Journal of Clinical Pharmacy and Therapeutics (2010) 35, 497–519

doi:10.1111/j.1365-2710.2009.01107.x

REVIEW ARTICLE

Toenail onychomycosis: an important global disease burden 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. Burnet Dip App Sc (Pod) and C. Sharpe BPod *School of Pharmacy, University of Tasmania, Hobart, Tasmania and Department of Podiatry, Royal Hobart 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 countries, 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 individuals 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 recommended 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 onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged. 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]  2010 The Authors. JCPT  2010 Blackwell Publishing Ltd

Keywords: dermatophytes, diagnosis, epidemiology, 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-dermatophytic moulds (2). The dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes are the main causative pathogens, responsible for 80–90% of cases (3–6). 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 2–11% of the onychomycosis cases reported. Yeasts, including Candida spp., account for 2–10% of fungal nail infections (5, 7–11). Dermatophytes are normally transmitted through infected moist floor areas and are less often transmitted via direct personal contact. Non-dermatophytic fungi have been frequently 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 onychomycosis and has been associated with onychomycosis in 30–59% of cases (13, 14). The secondary spread of fungal organisms may lead to the infection of web spaces, toes, nail plates, sole, heel and across the whole foot (14, 15). 497

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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 onychomycosis 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 population (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 infections (17, 18). The incidence of tinea pedis was rare in Europe, before the arrival of T. rubrum. Increased population mobility that resulted from world wars, mass migration and recreational travel led to the translocation 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 reported in 1928 (17, 20). World War II and the Korean and Vietnam wars, increased participation in fitness 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 century (21). After the Vietnam War, T. rubrum surpassed 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 onychomycosis (23). A few other studies reported a similar prevalence for onychomycosis worldwide; a Finnish study (n = 800) reported a prevalence of

8Æ4% and two large Canadian studies (n = 2001; n = 15 000) reported a prevalence ranging from 6Æ5% to 9Æ1% for onychomycosis (24–26). Many authors 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 2Æ18% (29). A United States study in 1997 (n = 1038) revealed a much higher prevalence of onychomycosis (8Æ7%) (30) and a large-scale multicentre North American study published in 2000 (n = 1832) estimated the prevalence of onychomycosis to be 13Æ8% (31). An Indonesian study has demonstrated a similar pattern: the study concluded that the average incidence of onychomycosis has increased from 3Æ5% in 1997–1998 to 4Æ7% 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 onychomycosis 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 onychomycosis. 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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Toenail onychomycosis: an important global disease burden 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).

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 injuries may also contribute to the higher incidence of onychomycosis in males (37). Onychomycosis is seen in only a small proportion (approximately 0Æ4%) of children (1, 38). The lower prevalence of onychomycosis in children compared to adults may be due to reduced exposure to infected environments (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

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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 (44–46). 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 nondermatophytic mould, Scytalidium dimidiatum. In addition, increased risk of onychomycosis is reported in individuals who are exposed to saprophytic fungi (4, 34, 49, 50). It has been proposed that the high prevalence of onychomycosis in the community 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 (51–53). 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 onychomycosis-tinea pedis infections (2Æ5-fold) in athletes, compared with non-athletes (48, 55). Onychomycosis 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

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in sports persons are the speed ⁄ intensity involved with sport (runners), the sudden starting and stopping nature of the sport (e.g. tennis, squash, soccer and cricket), practising sports without protective footwear (e.g. gymnasts, ballet dancers), frequency of nail injuries, prevalent use of synthetic clothing and shoes that retain sweat, water sports and communal bathing (48, 55–57). 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 (normal range 1200–1400) and onychomycoses tend to be more widespread, usually affecting all finger and toe nails (10, 58). Proximal subungual onychomycosis has been considered as an indication of HIV infection. However, transplant recipients, individuals on immunosuppressive treatments and individuals 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 onychomycosis, usually caused by T. mentagrophytes (34, 43, 44, 59, 60). Diabetes Approximately 34% of diabetics have onychomycosis (61, 62) and they are almost three times more likely to develop onychomycosis than non-diabetics (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 diabetics (typically with poor circulation of the lower extremities, neuropathy and impaired wound healing) having a generally higher risk of developing 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 onychomycosis 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 oxygenation 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 ⁄ preventing the 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 hyponychium 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 0Æ5–1Æ0 mm in thickness, 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 threequarters of the total nail thickness. The ventral nail plate is made up of soft hyponychial keratin and typically contains 1–2 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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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 proliferative 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 accelerate the growth of the human nail plate include calcium ⁄ vitamin D, levodopa, retinoids, oral contraceptives and antifungal agents such as fluconazole, itraconazole and terbinafine (69–73). 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 possessing 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 permeation probably contributes to the mediocre therapeutic 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 progresses 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

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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 common form, but it is more common in AIDS patients and subjects who are otherwise immunocompromised (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 manifestation 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 distributed across the dorsal surface. Trichophyton mentagrophytes and T. rubrum are the key pathogens involved with this infection. However, several nondermatophyte 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 penetration 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. soudanense 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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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, 82–85). Accurate diagnosis based on the clinical symptoms alone is often difficult. Tinea pedis and tinea mannum often occur concomitantly with onychomycosis (10, 13, 36). The presence of these conditions may offer useful clinical evidence for the diagnosis of onychomycosis. Currently, the diagnosis 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 clinical conditions that clinically mimic onychomycosis, such as psoriasis of the nail, eczema, bacterial infections, contact dermatitis, traumatic onychodystrophies, chronic onycholysis, lichen planus, chronic paronychia, haemorrhage or trauma, onychogryphosis, median canalicular dystrophy, pincer nail, yellow nail syndrome, subungual malignant melanoma and subungual squamous cell carcinoma (10, 46, 67, 87–90). It is often difficult to differentiate the clinical manifestations of nail psoriasis from onychomycosis. 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 areata 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 onychomycosis is often found to be more common in psoriasis subjects than in the rest of the population, with an estimated prevalence of 13–22%. Histopathological examination of the nail plate is recommended 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 Darier’s disease, lichen planus and ichthyotic conditions such as keratosis, ichthyosis 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, onycholysis 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 longitudinal 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 fungal ⁄ dermatophytic antigens in the nail plate may

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predispose to other clinical conditions in onychomycosis subjects. These include asthma ⁄ sensitization 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 workrelated difficulties are the most commonly-reported 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 onychomycosis, the number and location of nails affected, causative fungi, concomitant drugs,

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antifungal resistance, treatment cost and patient ⁄ physician preference, must be reviewed before 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 significant 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 or clothing 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 antifungals can be difficult (101, 102). Increased penetration 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 different strategy to remove the affected nail(s). Because the complete removal of the nail plate allows the distal soft tissue to expand and promotes ingrown nails, partial nail avulsion is preferred over total nail avulsion (4, 99, 103, 104). Chemical treatment Chemical avulsion, similar to mechanical debridement, 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, however, the surrounding skin becomes irritated following this procedure. Chemical avulsion is normally performed with 40% urea paste, combined with 2% tolnaftate or 1% bifonazole. This is applied to the nail plate, which is then bandaged for a week. Complete chemical avulsion is performed only in patients with onychogryphosis (7, 76, 99, 103).

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Clinical examination and diagnosis

Negative culture/Biopsy

Symptomatic treatment of the nail dystrophy/infection

Positive culture/Biopsy of the nail specimen

First line therapy oral medications

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

Terbinafine

Itraconazole

Fluconazole

Amorolfine

Child 0Æ05) difference in efficacy compared 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-

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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 weekly for 15 months (n = 47)] in comparison with terbinafine alone [C: terbinafine 250 mg ⁄ daily for 12 weeks (n = 48)]. Two of the combined treatment regimens [A (75Æ0%) and B (90Æ0%)] demonstrated improved mycological cure rates compared with the systemic treatment alone [C (68Æ0%)], with amorolfine-terbinafine 12 weeks therapy showing the highest mycological cure rates (134). Amorolfine and itraconazole Lecha (2001) reported the efficacy of two alternative regimens of amorolfine-itraconazole therapies [A: itraconazole 200 mg ⁄ daily for 6 weeks plus amorolfine 5% lacquer for 24 weeks, (n = 40); B: itraconazole 200 mg ⁄ daily for 12 weeks plus amorolfine 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 < 0Æ05) higher mycological cure rates [A (91Æ4%); B (97Æ2%) compared with monotherapy C (68Æ0%)] (135). Amorolfine and fluconazole In vitro screening results suggest a potential synergy with amorolfine–fluconazole combination when tested against pathogens that are frequently reported as causative agents for onychomycosis (139). Boosted antifungal therapy Boosted antifungal therapy (boosted oral and topical therapy) has been proposed as an effective tool to achieve better therapeutic success in nonresponsive onychomycosis cases. The BOAT (boosted oral antifungal treatment) and BATT (boosted antifungal topical treatment) approaches include application of a piece of SDA (Sabouraud’s dextrose agar) to the nail in conjunction with oral ⁄ topical antifungal therapy. The resting fungal elements 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 approximately 48 h in oral therapy. Pilot investigations of BOAT therapy (90% cure, n = 10) and BATT therapy (85% cure, n = 13) suggest a promising treatment 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 reproduction of light-averse fungi in the diseased nail plate (143). COMPLIANCE

Patient compliance is an extremely important factor to achieve optimal therapeutic success in antifungal therapy (144). Prolonged treatment is required to achieve disease-free nails in individuals with onychomycosis and this often leads to compliance problems (46). Management of onychomycosis in special patient populations such as children, elderly and immunocompromised individuals can be difficult due to poor compliance (100). The previously reported key determinants of patient compliance with oral antifungal medications 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 therapies. 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 compliance with antifungal agents used for the treatment of onychomycosis. The authors of a study conducted in China found an overall compliance rate of about 45% for oral antifungal agents (intermittent 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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achieve better therapeutic outcomes for the management of onychomycosis. Doctors and pharmacists should stress the importance of compliance with the prescribed treatment schedule. A treatment calendar would be useful to assist patients to comply 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 antifungal regimen was as follows (1999 values): griseofulvin 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 followup study would be informative. Topical treatment has been shown to be less expensive than oral treatments. Marty et al. estimated treatment cost (2005 values) per cure of different 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 ciclopirox (applied once daily) cost €273 ⁄ patient cured and it 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 superinfection by Gram-positive cocci such as staphylococci 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

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developing lower extremity complications such as foot ulcer and ⁄ or gangrene compared to diabetic patients without onychomycosis (149). Among the 120 000 non-traumatic amputations done each year in the United States, 45–83% 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 the United States, about $1Æ65 billion was spent on the management 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 15–35% (153). Approximately 50% of people aged >70 years have onychomycosis (20, 62, 63). An increased prevalence of onychomycosis has been observed in industrialized nations during the past few decades. Comparison of results from two US studies revealed a remarkable increase in onychomycosis (approximately 6-fold increase between 1979 and 2000) (17, 27–31, 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 (44–46). 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 (1989–1990) on 1Æ3 million treatment 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 Australia’s podiatry workload is considered to be committed towards the management of onychomycosis 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 (40–70%) and many patients

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have a long history of disease recurrence (20, 155). The term recurrence suggests both relapse and reinfection. In treatment relapse, infection is not completely cured and returns. This implies treatment failure. In re-infection the ailment is completely cured and is followed by a new infection by the same or a different organism (20, 125). Fungalfree nails are the goal of antifungal therapy in onychomycosis. Because of the slow growth pattern 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 fungusfree (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 dermatophytoma 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 footwear 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 immunodeficiency. Other previously implicated prognostic factors are co-existing bacterial ⁄ viral nail infections, erroneous diagnosis, poor compliance, antifungal 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 management strategies to prevent re-infection. The re-infection rate is often high. Given the influence

of predisposing factors, if an infection is not managed 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 reinfection (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 management 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 dystrophy moves proximal to the scratch, a viable infection that requires further medical management, is likely (107). CONCLUSION

Due to the high and increasing prevalence worldwide, especially in some patient populations, onychomycosis is a growing public health concern. It is a significant medical disorder and can cause serious 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 to minimize 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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the potential to infect other subjects. In some patients, such as those with diabetes, onychomycosis can lead to foot ulcerations, local and systemic bacterial infections and, in complicated cases, amputations. Onychomycosis-induced foot complications can contribute significant economic costs, which weigh particularly heavily on developed nations. Current medications are often ineffective in the long-term management of the condition and are often associated with high relapse rates. Compliance 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 onychomycosis. 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 immunocompromised. 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 infection 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 medications alone is limited. This warrants more research into the development of a safe and inexpensive 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 prophylactic 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 associated with the infection. REFERENCES 1. Elewski BE (2000) Onychomycosis: treatment, quality of life, and economic issues. American Journal of Clinical Dermatology, 1, 19–26.

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