sports without pro-

    tective footwear (e.g. gymnasts, ballet dancers),

    frequency of nail injuries, prevalent use of syn-

    thetic clothing and shoes that retain sweat, water

    sports and communal bathing (48, 5557). Toenail

    ailments can potentially affect athletic performance

    (34).

    Immunodeficiency

    Individuals infected with HIV have an increased

    risk of developing onychomycosis when their

    T-lymphocyte count is as low as 400 mm3 (normalrange 12001400) and onychomycoses tend to be

    more widespread, usually affecting all finger and

    toe nails (10, 58). Proximal subungual onychomy-

    cosis has been considered as an indication of HIV

    infection. However, transplant recipients, individ-

    uals on immunosuppressive treatments and indi-

    viduals with defective polymorphonuclear

    chemotaxis may exhibit a similar type of infection.

    Trichophyton rubrum is the causative fungus in most

    cases, except for cases of superficial white ony-

    chomycosis, usually caused by T. mentagrophytes

    (34, 43, 44, 59, 60).

    Diabetes

    Approximately 34% of diabetics have onychomy-

    cosis (61, 62) and they are almost three times more

    likely to develop onychomycosis than non-diabe-

    tics (63). Diabetics may have increased difficulty in

    doing regular foot check-ups due to obesity or

    complications of diabetes such as retinopathy

    and or cataracts (64). This may contribute to dia-betics (typically with poor circulation of the lower

    extremities, neuropathy and impaired wound

    healing) having a generally higher risk of devel-

    oping complications from onychomycosis (63).

    Diseased nails, with thick sharp edges, can injure

    the surrounding skin tissue and result in pressure

    erosion of the nail bed, injuries that may go

    unnoticed in diabetics due to sensory neuropathy

    (62). The injury may act as an entry point for

    bacteria, fungi or other pathogens, leading to

    limb-threatening complications or even possible

    amputation of the lower extremities.

    Peripheral vascular disease

    The prevalence of onychomycosis in subjects with

    peripheral vascular disease was estimated to be

    36%, with T. rubrum as the most common pathogen

    (8, 65). Increased propensity to develop onycho-

    mycosis in elderly and diabetic patients is partly

    attributed to the increased prevalence of peripheral

    vascular disease (65). Impaired perfusion of the

    lower extremities results in suboptimal oxygena-

    tion and reduced metabolic exchange of nutrients

    and other substances in the foot. This may result in

    the instigation and progression of onychomycosis,

    also hindering nail growth, delaying preventingthe clearance of infection and exposing the subject

    to re-infection (34, 43, 60).

    NAIL ANATOMY AND PHYSICAL

    CHARACTERISTICS

    Anatomical structures of the nail unit are shown in

    Fig. 1. The nail unit is formed continually from the

    nail matrix in a linear direction, with a minor

    contribution from the nail bed (46, 66). The hypo-

    nychium refers to the junction between the free

    edge of the nail plate and the end of the nail bed. It

    mainly acts as a protective barrier, stopping the

    entry of infectious pathogens to the distal end of

    the nail plate. The nail plate is about 0510 mm inthickness, and it consists of dorsal, intermediate

    and ventral layers. The dorsal nail plate mainly

    comprises hard keratin. The middle nail plate is

    also comprised of hard keratin and makes up three-

    quarters of the total nail thickness. The ventral nail

    plate is made up of soft hyponychial keratin and

    typically contains 12 cell layers (46, 66, 67). The

    nail plate originates from the matrix and the white

    crescent-shaped distal end of the matrix is referred

    Fig. 1. Anatomy of the human nail unit (lateral and

    dorsal view).

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    500 J. Thomas et al.

  • to as the lunula. The nail bed mainly consists of

    epithelial cells and it extends proximally from the

    edge of the lunula distally to the hyponychium (46,

    67, 68).

    The fingernails grow at an average rate of 3 mm

    per month whereas toenails grow only about 1 mm

    per month. Growth rate depends upon the prolif-

    erative capacity of the metabolically active matrix

    cells (46, 66, 69). Conditions favouring the growth

    of the human nail plate include pregnancy, warmer

    temperatures, male gender and minor injuries to

    the nail plate. Some medications found to acceler-

    ate the growth of the human nail plate include

    calcium vitamin D, levodopa, retinoids, oral con-traceptives and antifungal agents such as fluco-

    nazole, itraconazole and terbinafine (6973). Drugs

    known to enhance nail growth could potentially be

    used as an adjuvant treatment modality for the

    management of onychomycosis.

    The human nail plate behaves like a concentrated

    hydrophilic-gel membrane, with nail layers pos-

    sessing different barrier properties (68). The dorsal

    nail plate appears to be the main barrier to drug

    penetration. The lipid content in the nail plate is

    relatively low compared to that of the skin (68). Poor

    permeation of drugs across the nail plate necessitates

    long duration of therapy to maintain the effective

    drug concentration in the nail plate. Poor drug per-

    meation probably contributes to the mediocre ther-

    apeutic success of conventional topical antifungal

    therapies for onychomycosis treatment (2).

    MORPHOLOGY AND CLINICAL

    PRESENTATION

    Based on the mode and site of fungal invasion of the

    diseased nail plate, five categories of onychomycosis

    have been established: distal and lateral subungual,

    superficial white, proximal subungual, endonyx

    and total dystrophic onychomycoses (46, 74).

    Distolateral onychomycosis

    Distolateral subungual onychomycosis is the most

    common form of onychomycosis. Infection pro-

    gresses mainly to the matrix from the distal to the

    proximal, through the distal-lateral margins or via

    the lateral groove of the nail plate, beginning at the

    hyponychium. The infection is typically caused by

    Trichophyton spp. and occasionally by Scytalidium

    spp., Candida spp. and other non-dermatophytes (3,

    43, 74, 75). Mild infection (paronychia) normally

    develops, resulting in subungual hyperkeratosis,

    onycholysis (detachment of nail plate from the nail

    bed) and nail thickening. The subungual space may

    serve as a base for infectious bacteria and fungi,

    causing a yellowish discolouration of the nail plate

    (4, 46, 76, 77).

    Proximal subungual onychomycosis

    Proximal subungual onychomycosis is a less com-

    mon form, but it is more common in AIDS patients

    and subjects who are otherwise immunocompro-

    mised (5, 20, 77). It is considered an early clinical

    marker of HIV infection. The chief aetiological

    agents associated with infection are T. rubrum,

    C. albicans, Fusarium spp., Aspergillus spp. and

    Scopulariopsis brevicaulis. In this clinical manifesta-

    tion of onychomycosis, fungi invade the area under

    the nail cuticle, leading to infection of the proximal

    nail plate. This infection proliferates distally within

    the nail plate (2, 3, 8, 46, 67, 75).

    Superficial white onychomycosis

    Superficial white onychomycosis involves the

    infection of the dorsal surface of the nail plate (9,

    78). It is present as opaque white patches distrib-

    uted across the dorsal surface. Trichophyton ment-

    agrophytes and T. rubrum are the key pathogens

    involved with this infection. However, several non-

    dermatophyte moulds, including Fusarium spp.,

    Acremonium spp., Aspergillus spp., have also been

    isolated, with the fungal elements mainly located in

    the upper layers of the nail keratin (7, 8, 43, 74, 79).

    Endonyx onychomycosis

    Endonyx onychomycosis is a newly-described form

    of onychomycosis. It involves fungal invasion of

    the superficial nail surface as well as deeper pen-

    etration of the nail plate (75, 77). Nail thickening,

    lifting and inflammatory changes are found to be

    absent in this pattern of onychomycosis. This type

    of fungal invasion is mainly caused by T. soudan-

    ense and T. violaceum. Lamellar splitting, coarse

    pitting and milky white patches within the affected

    nail plates are the key features of this fungal nail

    infection (67, 80, 81).

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    Toenail onychomycosis: an important global disease burden 501

  • Total dystrophic onychomycosis

    Total dystrophic onychomycosis is an end stage of

    any type of longstanding onychomycosis. Mostly it

    appears with (nearly) complete destruction of the

    infected nail plate (2). Typically, two subtypes of

    this form of onychomycosis are reported, primary

    and secondary total dystrophic onychomycosis.

    Primary total dystrophic onychomycosis mostly

    occurs in patients with chronic mucocutaneous

    candidiasis (4, 76).

    DIAGNOSIS OF ONYCHOMYCOSIS

    The accurate diagnosis of onychomycosis is

    important for its successful treatment. The cost and

    long duration of the therapy, the risk of developing

    adverse drug reactions, and possible interactions

    with concomitant medications all underline the

    importance of accurate diagnosis of the condition

    before commencing therapy (7, 74, 80, 8285).

    Accurate diagnosis based on the clinical symptoms

    alone is often difficult. Tinea pedis and tinea

    mannum often occur concomitantly with onycho-

    mycosis (10, 13, 36). The presence of these condi-

    tions may offer useful clinical evidence for the

    diagnosis of onychomycosis. Currently, the diag-

    nosis of onychomycosis is confirmed by clinical

    examination and screening of the collected nail

    specimen by direct microscopy and fungal culture

    (5, 8, 46, 60, 67, 76, 86).

    Apparently 50% of nail disorders that are

    believed to be onychomycosis are in fact other

    types of nail disorders (67). It is recommended that

    care should be taken to correctly identify the signs

    and symptoms of onychomycosis from other clin-

    ical conditions that clinically mimic onychomyco-

    sis, such as psoriasis of the nail, eczema, bacterial

    infections, contact dermatitis, traumatic onych-

    odystrophies, chronic onycholysis, lichen planus,

    chronic paronychia, haemorrhage or trauma, ony-

    chogryphosis, median canalicular dystrophy, pin-

    cer nail, yellow nail syndrome, subungual

    malignant melanoma and subungual squamous

    cell carcinoma (10, 46, 67, 8790).

    It is often difficult to differentiate the clinical

    manifestations of nail psoriasis from onychomy-

    cosis. Both dermatological conditions can result in

    morphological changes of the nail plate that

    include subungual hyperkeratosis, onycholysis,

    leukonychia, splinter haemorrhages and dystrophy

    (46, 91). Involvement of psoriasis can be diagnosed

    by pitting of the nail plate; however, alopecia are-

    ata and chronic paronychia can also be associated

    with nail pitting. In nail psoriasis small, irregular,

    salmon-coloured, visible oil drops can be found on

    the nail plate. This phenomenon is not normally

    associated with onychomycosis (15, 36, 57). Both

    onychomycosis and psoriasis can co-exist in the

    same nail plate. It has been observed that onycho-

    mycosis is often found to be more common in

    psoriasis subjects than in the rest of the population,

    with an estimated prevalence of 1322%. Histo-

    pathological examination of the nail plate is rec-

    ommended for the confirmation of nail psoriasis in

    the absence of skin lesions (10, 46, 67, 87, 90, 91).

    Other dystrophic nail conditions mimicking

    onychomycosis are Dariers disease, lichen planus

    and ichthyotic conditions such as keratosis, ich-

    thyosis and deafness syndrome. Approximately

    10% of the subjects infected with lichen planus

    have abnormal nails, but in the majority of cases it

    is associated with clinical signs such as thinning of

    the nail plate, subungual hyperkeratosis, onychol-

    ysis and dorsal pterygium (15, 36, 57). Often yellow

    nail syndrome is falsely identified as a fungal

    infection. Light green-yellowish pigmentation of

    the nail plate, hardness and its elevated longitudi-

    nal curvature are the key clinical characteristics of

    this nail disease (10, 46, 67, 87, 90).

    Repetitive trauma to the nail plate can also result

    in the abnormal appearance of nails. It can result in

    distal onycholysis leading to the colonization of the

    affected space by infectious pathogens and the

    discolouration of the nail plate. A clipping of the

    infected nail area followed by the examination of

    the nail bed will help to differentiate between nail

    trauma and onychomycosis. The nail bed will

    appear normal if the symptoms are caused by

    trauma rather than onychomycosis (10, 46, 67, 90).

    WHY DOES ONYCHOMYCOSIS NEED TO BE

    TREATED?

    Clinical issues

    Onychomycosis can become a source of infectious

    fungal bacterial lesions in other parts of the body(92). In addition, the presence of sensitizing fun-

    gal dermatophytic antigens in the nail plate may

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    502 J. Thomas et al.

  • predispose to other clinical conditions in onycho-

    mycosis subjects. These include asthma sensitiza-tion of the respiratory tract and skin conditions,

    such as atopic dermatitis, urticaria and erythema

    nodosum (92). In diabetics, onychomycosis and

    dermatomycoses can complicate foot problems,

    and can lead to ulceration. These wounds may

    consequently lead to osteomyelitis, cellulitis and

    tissue necrosis and may result in lower extremity

    amputation (1, 51, 93). It was estimated that around

    240 million people around the world had diabetes

    in 2007 and that this could increase to 333 million

    by 2025 (94). Approximately 34% of the diabetic

    population has onychomycosis (61, 62). Diabetic

    individuals are almost 3-fold more likely to

    develop onychomycosis than non-diabetics and

    have a higher propensity to develop dermatophytic

    infections (15, 63).

    Quality-of-life issues

    Onychomycosis has a significant impact on

    patients quality of life (QoL) (1, 2). Approximately

    half of all patients with onychomycosis experience

    pain or other types of discomfort with reduced

    quality of life. Onychomycosis has been found to

    affect the physical, functional, psychosocial and

    emotional aspects of life (7, 95). About 30% of the

    patient population have difficulty in wearing

    footwear (20). Although it is not a life-threatening

    condition, many important functional purposes of

    the nails may be severely compromised. Difficulty

    in walking, emotional embarrassment and work-

    related difficulties are the most commonly-repor-

    ted issues. However, severe cases appear to even

    have a negative influence on patients sex lives, and

    the self-esteem of female subjects has been found to

    be significantly affected due to the unsightly and

    contagious-looking nail plate (20, 96). Socks and

    stockings may frequently be damaged, due to the

    constant friction with sharp, dystrophic diseased

    nails in patients with onychomycosis and this may

    result in increased financial expenditure (97, 98).

    TREATMENT

    It is important to consider several factors before

    starting antifungal therapy. The severity of ony-

    chomycosis, the number and location of nails

    affected, causative fungi, concomitant drugs,

    antifungal resistance, treatment cost and

    patient physician preference, must be reviewedbefore commencing the treatment regimen. In

    general, treatment modalities for onychomycosis

    include oral, topical, mechanical and chemical, or a

    combination of these options (7, 10, 99, 100).

    Mechanical

    Nail filing, trimming, curettage and debridement

    have been found to have a key role and are sig-

    nificant adjuvants to topical and oral treatments.

    These often make the nail thin, decrease the fungal

    burden, improve the penetration of topical drugs,

    prevent ulcerations trauma caused by footwear orclothing in patients with diabetes and, above all,

    can provide a better cosmetic result. In clinical

    cases when patients present with dermatophytoma

    (abnormal nails with clumps of dermatophyte

    hyphae) on the nail plate, the penetration of anti-

    fungals can be difficult (101, 102). Increased pen-

    etration of antifungal drugs through the nail plate,

    following debridement, is more likely to produce

    optimal therapeutic results. Debridement alone is

    very unlikely to cure onychomycosis, whereas

    debridement of the infected nail by a trained

    healthcare professional, along with antifungal

    therapy, may be helpful in its management (15,

    20).

    Total or partial surgical nail avulsion is a dif-

    ferent strategy to remove the affected nail(s).

    Because the complete removal of the nail plate

    allows the distal soft tissue to expand and pro-

    motes ingrown nails, partial nail avulsion is pre-

    ferred over total nail avulsion (4, 99, 103, 104).

    Chemical treatment

    Chemical avulsion, similar to mechanical debride-

    ment, is generally employed as an adjunct to oral or

    topical therapy. It is a painless method of removing

    the diseased section of the nail plate. Often, how-

    ever, the surrounding skin becomes irritated fol-

    lowing this procedure. Chemical avulsion is

    normally performed with 40% urea paste, com-

    bined with 2% tolnaftate or 1% bifonazole. This is

    applied to the nail plate, which is then bandaged

    for a week. Complete chemical avulsion is per-

    formed only in patients with onychogryphosis (7,

    76, 99, 103).

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    Toenail onychomycosis: an important global disease burden 503

  • Oral antifungal agents

    Oral antifungal agents are considered to be the

    most effective agents among the various treatment

    options currently available for the management of

    onychomycosis (1, 99). Before commencing ther-

    apy, it is highly recommended to consider any

    concomitant medications and the patients prefer-

    ence, especially when treating persons who have

    diabetes mellitus, liver disease or are immuno-

    compromised (7, 105). Although ketoconazole and

    fluconazole are often prescribed for the treatment

    of onychomycosis, only griseofulvin, itraconazole

    and terbinafine are approved by the US Food and

    Drug Administration (FDA) and currently licensed

    for the treatment of this condition in the United

    States and United Kingdom (1, 4, 7, 44, 51, 82, 99,

    100, 104106).

    First-line onychomycosis management strategies

    include oral administration of terbinafine, itraco-

    nazole or fluconazole (Fig. 2). The use of ketoco-

    nazole should be discouraged due to its potential

    hepatotoxicity. Griseofulvin is no longer widely

    used because it needs a longer duration of treat-

    ment and has been associated with high relapse

    rates (107). A cumulative meta-analysis reported

    mycological cure rates (range) of oral antifungal

    agents in onychomycosis treatment for terbinafine

    Negative culture/Biopsy

    Positive culture/Biopsy of the nail specimen

    First line therapyoral medications

    Itraconazole

    Standard treatment: 200 mg/d 12 weeks

    Pulse treatment: 200 mg twice-daily 1 week/month 23 pulses2 pulses for fingernailsand 3 for toenails

    Fluconazole

    150300 mg/week 1248weeks

    Topical therapy: in mild to moderate cases of distal or superficial onychomycosis

    Amorolfine

    Once weekly 48 weeks

    File down infected nailsonce a week

    Treatment follow-up at 40 4 weeks Positive culture/ Biopsy of

    the nail specimen

    Clinical examination and diagnosis

    Symptomatic treatment of the nail dystrophy/infection

    Patient presents to a healthcare setting

    Mycological cure Prophylactic topical treatment Patient education to prevent disease recurrence

    Terbinafine

    Child

  • Table

    2.

    Aco

    mp

    aris

    on

    of

    effi

    cacy

    of

    anti

    fun

    gal

    dru

    gs

    use

    din

    the

    trea

    tmen

    to

    fo

    ny

    cho

    my

    cosi

    s

    Stu

    dy

    Tre

    atm

    ent

    reg

    imen

    (mgd

    ay)

    Len

    gth

    of

    trea

    tmen

    t

    Len

    gth

    of

    foll

    ow

    -up

    My

    colo

    gic

    al

    cure

    Rel

    apse

    rate

    a

    Gri

    seo

    fulv

    in

    (Ko

    rtin

    get

    al.

    1993

    )(1

    58)

    990

    (UM

    SG

    )b78

    wee

    ks

    77w

    eek

    s23

    6(6%

    )

    660

    (UM

    SG

    )78

    wee

    ks

    77w

    eek

    s23

    6(6%

    )

    (Fae

    rgem

    annet

    al.

    1995

    )(1

    59)

    500

    52w

    eek

    s52

    wee

    ks

    194

    1(4

    6%)

    (Vil

    lars

    and

    Jon

    es19

    92)

    (160

    )40

    %

    (Sal

    goet

    al.

    2003

    )(2

    0)50

    %

    Ter

    bin

    afin

    e

    (Gal

    imb

    ertiet

    al.

    1996

    )(1

    61)

    250

    12w

    eek

    s36

    wee

    ks

    192

    2(8

    2%)

    (Dra

    keet

    al.

    1997

    )(1

    62)

    250

    12w

    eek

    s48

    wee

    ks

    1241

    42(8

    7%)

    (Go

    od

    fiel

    det

    al.

    1992

    )(1

    63)

    250

    12w

    eek

    s36

    wee

    ks

    374

    5(8

    2%)

    (Sig

    urg

    eirs

    sonet

    al.

    2006

    )(1

    64)

    250

    12w

    eek

    s48

    wee

    ks

    2263

    90(5

    8%)

    350

    (2w

    eek

    s

    3p

    uls

    es)

    12w

    eek

    s48

    wee

    ks

    1603

    74(4

    3%)

    (Hei

    kk

    ila

    and

    Stu

    bb

    2002

    )(1

    20)

    250

    12w

    eek

    s4

    yea

    rs92

    0(4

    5%)

    250

    16w

    eek

    s4

    yea

    rs11

    7(6%

    )

    Itra

    con

    azo

    le

    (Ev

    ans

    and

    Sig

    urg

    eirs

    son

    1999

    (119

    )

    400

    (1w

    eek

    s

    3p

    uls

    es)

    12w

    eek

    s72

    wee

    ks

    411

    07(3

    8%)

    (De

    Bac

    ker

    etal.

    1996

    )(1

    65)

    200

    12w

    eek

    s48

    wee

    ks

    771

    68(4

    6%)

    (Sch

    emer

    etal.

    1999

    )(16

    6)20

    016

    wee

    ks

    48w

    eek

    s11

    16

    (68%

    )

    200

    (1w

    eek

    s

    3p

    uls

    es)

    16w

    eek

    s48

    wee

    ks

    81

    6(6

    0%)

    200

    16w

    eek

    s48

    wee

    ks

    101

    6(6

    3%)

    200

    (1w

    eek

    s

    4p

    uls

    es)

    16w

    eek

    s48

    wee

    ks

    101

    6(6

    3%)

    (Sig

    urg

    eirs

    sonet

    al.

    2002

    )(1

    67)

    400

    (1w

    eek

    s

    34

    pu

    lses

    )12

    16

    wee

    ks

    45

    yea

    rs17

    32

    (53%

    )

    (Hei

    kk

    ila

    and

    Stu

    bb

    2002

    )(1

    20)

    400

    (1w

    eek

    s

    3p

    uls

    es)

    12w

    eek

    s4

    yea

    rs13

    18

    (72%

    )

    400

    (1w

    eek

    s

    4p

    uls

    es)

    16w

    eek

    s4

    yea

    rs11

    17

    (65%

    )

    (De

    Cu

    yp

    eran

    dH

    ind

    ryck

    x19

    99)

    (168

    )20

    012

    wee

    ks

    2y

    ears

    66

    (100

    %)

    Flu

    con

    azo

    le

    (Hav

    uet

    al.

    2000

    )(1

    69)

    150c

    24w

    eek

    s60

    wee

    ks

    204

    1(4

    9%)

    (Lin

    get

    al.

    1998

    )(1

    70)

    450c

    24w

    eek

    s12

    wee

    ks

    287

    8(3

    6%)

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    Toenail onychomycosis: an important global disease burden 505

  • (mean SEM) of (78 6 to 76 3%), fluconazole

    (53 6 to 48 5%), griseofulvin (55 8 to

    60 6%), itraconazole continuous (63 5 to 59

    5%) and itraconazole pulse (75 10 to 63 7%)

    (108). Terbinafine, followed by itraconazole, have

    been recommended as the drugs of choice for the

    treatment of dermatophytic toenail onychomycosis.

    Terbinafine and itraconazole have better cure rates

    than other antifungal agents (Table 2). Fluconazole

    is recommended as the first choice for the treat-

    ment of candidal onychomycosis (76). The long-

    term results (Table 2) from follow-up studies sug-

    gest that the current antifungal interventions are

    inefficient for the long-term management eradica-tion of the infection (102120). Larger follow-up

    studies (45 years) must draw a clearer picture of

    long-term patient outcomes (121123).

    Griseofulvin

    Griseofulvin was the first oral antifungal drug

    approved for the treatment of onychomycosis. It

    exhibits a fungi-static mode of action by interacting

    with microtubule-associated proteins and results in

    the inhibition of fungal cell division (9, 99, 109).

    The antifungal efficacy of griseofulvin is mainly

    limited to dermatophytes (10). Its utility for the

    treatment of dermatophytic onychomycosis is lim-

    ited by its long treatment duration, high dose

    requirement (1000 mg day) and high relapse rates(approximately 50%) (7, 46). Administration of a

    high dose of griseofulvin over a long period of time

    is known to cause adverse drug reactions in

    patients, including gastrointestinal disturbances,

    photosensitivity, skin rashes, headache, fatigue,

    urticaria and hepatotoxicity (9, 20, 51, 99, 105, 106,

    110). The use of griseofulvin for the management of

    onychomycosis has decreased since the arrival of

    newer broad spectrum antifungal drugs (106).

    Azoles (imidazoles and triazoles)

    From the mid 1940s the azole family of antifungal

    agents became an essential tool in the management

    of invasive fungal infections (111). Azoles used

    to treat onychomycosis include ketoconazole, itra-

    conazole and fluconazole. Azoles impair fungal

    cell wall synthesis by inhibiting the cytochrome

    P-450 (CYP) enzyme lanosterol 14-a-demethylase,inhibiting the conversion of lanosterol to ergosterolT

    able

    2.

    (Co

    nti

    nu

    ed)

    Stu

    dy

    Tre

    atm

    ent

    reg

    imen

    (mgd

    ay)

    Len

    gth

    of

    trea

    tmen

    t

    Len

    gth

    of

    foll

    ow

    -up

    My

    colo

    gic

    al

    cure

    Rel

    apse

    rate

    a

    450c

    36w

    eek

    s12

    wee

    ks

    408

    5(5

    9%)

    450c

    36w

    eek

    s24

    wee

    ks

    52

    0(2

    5%)

    Am

    oro

    lfin

    e5%

    lacq

    uer

    (Lau

    har

    anta

    1992

    )(1

    24)

    On

    cew

    eek

    lyd

    24w

    eek

    s12

    wee

    ks

    60%

    (Rei

    nel

    etal.

    1993

    )(1

    27)

    On

    cew

    eek

    lyd

    24w

    eek

    s12

    wee

    ks

    71%

    Cic

    lop

    iro

    x3%

    lacq

    uer

    (Gu

    pta

    and

    Jose

    ph

    2000

    )(1

    30)

    On

    ced

    aily

    48w

    eek

    s34

    %

    (Gu

    pta

    etal.

    2000

    )(1

    31)

    On

    ced

    aily

    48w

    eek

    s36

    %

    aM

    yco

    log

    ical

    rela

    pse

    .bU

    ltra

    mic

    rosi

    zeg

    rise

    ofu

    lvin

    .c P

    resc

    rib

    edd

    ose

    per

    wee

    ks.

    dT

    op

    ical

    ther

    apy

    ,d

    ose

    dep

    end

    so

    nth

    ein

    fect

    edn

    ail

    area

    .

    Mo

    difi

    edfr

    om

    (155

    ,17

    1,17

    2).

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    506 J. Thomas et al.

  • (99). This leads to increased fungal cell permeabil-

    ity and cessation of fungal cell division and

    growth. They are fungistatic, not fungicidal, except

    at very high concentrations. They have a broad

    spectrum activity against fungi, including derma-

    tophytes, yeasts and other fungi (109, 112).

    Ketoconazole was approved by the FDA in 1981.

    Originally, it was used for the systemic treatment

    of onychomycoses and other forms of tinea, with

    cure rates similar to those seen with griseofulvin.

    Since drug-induced hepatitis caused some fatali-

    ties, systemic ketoconazole is no longer routinely

    recommended for the management of onychomy-

    cosis due to its potential hepatotoxicity and

    because of the availability of more efficacious and

    safer antifungal therapeutic options (3, 46, 106,

    113).

    Fluconazole

    Fluconazole is not approved for the treatment of

    onychomycosis in the United States; however, it is

    licensed in many other countries. Because of its

    long plasma half-life (between 20 and 50 h), it can

    be given at 24 h or even longer intervals. Flucona-

    zole can be detected in the body even up to

    5 months after cessation of oral therapy (7). For the

    management of onychomycosis, pulse therapy

    with 150, 300 or 450 mg once a week is recom-

    mended for up to 12 months (9, 110). In vitro data

    show high activity against dermatophytes and

    yeasts (103). Adverse drug reactions reported

    include mostly mild gastrointestinal disturbances,

    skin rashes, headache and insomnia (110, 114). At

    present, no guidelines are available regarding

    obtaining laboratory tests when this drug is pre-

    scribed. However, the manufacturers suggest a

    liver function test prior to the commencement of

    therapy and at regular intervals, depending on the

    dose and duration of treatment (5, 7, 9, 46, 99, 105,

    106, 110, 114).

    Itraconazole

    Itraconazole was the first systemic antifungal agent

    approved for the treatment of onychomycosis (1). It

    is mainly fungistatic. In vitro data demonstrate its

    broad spectrum of activity against dermatophytes

    and yeasts, as well as other moulds (103, 115). It has

    high affinity for keratinized tissues, resulting in

    tissue levels higher than that of plasma levels (9).

    When oral itraconazole is administered at a dose of

    100 or 200 mg day, it remains in the lipophiliccytoplasm of keratinocytes in the nail plates, and

    builds up in the nail plate after about 3 months of

    therapy, eliciting a drug reservoir effect lasting up

    to 7 months after discontinuation of therapy (106).

    This facilitates the briefer duration of itraconazole

    therapy for the management of onychomycosis (1,

    106, 116). For the management of onychomycosis,

    itraconazole is generally given as a continuous

    dose (200 mg daily) for 3 months or pulse therapy(200 mg twice daily) for the first week only of each

    month for 3 months. Typically, two pulse treat-

    ments are recommended for fingernail infections

    and three pulse treatments for toenail infections

    (110). It is metabolized by the liver and many early

    studies have highlighted the hepatic toxicity of

    itraconazole (115, 117). The manufacturers advise

    monitoring liver function in patients receiving

    continuous itraconazole for more than 1 month or

    at anytime if symptoms of hepatic dysfunction

    develop (5, 7, 9, 20, 38, 46, 99, 106, 110, 118).

    Terbinafine

    Terbinafine is the drug of choice for the manage-

    ment of onychomycosis. Terbinafine was the first

    oral synthetic alkylamine approved for the treat-

    ment of onychomycosis (99, 103). It exhibits mainly

    a fungicidal mode of action, by inhibiting fungal

    ergosterol synthesis at the squalene epoxidation

    stage, leading to membrane disruption and

    destruction of the fungal cell wall (106). In vitro

    data suggest its fungicidal activity against derma-

    tophytes. However, it is fungistatic against yeasts

    and moulds such as Aspergillus fumigatus and

    Scopulariopsis brevicaulis (99, 103). Studies have

    demonstrated its higher cure rates compared with

    itraconazole for the treatment of onychomycosis

    (119, 120). Pharmacokinetic data have shown that

    terbinafine accumulates in adipose tissue and

    provides a drug depot effect. Within 24 h of the

    first dose, terbinafine appears in the stratum

    corneum and maintains a therapeutically active

    drug concentration in the nails. The mean active

    drug concentration persists in the body up to

    3 months after termination of oral therapy (103).

    For the treatment of toenail onychomycosis, a

    dose of 250 mg daily for 12 or more weeks is

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    Toenail onychomycosis: an important global disease burden 507

  • recommended (110). The most commonly reported

    side effects are nausea, vomiting and other gas-

    trointestinal side effects. Other side effects include

    taste disturbances and hair loss. Due to potential

    terbinafine-induced hepatotoxicity, manufacturers

    suggest performing liver function tests for patients

    before commencing therapy and after 46 weeks of

    therapy (5, 7, 9, 20, 38, 46, 99, 106, 110).

    Topical antifungal agents

    In the early days of disease management, topical

    ointments and disinfectants were used to treat

    onychomycosis (2). Earlier treatment options had

    poor pharmaceutical properties and a non-specific

    spectrum of action and consequently had mediocre

    therapeutic outcomes (2, 121). Several studies

    investigated the usefulness of topical lacquers for

    the management of onychomycosis (124) and

    demonstrated mycological cure and clinical

    improvement (Table 2) (4, 99, 121). However, it is

    fairly difficult to draw constructive comparisons

    with those results obtained from the systemic

    therapies. Currently, topical treatment options are

    only advocated for the management of superficial

    white onychomycosis and in very early cases of

    distolateral onychomycosis, where the infection is

    limited to the distal edge of the nail plate or in

    cases where patients are restricted from using oral

    antifungal medications (107).

    Newer antifungal topical agents have been for-

    mulated to deliver better penetration into the nail

    unit, increasing their therapeutic effectiveness. The

    latest developments in topical onychomycosis

    therapy are ciclopirox and amorolfine nail lacquers.

    The different formulation excipients in the lacquer,

    such as solvents, polymers and plasticizers, facili-

    tate the maintenance of an increased concentration

    of the active drug moiety in the nail plate (99).

    Upon application of the lacquer formulation, after

    the evaporation of the solvent, the concentration of

    ciclopirox and amorolfine in the lacquer film resi-

    due rises to 35% and 25%, respectively (122, 123).

    The residual lacquer film acts as a drug reservoir

    and allows the active ingredient to remain in con-

    tact with the diseased nail plate for a longer period

    of time, increasing the potential for better treatment

    outcome. The residual lacquer film, furthermore,

    enhances the hydration of the nail plate and

    amplifies the diffusion of the active drug through

    the diseased nail plate (2, 9, 44, 82, 100, 104, 122,

    123).

    Amorolfine

    Amorolfine is a phenyl-propyl morpholine deriv-

    ative, is licensed for the management of onycho-

    mycosis in Australia, the United Kingdom,

    Germany, France, Italy and some other countries,

    but not in the United States (125). Similar to other

    antifungal agents, amorolfine interferes with the

    ergosterol biosynthesis pathway, inhibiting the D14-reductase and D7-8-isomerase enzymes. Inhibitionof these enzymes impairs cellular growth and

    membrane function and causes cell death (7, 99,

    110, 126). It has a broad spectrum antimycotic

    action against dermatophytes (Trichophyton, Mi-

    crosporum and Epidermophyton species), and yeasts

    (Candida, Cryptococcus and Malassezia species) (9,

    122). Application is recommended once or twice

    weekly until the nail re-grows. This usually

    requires 6 months for fingernails and 12 months

    for toenails. It is advised to file down and thor-

    oughly degrease the nails before applying the lac-

    quer. The treatment is generally well tolerated with

    the development of chromonychia in rare cases,

    presumably due to the oxidation of formulation

    excipients (9). It is reported that amorolfine pene-

    trates into the subungual debris and maintains

    effective active drug concentrations even 2 weeks

    after cessation of application (2, 5, 9). The efficacy

    of amorolfine for the management of onychomy-

    cosis (Table 2) has been previously reported (117,

    118). Amorolfine (5% once weekly lacquer for up to

    24 weeks) is reported to have 6071% mycological

    cure rates in randomized clinical studies, for the

    management of onychomycosis (124, 127).

    Ciclopirox

    Ciclopirox 8% nail lacquer is the only nail lacquer

    approved by the FDA for the treatment of ony-

    chomycosis in the United States (122). Ciclopirox is

    approved in more than 40 countries worldwide

    and the efficacy of ciclopirox nail lacquer (8%) in

    the management of onychomycosis has been

    reported in various randomized controlled trials

    (Table 2) (99, 117, 118). It is a synthetic hydroxy-

    pyridone derivative that carries broad-spectrum

    fungistatic and fungicidal activity. It has been

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    508 J. Thomas et al.

  • suggested that its antifungal action is due to the

    chelation of polyvalent cations (Fe3+ or Al3+),

    leading to the inhibition of metal dependent

    enzymes (cytochromes) that degrade toxic perox-

    ides within the fungal cell (122, 128). At higher

    concentration, ciclopirox subdues the cellular

    uptake of essential compounds and impairs the

    fungal cell membrane resulting in the leakage of

    potassium ions and other intracellular material

    (129). It has in vitro activity against dermatophytes

    (Trichophyton species, Microsporum species, Epi-

    dermophyton floccosum), yeasts (Candida species,

    Malassezia species, Cryptococcus neoformans) and

    various other fungi including Aspergillus species,

    Penicillum species and Fusarium species (122). In

    common with amorolfine, treatment guidelines

    recommend that a healthcare professional debride

    and trim the diseased nails to improve the thera-

    peutic outcomes. In practice, patients are often

    trained to debride the nail bed themselves (2). The

    most commonly reported side effects include irri-

    tation, a burning sensation and pruritis (2, 5, 9).

    Mycological cure rates ranging from 29% to 36%

    for ciclopirox 8% (applied once daily for up to

    48 weeks) have been reported (130, 131).

    ADJUVANT INTERVENTION OPTIONS

    Combination therapy for the management of ony-

    chomycosis is a relatively new concept. It includes

    the combination of oral and topical antifungal

    therapy. Many authors have reported distinct

    improvement of mycological and clinical outcomes

    associated with the combination approach (97, 132

    135). Combination therapy benefits from synergic

    effects of the antifungal drugs and consequently

    brings out increased therapeutic effects in a more

    rapid fashion (132). Furthermore, combination

    therapy amplifies the in vivo fungicidal action,

    minimizes the emergence of antifungal resistance,

    shortens the length of therapy, extends the spec-

    trum of activity and reduces the dose of the sys-

    temic antifungal drug, thereby diminishing the

    potential for toxicity (58). A combination approach

    is recommended by Baran (2008) for non-

    responders to topical therapy after a treatment

    period of 6 months. An oral medication is com-

    bined with the topical treatment. However, based

    on the prognostic factors, the combination

    approach should be considered as a first-line ther-

    apy when there is a high likelihood of treatment

    failure (58). Combining topical and oral antifungal

    treatments could provide a dual front to success-

    fully countering the invasive fungal siege on nails

    while providing high antifungal concentrations

    across the nail unit (88). Complementary drug

    penetration is the key motivation behind combin-

    ing oral and topical treatments (136).

    Ciclopirox and terbinafine

    A randomized, evaluator-blinded, multicentre

    study reported mycological cure rates of 667%for combination therapy (n = 21) (terbinafine

    250 mg daily for 14 weeks and 912 weeks, plusdaily application of ciclopirox nail lacquer for

    48 weeks) which was better than the cure rates of

    560% following monotherapy (n = 25) (terbinafine250 mg daily for weeks 112) (136).

    An Israeli open label randomized trial reported

    better mycological cure rates for the combination

    therapy regimen (n = 34) (terbinafine 250 mg dailyfor 16 weeks plus ciclopirox 8% once daily for

    9 months; 882%) compared with monotherapy(n = 34) (terbinafine 250 mg for 16 weeks, 647%)(137).

    Terbinafine and ciclopirox or amorolfine

    A recent Indian study assessed the efficacy of oral

    terbinafine as a monotherapy and in combination

    with ciclopirox 8% or amorolfine 5% topical nail

    lacquers. The three treatment groups [A: mono-

    therapy (n = 48); terbinafine 250 mg twice daily forthe first 7 days of every month for 4 months; B:

    combination therapy (n = 24); terbinafine regimen

    plus ciclopirox 8% once daily therapy for 4 months;

    C: combination therapy (n = 24); terbinafine regi-

    men plus amorolfine once weekly for 4 months]

    demonstrated comparable mycological cure rates: A

    (826%), B (833%) and C (700%). Combinationtherapy with topical ciclopirox or amorolfine did not

    reveal any significant (P > 005) difference in efficacycompared with the terbinafine monotherapy (138).

    Amorolfine and terbinafine

    A multicentre randomized, parallel group trial

    investigated the efficacy of two different courses of

    terbinafine combined with amorolfine [A: amorol-

    2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519

    Toenail onychomycosis: an important global disease burden 509

  • fine 250 mg daily for 6 weeks plus amorolfine 5%once weekly for 15 months (n = 50); B: amorolfine

    250 mg daily for 12 weeks plus 5% once weeklyfor 15 months (n = 47)] in comparison with terbi-

    nafine alone [C: terbinafine 250 mg daily for12 weeks (n = 48)]. Two of the combined treatment

    regimens [A (750%) and B (900%)] demonstratedimproved mycological cure rates compared with

    the systemic treatment alone [C (680%)], withamorolfine-terbinafine 12 weeks therapy showing

    the highest mycological cure rates (134).

    Amorolfine and itraconazole

    Lecha (2001) reported the efficacy of two alterna-

    tive regimens of amorolfine-itraconazole therapies

    [A: itraconazole 200 mg daily for 6 weeks plusamorolfine 5% lacquer for 24 weeks, (n = 40); B:

    itraconazole 200 mg daily for 12 weeks plusamorolfine 5% lacquer for 24 weeks (n = 33)],

    compared with itraconazole monotherapy [C:

    itraconazole 200 mg daily for 12 weeks (n = 32)].Both combination treatment groups evidenced

    significantly (P < 005) higher mycological curerates [A (914%); B (972%) compared with mono-therapy C (680%)] (135).

    Amorolfine and fluconazole

    In vitro screening results suggest a potential synergy

    with amorolfinefluconazole combination when

    tested against pathogens that are frequently repor-

    ted as causative agents for onychomycosis (139).

    Boosted antifungal therapy

    Boosted antifungal therapy (boosted oral and top-

    ical therapy) has been proposed as an effective tool

    to achieve better therapeutic success in non-

    responsive onychomycosis cases. The BOAT

    (boosted oral antifungal treatment) and BATT

    (boosted antifungal topical treatment) approaches

    include application of a piece of SDA (Sabourauds

    dextrose agar) to the nail in conjunction with

    oral topical antifungal therapy. The resting fungalelements or spores in the nail plate, that are more

    resistant to antifungal agents than active fungi,

    contribute partly to treatment failure and infection

    recurrence. Boosted treatment interventions may

    boost the maturation of fungal conidia to hyphae

    and increase the antifungal drugs efficacy by

    enhancing fungal susceptibility (140). Typically, an

    SDA portion is maintained on the nail plate for

    1 week during topical therapy and for approxi-

    mately 48 h in oral therapy. Pilot investigations of

    BOAT therapy (90% cure, n = 10) and BATT ther-

    apy (85% cure, n = 13) suggest a promising treat-

    ment option for the management of onychomycosis

    in chronic and difficult-to-treat cases (141, 142).

    Other novel approaches for the treatment of

    onychomycosis include creating tiny holes in the

    nail plate to facilitate its penetration by drugs.

    Another approach involves the use of a short

    wavelength light to disrupt the growth and repro-

    duction of light-averse fungi in the diseased nail

    plate (143).

    COMPLIANCE

    Patient compliance is an extremely important fac-

    tor to achieve optimal therapeutic success in anti-

    fungal therapy (144). Prolonged treatment is

    required to achieve disease-free nails in individuals

    with onychomycosis and this often leads to com-

    pliance problems (46). Management of onychomy-

    cosis in special patient populations such as

    children, elderly and immunocompromised indi-

    viduals can be difficult due to poor compliance

    (100). The previously reported key determinants of

    patient compliance with oral antifungal medica-

    tions in onychomycosis treatment are: duration of

    therapy, ease of swallowing, frequency of daily

    intake and the number of oral drugs per intake

    (145). Intermittent antifungal regimens were found

    to have better acceptance over continuous thera-

    pies. This is due to a shorter treatment duration,

    fewer tablets, fewer adverse reactions and cost

    effectiveness (145). There is little information

    available in the literature describing patient com-

    pliance with antifungal agents used for the treat-

    ment of onychomycosis. The authors of a study

    conducted in China found an overall compliance

    rate of about 45% for oral antifungal agents (inter-

    mittent pulse itraconazole, intermittent terbinafine,

    continuous terbinafine) (146). The major factors

    reported to have a negative influence on compliance

    were: adverse effects of the medications (30%),

    discontinuation of therapy owing to early detected

    progress (22%) and financial constraints (16%)

    (146). Patient education is highly important to

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    510 J. Thomas et al.

  • achieve better therapeutic outcomes for the man-

    agement of onychomycosis. Doctors and pharma-

    cists should stress the importance of compliance

    with the prescribed treatment schedule. A treatment

    calendar would be useful to assist patients to com-

    ply with the treatment schedule (including dates for

    laboratory testing, follow-up visits and also to

    record potential adverse drug reactions) (46).

    COST OF TREATMENT INTERVENTIONS

    Gupta and Lambert summarized the expected cost

    (drug acquisition cost, medical management cost

    and cost of managing adverse reactions) involved

    per patient for mycological cures in the treatment of

    pedal onychomycosis (147). The cost of the antifun-

    gal regimen was as follows (1999 values): griseoful-

    vin US$4917, itraconazole (continuous therapy)

    US$2072, itraconazole (pulse therapy) US$1072,

    terbinafine US$1042 and fluconazole US$1449 (147).

    As the given values are nearly 10 years old, a follow-

    up study would be informative.

    Topical treatment has been shown to be less

    expensive than oral treatments. Marty et al. esti-

    mated treatment cost (2005 values) per cure of dif-

    ferent antifungal nail lacquers (148). These costs did

    not include the diagnostic cost and other medical

    management costs associated with the treatment.

    Treatment costs for the two widely recommended

    nail lacquers were given as: amorolfine (applied

    once weekly) 118 patient cured, whereas ciclopi-rox (applied once daily) cost 273 patient cured andit was shown to be more costly than amorolfine (148).

    FINANCIAL IMPLICATIONS OF

    ONYCHOMYCOSIS

    In the majority of cases, foot infections start as a

    minor dermatophytic infection. Superficial mycotic

    infections can disrupt the skin integrity, thereby

    leading to a point of entry for bacterial superin-

    fection by Gram-positive cocci such as staphylo-

    cocci and streptococci (15). As these complications

    can result in hospitalization and even amputations,

    prevention of complications and active treatment

    of dermatophytic infections are essential. Diabetes

    is the most common cause of non-traumatic

    amputation in the United States, Australia and

    Europe. Moreover, diabetic patients infected with

    onychomycosis have a 3-fold higher risk for

    developing lower extremity complications such as

    foot ulcer and or gangrene compared to diabeticpatients without onychomycosis (149). Among the

    120 000 non-traumatic amputations done each year

    in the United States, 4583% are due to diabetes

    (150, 151). In 2003, $2 billion was spent on lower

    extremity (toe, leg and foot) amputations in the

    United States, with a total of 112 551 amputations

    costing $16 826 procedure (64). In 2001, in theUnited States, about $165 billion was spent on themanagement of diabetes-related lower extremity

    amputations (152). In Australia, diabetes-related

    foot problems and complications are the major

    causes of hospitalizations in people with diabetes,

    costing AUS$48 million year (151).The ageing population across the developed

    countries is a concern; by 2030, in most of the

    advanced economies, the fraction of the population

    aged over 65 years will be about 1535% (153).

    Approximately 50% of people aged >70 years have

    onychomycosis (20, 62, 63). An increased prevalence

    of onychomycosis has been observed in industrial-

    ized nations during the past few decades. Compar-

    ison of results from two US studies revealed a

    remarkable increase in onychomycosis (approxi-

    mately 6-fold increase between 1979 and 2000) (17,

    2731, 33). This is presumably due to the ageing

    population, use of immunosuppressant therapies,

    involvement in fitness activities and increased use of

    conventional occlusive footwear in comparison to

    the open-toed type of footwear in third world

    nations (4446). An American study illustrates the

    potential financial burden of onychomycosis.

    Elewski reported that $US43 million (as per 1997

    values) was spent on onychomycosis management

    over a 1-year period (19891990) on 13 milliontreatment visits by 662 000 subjects, aged > 65 years

    (1). In 1999, in the United States approximately

    US$250 million was spent on the debridement of

    mycotic toenails alone (15). Furthermore, one-third

    of Australias podiatry workload is considered to be

    committed towards the management of onycho-

    mycosis and related problems (154). These data

    underline the health-related challenges ahead for

    the vulnerable ageing population.

    TREATMENT FAILURE OR RELAPSE

    Onychomycosis has often been associated with

    high recurrence rates (4070%) and many patients

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    Toenail onychomycosis: an important global disease burden 511

  • have a long history of disease recurrence (20, 155).

    The term recurrence suggests both relapse and re-

    infection. In treatment relapse, infection is not

    completely cured and returns. This implies treat-

    ment failure. In re-infection the ailment is com-

    pletely cured and is followed by a new infection by

    the same or a different organism (20, 125). Fungal-

    free nails are the goal of antifungal therapy in

    onychomycosis. Because of the slow growth pat-

    tern of the toenails, up to 18 months is required for

    the nail plate to grow out fully. Therapeutic success

    of antifungal therapy of onychomycosis depends

    on the newly grown-out nail plate, being fungus-

    free (66, 155).

    Onychomycosis is a deep-seated, recalcitrant

    fungal infection. The in vitro activity of antifungal

    drugs does not always correlate with their clinical

    efficacy. This may be attributed to the carriage of

    arthroconidia and chlamydoconidia (resting fungal

    elements) in the nail plate (140, 156). Other nail

    characteristics such as nail thickness (>2 mm), slow

    outgrowth, severe onycholysis and dermatophy-

    toma also contribute to the failure of antifungal

    therapy (155). The resting fungal elements are

    highly resistant to antifungal therapy and appear to

    survive in the nail plate environment, and in foot-

    wear for long periods of time, even contributing to

    the recurrence of infection after therapy is stopped

    (140, 157). The major risk factors for recurrence

    include family history, co-existing ancillary clinical

    conditions (diabetes, arterial and vascular diseases,

    Down syndrome, Raynaud syndrome), immune

    suppression and acquired or inherent immunode-

    ficiency. Other previously implicated prognostic

    factors are co-existing bacterial viral nail infec-tions, erroneous diagnosis, poor compliance, anti-

    fungal resistance and poor choice of antifungal

    therapy. Furthermore, the role of disease-causing

    fungi is also critical. Generally, onychomycosis

    caused by non-dermatophytic moulds does not

    respond to oral antifungal therapy and current

    effective management options are limited (34, 76,

    136, 144).

    RECOMMENDATIONS FOR PREVENTION

    AND RECURRENCE

    The nature of the infection requires careful man-

    agement strategies to prevent re-infection. The

    re-infection rate is often high. Given the influence

    of predisposing factors, if an infection is not man-

    aged carefully, re-infection may occur in virtually

    every patient. Upon the completion of antifungal

    therapy fungal-free nails may be achieved but

    precautionary measures should be taken against re-

    infection (20, 155). Numerous strategies have been

    discussed (Table 3) for the efficient prevention of

    recurrence. Regular prophylactic application of a

    topical antifungal to the feet and toenails may be

    beneficial. Therapeutic guidelines for the manage-

    ment of onychomycosis have suggested that, at the

    time of clinical assessment, marking a line with a

    scalpel blade at the base of the nail dystrophy may

    be helpful for treatment follow-up. If the newly

    grown-out nail remains distal to the marking no

    further treatment is needed, whereas if the dys-

    trophy moves proximal to the scratch, a viable

    infection that requires further medical manage-

    ment, is likely (107).

    CONCLUSION

    Due to the high and increasing prevalence world-

    wide, especially in some patient populations, ony-

    chomycosis is a growing public health concern. It is

    a significant medical disorder and can cause seri-

    ous complications in some patient populations. The

    patients affected harbour a fungal reservoir, with

    Table 3. Recommended guidelines for the prevention

    and recurrence of toenail onychomycosis

    Protect toes from sources of infection

    Treat tinea pedis (self and other household members)

    Launder socks in hot water, after soaking in a

    disinfectant solution

    Avoid bare-footed walking through damp areas

    Wear protective footwear at pool and gym

    Avoid sharing of socks

    Discard old shoes (they may have fungal

    spores in them)

    Use cotton socks and change them at regular intervals

    Use aluminium hexahydrate solution powder tominimize sweating

    Wear correctly fitting footwear

    Wear shoes made of breathable material and

    open toed footwear

    Keep nails short and cut them straight

    Use antifungal foot powders often

    Modified from (20, 34, 76, 155, 173).

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    512 J. Thomas et al.

  • the potential to infect other subjects. In some

    patients, such as those with diabetes, onychomy-

    cosis can lead to foot ulcerations, local and sys-

    temic bacterial infections and, in complicated cases,

    amputations. Onychomycosis-induced foot com-

    plications can contribute significant economic

    costs, which weigh particularly heavily on devel-

    oped nations.

    Current medications are often ineffective in the

    long-term management of the condition and are

    often associated with high relapse rates. Compli-

    ance to prescribed treatment regimens is critical to

    achieving therapeutic success. Before commencing

    the therapy, the patient must be educated about the

    importance of adhering to the treatment protocol.

    Currently, only oral medications are recommended

    as first-line treatment for the management of ony-

    chomycosis. Oral treatments have better cure rates

    compared to the topical treatments. However, oral

    medication may not be suitable for some groups

    such as in children, the elderly, patients with liver

    disease and individuals who are immunocompro-

    mised. Currently available topical formulations are

    costly and have mediocre therapeutic success.

    Combination therapy is recommended as a useful

    approach for the better management of the infec-

    tion in non-responders and in difficult to treat

    cases. Topical treatment can be used as an adjuvant

    therapy along with oral medications to improve the

    cure rate. The therapeutic utility of topical medi-

    cations alone is limited. This warrants more

    research into the development of a safe and inex-

    pensive topical treatment for the management of

    the infection in a broader range of patients. Such a

    treatment may also be used to reduce treatment

    recurrence relapse and may be useful as a pro-phylactic agent for populations such as diabetics,

    with a high risk of extremity complications,

    potentially leading to amputations. Furthermore, it

    may help to improve the aesthetic appeal of the

    nail plate(s) in onychomycosis patients, and it

    could potentially improve individuals quality of

    life, thereby reducing the embarrassment associ-

    ated with the infection.

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