Thomas Jacobson 2010

Journal of Clinical Pharmacy and Therapeutics (2010) 35, 497519
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.
thomas@utas.edu.au
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 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, including 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 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 3059% 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).
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J. Thomas et al.
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
84% and two large Canadian studies (n = 2001;

n = 15 000) reported a prevalence ranging from
65% to 91% for onychomycosis (2426). 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 218% (29). A United States
study in 1997 (n = 1038) revealed a much higher
prevalence of onychomycosis (87%) (30) and a
large-scale multicentre North American study
published in 2000 (n = 1832) estimated the prevalence 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 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
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
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
04%) 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
499
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 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 (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 onychomycosis-tinea pedis infections (25-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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J. Thomas et al.
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, 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 (normal
range 12001400) 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 0510 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 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).
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 (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 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
501
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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J. Thomas et al.
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 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, 8790).
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 1322%. 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 Dariers 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
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,
503
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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J. Thomas et al.
Patient presents to a healthcare setting
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 <20 kg: 62.5 mg/d

Child 2040 kg: 125 mg/d
Standard treatment:
200 mg/d 12 weeks
150300 mg/week 1248

weeks
Once weekly 48 weeks
Adult 250 mg/day

Up to 6 weeks for
fingernails and 12 weeks
or more for toenails
Pulse treatment:
200 mg twice-daily 1
week/month 23 pulses
2 pulses for fingernails
and 3 for toenails
Treatment
follow-up at
40 4 weeks
Negative culture/ Biopsy of
the nail specimen
Mycological cure
Prophylactic topical treatment
Patient education to prevent
disease recurrence
File down infected nails

once a week
Positive culture/ Biopsy of

the nail specimen
Combination therapy
Mechanical treatment
Chemical treatment
Fig. 2. Onychomycosis treatment algorithm based on the approved treatment therapies in Australia. Modified from
(107, 110).
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 therapy, it is highly recommended to consider any
concomitant medications and the patients preference, especially when treating persons who have
diabetes mellitus, liver disease or are immunocompromised (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, itraconazole or fluconazole (Fig. 2). The use of ketoconazole should be discouraged due to its potential
hepatotoxicity. Griseofulvin is no longer widely
used because it needs a longer duration of treatment 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
(De Cuyper and Hindryckx 1999) (168)

Fluconazole
(Havu et al. 2000) (169)
(Ling et al. 1998) (170)
(Sigurgeirsson et al. 2002) (167)

(Heikkila and Stubb 2002) (120)
Itraconazole
(Evans and Sigurgeirsson
1999 (119)
(De Backer et al. 1996) (165)
(Schemer et al. 1999)(166)
(Heikkila and Stubb 2002) (120)
(Faergemann et al. 1995) (159)

(Villars and Jones 1992) (160)
(Salgo et al. 2003) (20)
Terbinafine
(Galimberti et al. 1996) (161)
(Drake et al. 1997) (162)
(Goodfield et al. 1992) (163)
(Sigurgeirsson et al. 2006) (164)
Griseofulvin
(Korting et al. 1993) (158)
Study
12
12
12
12
12
12
16
250
250
250
250
350 (2 weeks 3 pulses)
250
250
150c
450c
(1
(1
(1
(1
weeks
weeks
weeks
weeks
4 pulses)
3 4 pulses)
3 pulses)
4 pulses)
24 weeks
24 weeks
12 weeks
16 weeks
16 weeks
16 weeks
16 weeks
12 16 weeks
12 weeks
16 weeks
12 weeks
200
200
200
200
200
400
400
400
200
(1 weeks 3 pulses)
12 weeks
400 (1 weeks 3 pulses)
weeks
weeks
weeks
weeks
weeks
weeks
weeks
78 weeks
78 weeks
52 weeks
Length of
treatment
990 (UMSG)b
660 (UMSG)
500
Treatment regimen
(mg day)
Table 2. A comparison of efficacy of antifungal drugs used in the treatment of onychomycosis
60 weeks
12 weeks
48 weeks
48 weeks
48 weeks
48 weeks
48 weeks
45 years
4 years
4 years
2 years
72 weeks
36 weeks
48 weeks
36 weeks
48 weeks
48 weeks
4 years
4 years
77 weeks
77 weeks
52 weeks
Length of
follow-up
(82%)
(87%)
(82%)
(58%)
(43%)
(46%)
(68%)
(60%)
(63%)
(63%)
20 41 (49%)
28 78 (36%)
77 168
11 16
8 16
10 16
10 16
41 107 (38%)
19 22
124 142
37 45
226 390
160 374
2 36 (6%)
2 36 (6%)
19 41 (46%)
Mycological
cure
17 32
13 18
11 17
66
(53%)
(72%)
(65%)
(100%)
9 20 (45%)
1 17 (6%)
40%
50%
Relapse ratea
505
J. Thomas et al.
(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 treatment of candidal onychomycosis (76). The longterm results (Table 2) from follow-up studies suggest that the current antifungal interventions are
inefficient for the long-term management eradication of the infection (102120). Larger follow-up
studies (45 years) must draw a clearer picture of
long-term patient outcomes (121123).
34%
36%
Mycological relapse.
Ultramicrosize griseofulvin.
c
Prescribed dose per weeks.
d
Topical therapy, dose depends on the infected nail area.
Modified from (155, 171, 172).
b
48 weeks
48 weeks
Once daily
Once daily
60%
71%
Amorolfine 5% lacquer
(Lauharanta 1992) (124)
(Reinel et al. 1993) (127)
Ciclopirox 3% lacquer
(Gupta and Joseph 2000) (130)
(Gupta et al. 2000) (131)
24 weeks
24 weeks
Griseofulvin
Once weeklyd
Once weeklyd
12 weeks
12 weeks
5 20 (25%)
40 85 (59%)
12 weeks
24 weeks
36 weeks
36 weeks
450c
450c
Mycological
cure
Length of
follow-up
Length of
treatment
Treatment regimen
(mg day)
Study
Table 2. (Continued)
Relapse ratea
506
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 limited 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, itraconazole 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 ergosterol
(99). This leads to increased fungal cell permeability 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 dermatophytes, 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 fatalities, systemic ketoconazole is no longer routinely
recommended for the management of onychomycosis 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. Fluconazole 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 recommended 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 prescribed. 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
507
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 lipophilic
cytoplasm 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 treatments 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 management of onychomycosis. Terbinafine was the first
oral synthetic alkylamine approved for the treatment 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 dermatophytes. 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
508
J. Thomas et al.
recommended (110). The most commonly reported

side effects are nausea, vomiting and other gastrointestinal 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 formulated 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, facilitate 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 residue 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 contact 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 derivative, is licensed for the management of onychomycosis 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 D14reductase and D7-8-isomerase enzymes. Inhibition
of 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, Microsporum 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 thoroughly degrease the nails before applying the lacquer. 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 penetrates 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 onychomycosis (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 onychomycosis 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 hydroxypyridone derivative that carries broad-spectrum
fungistatic and fungicidal activity. It has been
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 peroxides 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, Epidermophyton 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 therapeutic outcomes. In practice, patients are often
trained to debride the nail bed themselves (2). The
most commonly reported side effects include irritation, 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).
509
apy when there is a high likelihood of treatment

failure (58). Combining topical and oral antifungal
treatments could provide a dual front to successfully 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 combining 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, plus
daily application of ciclopirox nail lacquer for
48 weeks) which was better than the cure rates of
560% following monotherapy (n = 25) (terbinafine
250 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 daily
for 16 weeks plus ciclopirox 8% once daily for
9 months; 882%) compared with monotherapy
(n = 34) (terbinafine 250 mg for 16 weeks, 647%)
(137).
ADJUVANT INTERVENTION OPTIONS
Combination therapy for the management of onychomycosis 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 spectrum of activity and reduces the dose of the systemic antifungal drug, thereby diminishing the
potential for toxicity (58). A combination approach
is recommended by Baran (2008) for nonresponders to topical therapy after a treatment
period of 6 months. An oral medication is combined with the topical treatment. However, based
on the prognostic factors, the combination
approach should be considered as a first-line ther-
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: monotherapy (n = 48); terbinafine 250 mg twice daily for
the 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 regimen plus amorolfine once weekly for 4 months]
demonstrated comparable mycological cure rates: A
(826%), B (833%) and C (700%). Combination
therapy with topical ciclopirox or amorolfine did not
reveal any significant (P > 005) 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-
510
J. Thomas et al.
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 (750%) and B (900%)] demonstrated
improved mycological cure rates compared with
the systemic treatment alone [C (680%)], 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 < 005) higher mycological cure
rates [A (914%); B (972%) compared with monotherapy C (680%)] (135).
Amorolfine and fluconazole
In vitro screening results suggest a potential synergy
with amorolfinefluconazole 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 (Sabourauds
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
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
511
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, 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 the
United States, about $165 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 1535% (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,
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 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 Australias 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 (4070%) and many patients
512
J. Thomas et al.
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).
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.
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Journal of Clinical Pharmacy and Therapeutics (2010) 35, 497519

Toenail onychomycosis: an important global disease

Onychomycosis is a fungal infection of the nail

Keywords: dermatophytes, diagnosis, epidemiology, onychomycosis, toenail, treatment

Onychomycosis is a fungal infection of the nail

In 1853, onychomycosis was first described and

In post-industrialized countries, more than 10% of

84% and two large Canadian studies (n = 2001;

A summary of various predisposing factors for

Toenail onychomycosis: an important global disease burden

grooming the nails and maintaining foot hygiene,

caused by T. rubrum infection that appeared to be

in sports persons are the speed intensity involved

Peripheral vascular disease

Anatomical structures of the nail unit are shown in

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

Toenail onychomycosis: an important global disease burden

to as the lunula. The nail bed mainly consists of

Based on the mode and site of fungal invasion of the

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

Total dystrophic onychomycosis

The accurate diagnosis of onychomycosis is

leukonychia, splinter haemorrhages and dystrophy

WHY DOES ONYCHOMYCOSIS NEED TO BE

Toenail onychomycosis: an important global disease burden

It is important to consider several factors before

antifungal resistance, treatment cost and

Clinical examination and

Symptomatic treatment of the

First line therapy

Topical therapy: in mild to

Child <20 kg: 62.5 mg/d

150300 mg/week 1248

Once weekly 48 weeks

Adult 250 mg/day

File down infected nails

Positive culture/ Biopsy of

Oral antifungal agents

Drug Administration (FDA) and currently licensed

(De Cuyper and Hindryckx 1999) (168)

(Sigurgeirsson et al. 2002) (167)

(Heikkila and Stubb 2002) (120)

(Faergemann et al. 1995) (159)

400 (1 weeks 3 pulses)

Table 2. A comparison of efficacy of antifungal drugs used in the treatment of onychomycosis

Toenail onychomycosis: an important global disease burden

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

Griseofulvin was the first oral antifungal drug

Toenail onychomycosis: an important global disease burden

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

recommended (110). The most commonly reported

Toenail onychomycosis: an important global disease burden

suggested that its antifungal action is due to the

apy when there is a high likelihood of treatment

ADJUVANT INTERVENTION OPTIONS

Terbinafine and ciclopirox or amorolfine

fine 250 mg daily for 6 weeks plus amorolfine 5%

and increase the antifungal drugs efficacy by

Toenail onychomycosis: an important global disease burden

Gupta and Lambert summarized the expected cost

In the majority of cases, foot infections start as a

developing lower extremity complications such as

Onychomycosis has often been associated with

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