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REVIEW ARTICLE
Toenail onychomycosis: an important global diseaseburden
J. Thomas* BPharm MPharmSc, G. A. Jacobson* BPharm (Hons) PhD, C. K. Narkowicz* BSc(Hons) PhD, G. M. Peterson* BPharm (Hons) PhD MBA FSHP FACP AACPA MPS, H. BurnetDip App Sc (Pod) and C. Sharpe BPod*School of Pharmacy, University of Tasmania, Hobart, Tasmania and Department of Podiatry, RoyalHobart Hospital, Hobart, Tasmania, Australia
SUMMARY
Onychomycosis is a fungal infection of the nail
plate or nail bed. It does not usually cure itself
and it can trigger more infectious lesions in other
parts of the body. The reported prevalence of
onychomycosis is increasing in Western coun-
tries, presumably due to lifestyle changes and the
ageing of the population. Approximately 10% of
the general population, 20% of the population
aged >60 years, up to 50% of people aged
>70 years and up to one-third of diabetic indi-
viduals have onychomycosis. Care should be
taken for the accurate diagnosis and timely
treatment of toenail onychomycosis to prevent
complications. Current treatment options have
relatively limited therapeutic success, particularly
long-term. Oral medications are associated with
high recurrence rates and treatment failure, and
are not suitable for many cases due to potential
adverse effects. Topical medications are recom-
mended only for mild to moderate cases. The cost
of therapies may also be prohibitive in some
cases. In the light of these issues, more research is
warranted for the investigation and development
of more effective and economical options for the
treatment and prophylaxis of toenail onychomy-
cosis. In patient populations such as diabetic
individuals, where onychomycosis can provoke
lower extremity complications, professional
podiatry care of toenails and feet should be
encouraged.
Keywords: dermatophytes, diagnosis, epidemiol-
ogy, onychomycosis, toenail, treatment
INTRODUCTION
Onychomycosis is a fungal infection of the nail
plate or nail bed, leading to the gradual destruction
of the nail plate. Onychomycosis has been referred
to as the most prevalent of the nail ailments and
accounts for about 50% of all diseased nails and
about 30% of cutaneous fungal infections (1). It is
caused by dermatophytes, yeasts or non-dermato-
phytic moulds (2). The dermatophytes Trichophyton
rubrum and Trichophyton mentagrophytes are the
main causative pathogens, responsible for 8090%
of cases (36). Non-dermatophytic fungi such as
Acremonium spp., Alternaria spp., Aspergillus spp.,
Fusarium spp., Scytalidium spp. and Scopulariopsis
spp. have been found to be involved in 211% of
the onychomycosis cases reported. Yeasts, inclu-
ding Candida spp., account for 210% of fungal nail
infections (5, 711). Dermatophytes are normally
transmitted through infected moist floor areas and
are less often transmitted via direct personal con-
tact. Non-dermatophytic fungi have been fre-
quently associated with the infection of
traumatized nails in aged patients (11).
Onychomycosis is associated with less noticeable
symptoms than foot ulceration due to tinea pedis,
and is often considered a cosmetic problem and
overlooked (12). Tinea pedis can lead to onycho-
mycosis and has been associated with onychomy-
cosis in 3059% of cases (13, 14). The secondary
spread of fungal organisms may lead to the infec-
tion of web spaces, toes, nail plates, sole, heel and
across the whole foot (14, 15).
Received 18 May 2009, Accepted 18 May 2009
Correspondence: J. Thomas, School of Pharmacy, University of
Tasmania, Private Bag 26, Hobart, Tasmania, 7001, Australia.
Tel.: +61 (3) 6226 1069; fax: +61 (3) 6226 2870; e-mail: jackson.
Journal of Clinical Pharmacy and Therapeutics (2010) 35, 497519 doi:10.1111/j.1365-2710.2009.01107.x
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd 497
HISTORY OF ONYCHOMYCOSIS
In 1853, onychomycosis was first described and
reported by Meissner, a German medical student
(16). The history of onychomycosis is analogous to
that of T. rubrum, the major causative fungal
pathogen involved in the pathogenesis of onycho-
mycosis and tinea pedis (17). T. rubrum was until
recently, limited to Southeast Asia, Indonesia,
Northern Australia and West Africa (18). People
living in these regions are reported to have suffered
from chronic tinea corporis; however, tinea pedis
was not found among them. This was presumably
due to the lack of footwear among the local pop-
ulation (17, 18). However, the use of occlusive
footwear by European colonists and soldiers
provided a highly favourable environment for
T. rubrum to grow and cause pedal fungal infec-
tions (17, 18).
The incidence of tinea pedis was rare in Europe,
before the arrival of T. rubrum. Increased popula-
tion mobility that resulted from world wars, mass
migration and recreational travel led to the trans-
location and subsequent distribution of T. rubrum
from its original endemic regions to new ecological
environments in Europe and America (17, 19). The
first reported clinical case of tinea pedis in the
United States was encountered soon after World
War I. In the same country, the first documented
case of onychomycosis is said to have been repor-
ted in 1928 (17, 20). World War II and the Korean
and Vietnam wars, increased participation in fit-
ness activities, the use of occlusive footwear and
periodic and migratory movement of populations,
have contributed towards the increased prevalence
of tinea pedis and onychomycosis in the 20th cen-
tury (21). After the Vietnam War, T. rubrum sur-
passed T. mentagrophytes as the most commonly
isolated dermatophyte worldwide (21). In the
United States, it has been found that dermatophytic
fungi can be isolated from the plantar surface in
about 70% of the population (18, 22).
EPIDEMIOLOGY
In post-industrialized countries, more than 10% of
the general population is reported to have ony-
chomycosis (23). A few other studies reported a
similar prevalence for onychomycosis worldwide;
a Finnish study (n = 800) reported a prevalence of
84% and two large Canadian studies (n = 2001;n = 15 000) reported a prevalence ranging from
65% to 91% for onychomycosis (2426). Manyauthors believed that onychomycosis started as an
insignificant medical problem (27, 28). It has been
suggested that the prevalence of onychomycosis
has steadily increased over the past few decades
(17, 27, 28). Results from several population studies
support this. A 1979 United States study
(n = 20 000) reported the overall prevalence of
onychomycosis to be 218% (29). A United Statesstudy in 1997 (n = 1038) revealed a much higher
prevalence of onychomycosis (87%) (30) and alarge-scale multicentre North American study
published in 2000 (n = 1832) estimated the preva-
lence of onychomycosis to be 138% (31).An Indonesian study has demonstrated a similar
pattern: the study concluded that the average
incidence of onychomycosis has increased from
35% in 19971998 to 47% in 2003 (32). A survey(Achilles project, 1999) conducted among the
general population visiting physicians in Europe
(Belgium, Netherlands, Luxembourg, Switzerland,
Hungary, Great Britain, Poland) (n = 22 760) and in
East Asia (China, South Korea, Taiwan)
(n = 43 914) demonstrated a substantial onycho-
mycosis prevalence of 26% and 22%, respectively.
The Achilles project concluded that 2 out of 10
patients of the studied population showed signs of
onychomycosis (33).
RISK FACTORS
A summary of various predisposing factors for
onychomycosis is given in Table 1.
Age and gender
Onychomycosis is reported to be more prevalent in
the elderly and appears to occur more frequently in
males (21, 30, 31). Early studies have shown that
there is a correlation between age and onychomy-
cosis. Approximately 20% of the population aged
>60 years and up to 50% of the subjects aged
>70 years are reported to have onychomycosis (5,
20). The correlation between increasing age and
onychomycosis may be attributed to reduced
peripheral circulation, inactivity, suboptimal
immune status, diabetes, larger and distorted nail
surfaces, slower growing nails, difficulty in
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
498 J. Thomas et al.
grooming the nails and maintaining foot hygiene,
frequent nail injury and increased exposure to
disease-causing fungi (2, 5, 11, 34).
Gupta and colleagues postulated that the gender
difference may be attributable to the differences in
hormone levels (progesterone and other related
hormones) that result in a different capacity to
inhibit the growth of dermatophytes (24, 35, 36).
Increased use of occlusive footwear and nail inju-
ries may also contribute to the higher incidence of
onychomycosis in males (37). Onychomycosis is
seen in only a small proportion (approximately
04%) of children (1, 38). The lower prevalence ofonychomycosis in children compared to adults
may be due to reduced exposure to infected envi-
ronments (communal showers, public changing
rooms and saprophytic fungi), smaller nail surface
area, faster nail growth and lower prevalence of
tinea pedis and nail injuries (39).
Genetics
Some recent studies suggest a genetic basis for the
susceptibility to onychomycosis (20, 40). In an
American study, Zaias and colleagues reported
familial patterns of distal lateral onychomycosis
caused by T. rubrum infection that appeared to be
unrelated to interfamilial transmission (41, 42).
Several studies have reported the autosomal
dominant pattern of inheritance associated with
T. rubrum infection and highlighted the increased
risk of developing onychomycosis in subjects where
at least one parent had onychomycosis (34, 42, 43).
Environmental factors
Some authors suggest an association between
onychomycosis and the use of footwear. The
prevalence of onychomycosis is low in
regions societies where people do not wear shoes(4446). Perspiration of the foot within a shoe (and
usually also a sock) can generate a moist warm
environment that is ideal for fungal growth. Other
environmental factors said to influence the
prevalence of onychomycosis include bare-footed
walking through damp areas, increased usage of
non-breathing shoes, playing sports (see below),
use of community bathing facilities and injuries
(20, 34, 47, 48).
Frequent contact with source(s) of infection can
also instigate disease onset. For example, cases of
fingernail onychomycosis were reported in tealeaf
pluckers due to the geophilic dematiaceous non-
dermatophytic mould, Scytalidium dimidiatum. In
addition, increased risk of onychomycosis is repor-
ted in individuals who are exposed to saprophytic
fungi (4, 34, 49, 50). It has been proposed that the
high prevalence of onychomycosis in the commu-
nity has resulted in the heavy contamination of
swimming pools, public toilets and communal
bathing facilities with fungal hyphae and this may
have further increased the risk of developing the
infection (5153). The incidence of onychomycosis
has been shown to be three times more prevalent in
swimmers compared with non-swimmers (34, 54).
Sports
A Brazilian study reported a higher prevalence of
onychomycosis (2-fold) and concomitant onycho-
mycosis-tinea pedis infections (25-fold) in athletes,compared with non-athletes (48, 55). Onychomy-
cosis is often found in conjunction with tinea pedis.
Moreover, the presence of one infection can
increase the risk of the other occurring (48). The
key predisposing factors contributing to infection
Table 1. Predisposing factors for onychomycosis
Subject characteristics
Advancing age
Gender
Sub-optimal health
Inability to maintain foot hygiene
Genetic factors
Family history
Smoking
Systemic conditions
Immune deficiency
Diabetes
Peripheral vascular disease
Immunosuppressive medications
Environmental factors
Shared bathing facilities
Occlusive footwear
Sporting activities
Frequent nail trauma
Other
Concomitant fungal infections (e.g. tinea pedis)
Psoriasis
Modified from (2, 47).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 499
in sports persons are the speed intensity involvedwith sport (runners), the sudden starting and
stopping nature of the sport (e.g. tennis, squash,
soccer and cricket), practising sports without pro-
tective footwear (e.g. gymnasts, ballet dancers),
frequency of nail injuries, prevalent use of syn-
thetic clothing and shoes that retain sweat, water
sports and communal bathing (48, 5557). Toenail
ailments can potentially affect athletic performance
(34).
Immunodeficiency
Individuals infected with HIV have an increased
risk of developing onychomycosis when their
T-lymphocyte count is as low as 400 mm3 (normalrange 12001400) and onychomycoses tend to be
more widespread, usually affecting all finger and
toe nails (10, 58). Proximal subungual onychomy-
cosis has been considered as an indication of HIV
infection. However, transplant recipients, individ-
uals on immunosuppressive treatments and indi-
viduals with defective polymorphonuclear
chemotaxis may exhibit a similar type of infection.
Trichophyton rubrum is the causative fungus in most
cases, except for cases of superficial white ony-
chomycosis, usually caused by T. mentagrophytes
(34, 43, 44, 59, 60).
Diabetes
Approximately 34% of diabetics have onychomy-
cosis (61, 62) and they are almost three times more
likely to develop onychomycosis than non-diabe-
tics (63). Diabetics may have increased difficulty in
doing regular foot check-ups due to obesity or
complications of diabetes such as retinopathy
and or cataracts (64). This may contribute to dia-betics (typically with poor circulation of the lower
extremities, neuropathy and impaired wound
healing) having a generally higher risk of devel-
oping complications from onychomycosis (63).
Diseased nails, with thick sharp edges, can injure
the surrounding skin tissue and result in pressure
erosion of the nail bed, injuries that may go
unnoticed in diabetics due to sensory neuropathy
(62). The injury may act as an entry point for
bacteria, fungi or other pathogens, leading to
limb-threatening complications or even possible
amputation of the lower extremities.
Peripheral vascular disease
The prevalence of onychomycosis in subjects with
peripheral vascular disease was estimated to be
36%, with T. rubrum as the most common pathogen
(8, 65). Increased propensity to develop onycho-
mycosis in elderly and diabetic patients is partly
attributed to the increased prevalence of peripheral
vascular disease (65). Impaired perfusion of the
lower extremities results in suboptimal oxygena-
tion and reduced metabolic exchange of nutrients
and other substances in the foot. This may result in
the instigation and progression of onychomycosis,
also hindering nail growth, delaying preventingthe clearance of infection and exposing the subject
to re-infection (34, 43, 60).
NAIL ANATOMY AND PHYSICAL
CHARACTERISTICS
Anatomical structures of the nail unit are shown in
Fig. 1. The nail unit is formed continually from the
nail matrix in a linear direction, with a minor
contribution from the nail bed (46, 66). The hypo-
nychium refers to the junction between the free
edge of the nail plate and the end of the nail bed. It
mainly acts as a protective barrier, stopping the
entry of infectious pathogens to the distal end of
the nail plate. The nail plate is about 0510 mm inthickness, and it consists of dorsal, intermediate
and ventral layers. The dorsal nail plate mainly
comprises hard keratin. The middle nail plate is
also comprised of hard keratin and makes up three-
quarters of the total nail thickness. The ventral nail
plate is made up of soft hyponychial keratin and
typically contains 12 cell layers (46, 66, 67). The
nail plate originates from the matrix and the white
crescent-shaped distal end of the matrix is referred
Fig. 1. Anatomy of the human nail unit (lateral and
dorsal view).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
500 J. Thomas et al.
to as the lunula. The nail bed mainly consists of
epithelial cells and it extends proximally from the
edge of the lunula distally to the hyponychium (46,
67, 68).
The fingernails grow at an average rate of 3 mm
per month whereas toenails grow only about 1 mm
per month. Growth rate depends upon the prolif-
erative capacity of the metabolically active matrix
cells (46, 66, 69). Conditions favouring the growth
of the human nail plate include pregnancy, warmer
temperatures, male gender and minor injuries to
the nail plate. Some medications found to acceler-
ate the growth of the human nail plate include
calcium vitamin D, levodopa, retinoids, oral con-traceptives and antifungal agents such as fluco-
nazole, itraconazole and terbinafine (6973). Drugs
known to enhance nail growth could potentially be
used as an adjuvant treatment modality for the
management of onychomycosis.
The human nail plate behaves like a concentrated
hydrophilic-gel membrane, with nail layers pos-
sessing different barrier properties (68). The dorsal
nail plate appears to be the main barrier to drug
penetration. The lipid content in the nail plate is
relatively low compared to that of the skin (68). Poor
permeation of drugs across the nail plate necessitates
long duration of therapy to maintain the effective
drug concentration in the nail plate. Poor drug per-
meation probably contributes to the mediocre ther-
apeutic success of conventional topical antifungal
therapies for onychomycosis treatment (2).
MORPHOLOGY AND CLINICAL
PRESENTATION
Based on the mode and site of fungal invasion of the
diseased nail plate, five categories of onychomycosis
have been established: distal and lateral subungual,
superficial white, proximal subungual, endonyx
and total dystrophic onychomycoses (46, 74).
Distolateral onychomycosis
Distolateral subungual onychomycosis is the most
common form of onychomycosis. Infection pro-
gresses mainly to the matrix from the distal to the
proximal, through the distal-lateral margins or via
the lateral groove of the nail plate, beginning at the
hyponychium. The infection is typically caused by
Trichophyton spp. and occasionally by Scytalidium
spp., Candida spp. and other non-dermatophytes (3,
43, 74, 75). Mild infection (paronychia) normally
develops, resulting in subungual hyperkeratosis,
onycholysis (detachment of nail plate from the nail
bed) and nail thickening. The subungual space may
serve as a base for infectious bacteria and fungi,
causing a yellowish discolouration of the nail plate
(4, 46, 76, 77).
Proximal subungual onychomycosis
Proximal subungual onychomycosis is a less com-
mon form, but it is more common in AIDS patients
and subjects who are otherwise immunocompro-
mised (5, 20, 77). It is considered an early clinical
marker of HIV infection. The chief aetiological
agents associated with infection are T. rubrum,
C. albicans, Fusarium spp., Aspergillus spp. and
Scopulariopsis brevicaulis. In this clinical manifesta-
tion of onychomycosis, fungi invade the area under
the nail cuticle, leading to infection of the proximal
nail plate. This infection proliferates distally within
the nail plate (2, 3, 8, 46, 67, 75).
Superficial white onychomycosis
Superficial white onychomycosis involves the
infection of the dorsal surface of the nail plate (9,
78). It is present as opaque white patches distrib-
uted across the dorsal surface. Trichophyton ment-
agrophytes and T. rubrum are the key pathogens
involved with this infection. However, several non-
dermatophyte moulds, including Fusarium spp.,
Acremonium spp., Aspergillus spp., have also been
isolated, with the fungal elements mainly located in
the upper layers of the nail keratin (7, 8, 43, 74, 79).
Endonyx onychomycosis
Endonyx onychomycosis is a newly-described form
of onychomycosis. It involves fungal invasion of
the superficial nail surface as well as deeper pen-
etration of the nail plate (75, 77). Nail thickening,
lifting and inflammatory changes are found to be
absent in this pattern of onychomycosis. This type
of fungal invasion is mainly caused by T. soudan-
ense and T. violaceum. Lamellar splitting, coarse
pitting and milky white patches within the affected
nail plates are the key features of this fungal nail
infection (67, 80, 81).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 501
Total dystrophic onychomycosis
Total dystrophic onychomycosis is an end stage of
any type of longstanding onychomycosis. Mostly it
appears with (nearly) complete destruction of the
infected nail plate (2). Typically, two subtypes of
this form of onychomycosis are reported, primary
and secondary total dystrophic onychomycosis.
Primary total dystrophic onychomycosis mostly
occurs in patients with chronic mucocutaneous
candidiasis (4, 76).
DIAGNOSIS OF ONYCHOMYCOSIS
The accurate diagnosis of onychomycosis is
important for its successful treatment. The cost and
long duration of the therapy, the risk of developing
adverse drug reactions, and possible interactions
with concomitant medications all underline the
importance of accurate diagnosis of the condition
before commencing therapy (7, 74, 80, 8285).
Accurate diagnosis based on the clinical symptoms
alone is often difficult. Tinea pedis and tinea
mannum often occur concomitantly with onycho-
mycosis (10, 13, 36). The presence of these condi-
tions may offer useful clinical evidence for the
diagnosis of onychomycosis. Currently, the diag-
nosis of onychomycosis is confirmed by clinical
examination and screening of the collected nail
specimen by direct microscopy and fungal culture
(5, 8, 46, 60, 67, 76, 86).
Apparently 50% of nail disorders that are
believed to be onychomycosis are in fact other
types of nail disorders (67). It is recommended that
care should be taken to correctly identify the signs
and symptoms of onychomycosis from other clin-
ical conditions that clinically mimic onychomyco-
sis, such as psoriasis of the nail, eczema, bacterial
infections, contact dermatitis, traumatic onych-
odystrophies, chronic onycholysis, lichen planus,
chronic paronychia, haemorrhage or trauma, ony-
chogryphosis, median canalicular dystrophy, pin-
cer nail, yellow nail syndrome, subungual
malignant melanoma and subungual squamous
cell carcinoma (10, 46, 67, 8790).
It is often difficult to differentiate the clinical
manifestations of nail psoriasis from onychomy-
cosis. Both dermatological conditions can result in
morphological changes of the nail plate that
include subungual hyperkeratosis, onycholysis,
leukonychia, splinter haemorrhages and dystrophy
(46, 91). Involvement of psoriasis can be diagnosed
by pitting of the nail plate; however, alopecia are-
ata and chronic paronychia can also be associated
with nail pitting. In nail psoriasis small, irregular,
salmon-coloured, visible oil drops can be found on
the nail plate. This phenomenon is not normally
associated with onychomycosis (15, 36, 57). Both
onychomycosis and psoriasis can co-exist in the
same nail plate. It has been observed that onycho-
mycosis is often found to be more common in
psoriasis subjects than in the rest of the population,
with an estimated prevalence of 1322%. Histo-
pathological examination of the nail plate is rec-
ommended for the confirmation of nail psoriasis in
the absence of skin lesions (10, 46, 67, 87, 90, 91).
Other dystrophic nail conditions mimicking
onychomycosis are Dariers disease, lichen planus
and ichthyotic conditions such as keratosis, ich-
thyosis and deafness syndrome. Approximately
10% of the subjects infected with lichen planus
have abnormal nails, but in the majority of cases it
is associated with clinical signs such as thinning of
the nail plate, subungual hyperkeratosis, onychol-
ysis and dorsal pterygium (15, 36, 57). Often yellow
nail syndrome is falsely identified as a fungal
infection. Light green-yellowish pigmentation of
the nail plate, hardness and its elevated longitudi-
nal curvature are the key clinical characteristics of
this nail disease (10, 46, 67, 87, 90).
Repetitive trauma to the nail plate can also result
in the abnormal appearance of nails. It can result in
distal onycholysis leading to the colonization of the
affected space by infectious pathogens and the
discolouration of the nail plate. A clipping of the
infected nail area followed by the examination of
the nail bed will help to differentiate between nail
trauma and onychomycosis. The nail bed will
appear normal if the symptoms are caused by
trauma rather than onychomycosis (10, 46, 67, 90).
WHY DOES ONYCHOMYCOSIS NEED TO BE
TREATED?
Clinical issues
Onychomycosis can become a source of infectious
fungal bacterial lesions in other parts of the body(92). In addition, the presence of sensitizing fun-
gal dermatophytic antigens in the nail plate may
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
502 J. Thomas et al.
predispose to other clinical conditions in onycho-
mycosis subjects. These include asthma sensitiza-tion of the respiratory tract and skin conditions,
such as atopic dermatitis, urticaria and erythema
nodosum (92). In diabetics, onychomycosis and
dermatomycoses can complicate foot problems,
and can lead to ulceration. These wounds may
consequently lead to osteomyelitis, cellulitis and
tissue necrosis and may result in lower extremity
amputation (1, 51, 93). It was estimated that around
240 million people around the world had diabetes
in 2007 and that this could increase to 333 million
by 2025 (94). Approximately 34% of the diabetic
population has onychomycosis (61, 62). Diabetic
individuals are almost 3-fold more likely to
develop onychomycosis than non-diabetics and
have a higher propensity to develop dermatophytic
infections (15, 63).
Quality-of-life issues
Onychomycosis has a significant impact on
patients quality of life (QoL) (1, 2). Approximately
half of all patients with onychomycosis experience
pain or other types of discomfort with reduced
quality of life. Onychomycosis has been found to
affect the physical, functional, psychosocial and
emotional aspects of life (7, 95). About 30% of the
patient population have difficulty in wearing
footwear (20). Although it is not a life-threatening
condition, many important functional purposes of
the nails may be severely compromised. Difficulty
in walking, emotional embarrassment and work-
related difficulties are the most commonly-repor-
ted issues. However, severe cases appear to even
have a negative influence on patients sex lives, and
the self-esteem of female subjects has been found to
be significantly affected due to the unsightly and
contagious-looking nail plate (20, 96). Socks and
stockings may frequently be damaged, due to the
constant friction with sharp, dystrophic diseased
nails in patients with onychomycosis and this may
result in increased financial expenditure (97, 98).
TREATMENT
It is important to consider several factors before
starting antifungal therapy. The severity of ony-
chomycosis, the number and location of nails
affected, causative fungi, concomitant drugs,
antifungal resistance, treatment cost and
patient physician preference, must be reviewedbefore commencing the treatment regimen. In
general, treatment modalities for onychomycosis
include oral, topical, mechanical and chemical, or a
combination of these options (7, 10, 99, 100).
Mechanical
Nail filing, trimming, curettage and debridement
have been found to have a key role and are sig-
nificant adjuvants to topical and oral treatments.
These often make the nail thin, decrease the fungal
burden, improve the penetration of topical drugs,
prevent ulcerations trauma caused by footwear orclothing in patients with diabetes and, above all,
can provide a better cosmetic result. In clinical
cases when patients present with dermatophytoma
(abnormal nails with clumps of dermatophyte
hyphae) on the nail plate, the penetration of anti-
fungals can be difficult (101, 102). Increased pen-
etration of antifungal drugs through the nail plate,
following debridement, is more likely to produce
optimal therapeutic results. Debridement alone is
very unlikely to cure onychomycosis, whereas
debridement of the infected nail by a trained
healthcare professional, along with antifungal
therapy, may be helpful in its management (15,
20).
Total or partial surgical nail avulsion is a dif-
ferent strategy to remove the affected nail(s).
Because the complete removal of the nail plate
allows the distal soft tissue to expand and pro-
motes ingrown nails, partial nail avulsion is pre-
ferred over total nail avulsion (4, 99, 103, 104).
Chemical treatment
Chemical avulsion, similar to mechanical debride-
ment, is generally employed as an adjunct to oral or
topical therapy. It is a painless method of removing
the diseased section of the nail plate. Often, how-
ever, the surrounding skin becomes irritated fol-
lowing this procedure. Chemical avulsion is
normally performed with 40% urea paste, com-
bined with 2% tolnaftate or 1% bifonazole. This is
applied to the nail plate, which is then bandaged
for a week. Complete chemical avulsion is per-
formed only in patients with onychogryphosis (7,
76, 99, 103).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 503
Oral antifungal agents
Oral antifungal agents are considered to be the
most effective agents among the various treatment
options currently available for the management of
onychomycosis (1, 99). Before commencing ther-
apy, it is highly recommended to consider any
concomitant medications and the patients prefer-
ence, especially when treating persons who have
diabetes mellitus, liver disease or are immuno-
compromised (7, 105). Although ketoconazole and
fluconazole are often prescribed for the treatment
of onychomycosis, only griseofulvin, itraconazole
and terbinafine are approved by the US Food and
Drug Administration (FDA) and currently licensed
for the treatment of this condition in the United
States and United Kingdom (1, 4, 7, 44, 51, 82, 99,
100, 104106).
First-line onychomycosis management strategies
include oral administration of terbinafine, itraco-
nazole or fluconazole (Fig. 2). The use of ketoco-
nazole should be discouraged due to its potential
hepatotoxicity. Griseofulvin is no longer widely
used because it needs a longer duration of treat-
ment and has been associated with high relapse
rates (107). A cumulative meta-analysis reported
mycological cure rates (range) of oral antifungal
agents in onychomycosis treatment for terbinafine
Negative culture/Biopsy
Positive culture/Biopsy of the nail specimen
First line therapyoral medications
Itraconazole
Standard treatment: 200 mg/d 12 weeks
Pulse treatment: 200 mg twice-daily 1 week/month 23 pulses2 pulses for fingernailsand 3 for toenails
Fluconazole
150300 mg/week 1248weeks
Topical therapy: in mild to moderate cases of distal or superficial onychomycosis
Amorolfine
Once weekly 48 weeks
File down infected nailsonce a week
Treatment follow-up at 40 4 weeks Positive culture/ Biopsy of
the nail specimen
Clinical examination and diagnosis
Symptomatic treatment of the nail dystrophy/infection
Patient presents to a healthcare setting
Mycological cure Prophylactic topical treatment Patient education to prevent disease recurrence
Terbinafine
Child
Table
2.
Aco
mp
aris
on
of
effi
cacy
of
anti
fun
gal
dru
gs
use
din
the
trea
tmen
to
fo
ny
cho
my
cosi
s
Stu
dy
Tre
atm
ent
reg
imen
(mgd
ay)
Len
gth
of
trea
tmen
t
Len
gth
of
foll
ow
-up
My
colo
gic
al
cure
Rel
apse
rate
a
Gri
seo
fulv
in
(Ko
rtin
get
al.
1993
)(1
58)
990
(UM
SG
)b78
wee
ks
77w
eek
s23
6(6%
)
660
(UM
SG
)78
wee
ks
77w
eek
s23
6(6%
)
(Fae
rgem
annet
al.
1995
)(1
59)
500
52w
eek
s52
wee
ks
194
1(4
6%)
(Vil
lars
and
Jon
es19
92)
(160
)40
%
(Sal
goet
al.
2003
)(2
0)50
%
Ter
bin
afin
e
(Gal
imb
ertiet
al.
1996
)(1
61)
250
12w
eek
s36
wee
ks
192
2(8
2%)
(Dra
keet
al.
1997
)(1
62)
250
12w
eek
s48
wee
ks
1241
42(8
7%)
(Go
od
fiel
det
al.
1992
)(1
63)
250
12w
eek
s36
wee
ks
374
5(8
2%)
(Sig
urg
eirs
sonet
al.
2006
)(1
64)
250
12w
eek
s48
wee
ks
2263
90(5
8%)
350
(2w
eek
s
3p
uls
es)
12w
eek
s48
wee
ks
1603
74(4
3%)
(Hei
kk
ila
and
Stu
bb
2002
)(1
20)
250
12w
eek
s4
yea
rs92
0(4
5%)
250
16w
eek
s4
yea
rs11
7(6%
)
Itra
con
azo
le
(Ev
ans
and
Sig
urg
eirs
son
1999
(119
)
400
(1w
eek
s
3p
uls
es)
12w
eek
s72
wee
ks
411
07(3
8%)
(De
Bac
ker
etal.
1996
)(1
65)
200
12w
eek
s48
wee
ks
771
68(4
6%)
(Sch
emer
etal.
1999
)(16
6)20
016
wee
ks
48w
eek
s11
16
(68%
)
200
(1w
eek
s
3p
uls
es)
16w
eek
s48
wee
ks
81
6(6
0%)
200
16w
eek
s48
wee
ks
101
6(6
3%)
200
(1w
eek
s
4p
uls
es)
16w
eek
s48
wee
ks
101
6(6
3%)
(Sig
urg
eirs
sonet
al.
2002
)(1
67)
400
(1w
eek
s
34
pu
lses
)12
16
wee
ks
45
yea
rs17
32
(53%
)
(Hei
kk
ila
and
Stu
bb
2002
)(1
20)
400
(1w
eek
s
3p
uls
es)
12w
eek
s4
yea
rs13
18
(72%
)
400
(1w
eek
s
4p
uls
es)
16w
eek
s4
yea
rs11
17
(65%
)
(De
Cu
yp
eran
dH
ind
ryck
x19
99)
(168
)20
012
wee
ks
2y
ears
66
(100
%)
Flu
con
azo
le
(Hav
uet
al.
2000
)(1
69)
150c
24w
eek
s60
wee
ks
204
1(4
9%)
(Lin
get
al.
1998
)(1
70)
450c
24w
eek
s12
wee
ks
287
8(3
6%)
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 505
(mean SEM) of (78 6 to 76 3%), fluconazole
(53 6 to 48 5%), griseofulvin (55 8 to
60 6%), itraconazole continuous (63 5 to 59
5%) and itraconazole pulse (75 10 to 63 7%)
(108). Terbinafine, followed by itraconazole, have
been recommended as the drugs of choice for the
treatment of dermatophytic toenail onychomycosis.
Terbinafine and itraconazole have better cure rates
than other antifungal agents (Table 2). Fluconazole
is recommended as the first choice for the treat-
ment of candidal onychomycosis (76). The long-
term results (Table 2) from follow-up studies sug-
gest that the current antifungal interventions are
inefficient for the long-term management eradica-tion of the infection (102120). Larger follow-up
studies (45 years) must draw a clearer picture of
long-term patient outcomes (121123).
Griseofulvin
Griseofulvin was the first oral antifungal drug
approved for the treatment of onychomycosis. It
exhibits a fungi-static mode of action by interacting
with microtubule-associated proteins and results in
the inhibition of fungal cell division (9, 99, 109).
The antifungal efficacy of griseofulvin is mainly
limited to dermatophytes (10). Its utility for the
treatment of dermatophytic onychomycosis is lim-
ited by its long treatment duration, high dose
requirement (1000 mg day) and high relapse rates(approximately 50%) (7, 46). Administration of a
high dose of griseofulvin over a long period of time
is known to cause adverse drug reactions in
patients, including gastrointestinal disturbances,
photosensitivity, skin rashes, headache, fatigue,
urticaria and hepatotoxicity (9, 20, 51, 99, 105, 106,
110). The use of griseofulvin for the management of
onychomycosis has decreased since the arrival of
newer broad spectrum antifungal drugs (106).
Azoles (imidazoles and triazoles)
From the mid 1940s the azole family of antifungal
agents became an essential tool in the management
of invasive fungal infections (111). Azoles used
to treat onychomycosis include ketoconazole, itra-
conazole and fluconazole. Azoles impair fungal
cell wall synthesis by inhibiting the cytochrome
P-450 (CYP) enzyme lanosterol 14-a-demethylase,inhibiting the conversion of lanosterol to ergosterolT
able
2.
(Co
nti
nu
ed)
Stu
dy
Tre
atm
ent
reg
imen
(mgd
ay)
Len
gth
of
trea
tmen
t
Len
gth
of
foll
ow
-up
My
colo
gic
al
cure
Rel
apse
rate
a
450c
36w
eek
s12
wee
ks
408
5(5
9%)
450c
36w
eek
s24
wee
ks
52
0(2
5%)
Am
oro
lfin
e5%
lacq
uer
(Lau
har
anta
1992
)(1
24)
On
cew
eek
lyd
24w
eek
s12
wee
ks
60%
(Rei
nel
etal.
1993
)(1
27)
On
cew
eek
lyd
24w
eek
s12
wee
ks
71%
Cic
lop
iro
x3%
lacq
uer
(Gu
pta
and
Jose
ph
2000
)(1
30)
On
ced
aily
48w
eek
s34
%
(Gu
pta
etal.
2000
)(1
31)
On
ced
aily
48w
eek
s36
%
aM
yco
log
ical
rela
pse
.bU
ltra
mic
rosi
zeg
rise
ofu
lvin
.c P
resc
rib
edd
ose
per
wee
ks.
dT
op
ical
ther
apy
,d
ose
dep
end
so
nth
ein
fect
edn
ail
area
.
Mo
difi
edfr
om
(155
,17
1,17
2).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
506 J. Thomas et al.
(99). This leads to increased fungal cell permeabil-
ity and cessation of fungal cell division and
growth. They are fungistatic, not fungicidal, except
at very high concentrations. They have a broad
spectrum activity against fungi, including derma-
tophytes, yeasts and other fungi (109, 112).
Ketoconazole was approved by the FDA in 1981.
Originally, it was used for the systemic treatment
of onychomycoses and other forms of tinea, with
cure rates similar to those seen with griseofulvin.
Since drug-induced hepatitis caused some fatali-
ties, systemic ketoconazole is no longer routinely
recommended for the management of onychomy-
cosis due to its potential hepatotoxicity and
because of the availability of more efficacious and
safer antifungal therapeutic options (3, 46, 106,
113).
Fluconazole
Fluconazole is not approved for the treatment of
onychomycosis in the United States; however, it is
licensed in many other countries. Because of its
long plasma half-life (between 20 and 50 h), it can
be given at 24 h or even longer intervals. Flucona-
zole can be detected in the body even up to
5 months after cessation of oral therapy (7). For the
management of onychomycosis, pulse therapy
with 150, 300 or 450 mg once a week is recom-
mended for up to 12 months (9, 110). In vitro data
show high activity against dermatophytes and
yeasts (103). Adverse drug reactions reported
include mostly mild gastrointestinal disturbances,
skin rashes, headache and insomnia (110, 114). At
present, no guidelines are available regarding
obtaining laboratory tests when this drug is pre-
scribed. However, the manufacturers suggest a
liver function test prior to the commencement of
therapy and at regular intervals, depending on the
dose and duration of treatment (5, 7, 9, 46, 99, 105,
106, 110, 114).
Itraconazole
Itraconazole was the first systemic antifungal agent
approved for the treatment of onychomycosis (1). It
is mainly fungistatic. In vitro data demonstrate its
broad spectrum of activity against dermatophytes
and yeasts, as well as other moulds (103, 115). It has
high affinity for keratinized tissues, resulting in
tissue levels higher than that of plasma levels (9).
When oral itraconazole is administered at a dose of
100 or 200 mg day, it remains in the lipophiliccytoplasm of keratinocytes in the nail plates, and
builds up in the nail plate after about 3 months of
therapy, eliciting a drug reservoir effect lasting up
to 7 months after discontinuation of therapy (106).
This facilitates the briefer duration of itraconazole
therapy for the management of onychomycosis (1,
106, 116). For the management of onychomycosis,
itraconazole is generally given as a continuous
dose (200 mg daily) for 3 months or pulse therapy(200 mg twice daily) for the first week only of each
month for 3 months. Typically, two pulse treat-
ments are recommended for fingernail infections
and three pulse treatments for toenail infections
(110). It is metabolized by the liver and many early
studies have highlighted the hepatic toxicity of
itraconazole (115, 117). The manufacturers advise
monitoring liver function in patients receiving
continuous itraconazole for more than 1 month or
at anytime if symptoms of hepatic dysfunction
develop (5, 7, 9, 20, 38, 46, 99, 106, 110, 118).
Terbinafine
Terbinafine is the drug of choice for the manage-
ment of onychomycosis. Terbinafine was the first
oral synthetic alkylamine approved for the treat-
ment of onychomycosis (99, 103). It exhibits mainly
a fungicidal mode of action, by inhibiting fungal
ergosterol synthesis at the squalene epoxidation
stage, leading to membrane disruption and
destruction of the fungal cell wall (106). In vitro
data suggest its fungicidal activity against derma-
tophytes. However, it is fungistatic against yeasts
and moulds such as Aspergillus fumigatus and
Scopulariopsis brevicaulis (99, 103). Studies have
demonstrated its higher cure rates compared with
itraconazole for the treatment of onychomycosis
(119, 120). Pharmacokinetic data have shown that
terbinafine accumulates in adipose tissue and
provides a drug depot effect. Within 24 h of the
first dose, terbinafine appears in the stratum
corneum and maintains a therapeutically active
drug concentration in the nails. The mean active
drug concentration persists in the body up to
3 months after termination of oral therapy (103).
For the treatment of toenail onychomycosis, a
dose of 250 mg daily for 12 or more weeks is
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 507
recommended (110). The most commonly reported
side effects are nausea, vomiting and other gas-
trointestinal side effects. Other side effects include
taste disturbances and hair loss. Due to potential
terbinafine-induced hepatotoxicity, manufacturers
suggest performing liver function tests for patients
before commencing therapy and after 46 weeks of
therapy (5, 7, 9, 20, 38, 46, 99, 106, 110).
Topical antifungal agents
In the early days of disease management, topical
ointments and disinfectants were used to treat
onychomycosis (2). Earlier treatment options had
poor pharmaceutical properties and a non-specific
spectrum of action and consequently had mediocre
therapeutic outcomes (2, 121). Several studies
investigated the usefulness of topical lacquers for
the management of onychomycosis (124) and
demonstrated mycological cure and clinical
improvement (Table 2) (4, 99, 121). However, it is
fairly difficult to draw constructive comparisons
with those results obtained from the systemic
therapies. Currently, topical treatment options are
only advocated for the management of superficial
white onychomycosis and in very early cases of
distolateral onychomycosis, where the infection is
limited to the distal edge of the nail plate or in
cases where patients are restricted from using oral
antifungal medications (107).
Newer antifungal topical agents have been for-
mulated to deliver better penetration into the nail
unit, increasing their therapeutic effectiveness. The
latest developments in topical onychomycosis
therapy are ciclopirox and amorolfine nail lacquers.
The different formulation excipients in the lacquer,
such as solvents, polymers and plasticizers, facili-
tate the maintenance of an increased concentration
of the active drug moiety in the nail plate (99).
Upon application of the lacquer formulation, after
the evaporation of the solvent, the concentration of
ciclopirox and amorolfine in the lacquer film resi-
due rises to 35% and 25%, respectively (122, 123).
The residual lacquer film acts as a drug reservoir
and allows the active ingredient to remain in con-
tact with the diseased nail plate for a longer period
of time, increasing the potential for better treatment
outcome. The residual lacquer film, furthermore,
enhances the hydration of the nail plate and
amplifies the diffusion of the active drug through
the diseased nail plate (2, 9, 44, 82, 100, 104, 122,
123).
Amorolfine
Amorolfine is a phenyl-propyl morpholine deriv-
ative, is licensed for the management of onycho-
mycosis in Australia, the United Kingdom,
Germany, France, Italy and some other countries,
but not in the United States (125). Similar to other
antifungal agents, amorolfine interferes with the
ergosterol biosynthesis pathway, inhibiting the D14-reductase and D7-8-isomerase enzymes. Inhibitionof these enzymes impairs cellular growth and
membrane function and causes cell death (7, 99,
110, 126). It has a broad spectrum antimycotic
action against dermatophytes (Trichophyton, Mi-
crosporum and Epidermophyton species), and yeasts
(Candida, Cryptococcus and Malassezia species) (9,
122). Application is recommended once or twice
weekly until the nail re-grows. This usually
requires 6 months for fingernails and 12 months
for toenails. It is advised to file down and thor-
oughly degrease the nails before applying the lac-
quer. The treatment is generally well tolerated with
the development of chromonychia in rare cases,
presumably due to the oxidation of formulation
excipients (9). It is reported that amorolfine pene-
trates into the subungual debris and maintains
effective active drug concentrations even 2 weeks
after cessation of application (2, 5, 9). The efficacy
of amorolfine for the management of onychomy-
cosis (Table 2) has been previously reported (117,
118). Amorolfine (5% once weekly lacquer for up to
24 weeks) is reported to have 6071% mycological
cure rates in randomized clinical studies, for the
management of onychomycosis (124, 127).
Ciclopirox
Ciclopirox 8% nail lacquer is the only nail lacquer
approved by the FDA for the treatment of ony-
chomycosis in the United States (122). Ciclopirox is
approved in more than 40 countries worldwide
and the efficacy of ciclopirox nail lacquer (8%) in
the management of onychomycosis has been
reported in various randomized controlled trials
(Table 2) (99, 117, 118). It is a synthetic hydroxy-
pyridone derivative that carries broad-spectrum
fungistatic and fungicidal activity. It has been
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
508 J. Thomas et al.
suggested that its antifungal action is due to the
chelation of polyvalent cations (Fe3+ or Al3+),
leading to the inhibition of metal dependent
enzymes (cytochromes) that degrade toxic perox-
ides within the fungal cell (122, 128). At higher
concentration, ciclopirox subdues the cellular
uptake of essential compounds and impairs the
fungal cell membrane resulting in the leakage of
potassium ions and other intracellular material
(129). It has in vitro activity against dermatophytes
(Trichophyton species, Microsporum species, Epi-
dermophyton floccosum), yeasts (Candida species,
Malassezia species, Cryptococcus neoformans) and
various other fungi including Aspergillus species,
Penicillum species and Fusarium species (122). In
common with amorolfine, treatment guidelines
recommend that a healthcare professional debride
and trim the diseased nails to improve the thera-
peutic outcomes. In practice, patients are often
trained to debride the nail bed themselves (2). The
most commonly reported side effects include irri-
tation, a burning sensation and pruritis (2, 5, 9).
Mycological cure rates ranging from 29% to 36%
for ciclopirox 8% (applied once daily for up to
48 weeks) have been reported (130, 131).
ADJUVANT INTERVENTION OPTIONS
Combination therapy for the management of ony-
chomycosis is a relatively new concept. It includes
the combination of oral and topical antifungal
therapy. Many authors have reported distinct
improvement of mycological and clinical outcomes
associated with the combination approach (97, 132
135). Combination therapy benefits from synergic
effects of the antifungal drugs and consequently
brings out increased therapeutic effects in a more
rapid fashion (132). Furthermore, combination
therapy amplifies the in vivo fungicidal action,
minimizes the emergence of antifungal resistance,
shortens the length of therapy, extends the spec-
trum of activity and reduces the dose of the sys-
temic antifungal drug, thereby diminishing the
potential for toxicity (58). A combination approach
is recommended by Baran (2008) for non-
responders to topical therapy after a treatment
period of 6 months. An oral medication is com-
bined with the topical treatment. However, based
on the prognostic factors, the combination
approach should be considered as a first-line ther-
apy when there is a high likelihood of treatment
failure (58). Combining topical and oral antifungal
treatments could provide a dual front to success-
fully countering the invasive fungal siege on nails
while providing high antifungal concentrations
across the nail unit (88). Complementary drug
penetration is the key motivation behind combin-
ing oral and topical treatments (136).
Ciclopirox and terbinafine
A randomized, evaluator-blinded, multicentre
study reported mycological cure rates of 667%for combination therapy (n = 21) (terbinafine
250 mg daily for 14 weeks and 912 weeks, plusdaily application of ciclopirox nail lacquer for
48 weeks) which was better than the cure rates of
560% following monotherapy (n = 25) (terbinafine250 mg daily for weeks 112) (136).
An Israeli open label randomized trial reported
better mycological cure rates for the combination
therapy regimen (n = 34) (terbinafine 250 mg dailyfor 16 weeks plus ciclopirox 8% once daily for
9 months; 882%) compared with monotherapy(n = 34) (terbinafine 250 mg for 16 weeks, 647%)(137).
Terbinafine and ciclopirox or amorolfine
A recent Indian study assessed the efficacy of oral
terbinafine as a monotherapy and in combination
with ciclopirox 8% or amorolfine 5% topical nail
lacquers. The three treatment groups [A: mono-
therapy (n = 48); terbinafine 250 mg twice daily forthe first 7 days of every month for 4 months; B:
combination therapy (n = 24); terbinafine regimen
plus ciclopirox 8% once daily therapy for 4 months;
C: combination therapy (n = 24); terbinafine regi-
men plus amorolfine once weekly for 4 months]
demonstrated comparable mycological cure rates: A
(826%), B (833%) and C (700%). Combinationtherapy with topical ciclopirox or amorolfine did not
reveal any significant (P > 005) difference in efficacycompared with the terbinafine monotherapy (138).
Amorolfine and terbinafine
A multicentre randomized, parallel group trial
investigated the efficacy of two different courses of
terbinafine combined with amorolfine [A: amorol-
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 509
fine 250 mg daily for 6 weeks plus amorolfine 5%once weekly for 15 months (n = 50); B: amorolfine
250 mg daily for 12 weeks plus 5% once weeklyfor 15 months (n = 47)] in comparison with terbi-
nafine alone [C: terbinafine 250 mg daily for12 weeks (n = 48)]. Two of the combined treatment
regimens [A (750%) and B (900%)] demonstratedimproved mycological cure rates compared with
the systemic treatment alone [C (680%)], withamorolfine-terbinafine 12 weeks therapy showing
the highest mycological cure rates (134).
Amorolfine and itraconazole
Lecha (2001) reported the efficacy of two alterna-
tive regimens of amorolfine-itraconazole therapies
[A: itraconazole 200 mg daily for 6 weeks plusamorolfine 5% lacquer for 24 weeks, (n = 40); B:
itraconazole 200 mg daily for 12 weeks plusamorolfine 5% lacquer for 24 weeks (n = 33)],
compared with itraconazole monotherapy [C:
itraconazole 200 mg daily for 12 weeks (n = 32)].Both combination treatment groups evidenced
significantly (P < 005) higher mycological curerates [A (914%); B (972%) compared with mono-therapy C (680%)] (135).
Amorolfine and fluconazole
In vitro screening results suggest a potential synergy
with amorolfinefluconazole combination when
tested against pathogens that are frequently repor-
ted as causative agents for onychomycosis (139).
Boosted antifungal therapy
Boosted antifungal therapy (boosted oral and top-
ical therapy) has been proposed as an effective tool
to achieve better therapeutic success in non-
responsive onychomycosis cases. The BOAT
(boosted oral antifungal treatment) and BATT
(boosted antifungal topical treatment) approaches
include application of a piece of SDA (Sabourauds
dextrose agar) to the nail in conjunction with
oral topical antifungal therapy. The resting fungalelements or spores in the nail plate, that are more
resistant to antifungal agents than active fungi,
contribute partly to treatment failure and infection
recurrence. Boosted treatment interventions may
boost the maturation of fungal conidia to hyphae
and increase the antifungal drugs efficacy by
enhancing fungal susceptibility (140). Typically, an
SDA portion is maintained on the nail plate for
1 week during topical therapy and for approxi-
mately 48 h in oral therapy. Pilot investigations of
BOAT therapy (90% cure, n = 10) and BATT ther-
apy (85% cure, n = 13) suggest a promising treat-
ment option for the management of onychomycosis
in chronic and difficult-to-treat cases (141, 142).
Other novel approaches for the treatment of
onychomycosis include creating tiny holes in the
nail plate to facilitate its penetration by drugs.
Another approach involves the use of a short
wavelength light to disrupt the growth and repro-
duction of light-averse fungi in the diseased nail
plate (143).
COMPLIANCE
Patient compliance is an extremely important fac-
tor to achieve optimal therapeutic success in anti-
fungal therapy (144). Prolonged treatment is
required to achieve disease-free nails in individuals
with onychomycosis and this often leads to com-
pliance problems (46). Management of onychomy-
cosis in special patient populations such as
children, elderly and immunocompromised indi-
viduals can be difficult due to poor compliance
(100). The previously reported key determinants of
patient compliance with oral antifungal medica-
tions in onychomycosis treatment are: duration of
therapy, ease of swallowing, frequency of daily
intake and the number of oral drugs per intake
(145). Intermittent antifungal regimens were found
to have better acceptance over continuous thera-
pies. This is due to a shorter treatment duration,
fewer tablets, fewer adverse reactions and cost
effectiveness (145). There is little information
available in the literature describing patient com-
pliance with antifungal agents used for the treat-
ment of onychomycosis. The authors of a study
conducted in China found an overall compliance
rate of about 45% for oral antifungal agents (inter-
mittent pulse itraconazole, intermittent terbinafine,
continuous terbinafine) (146). The major factors
reported to have a negative influence on compliance
were: adverse effects of the medications (30%),
discontinuation of therapy owing to early detected
progress (22%) and financial constraints (16%)
(146). Patient education is highly important to
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
510 J. Thomas et al.
achieve better therapeutic outcomes for the man-
agement of onychomycosis. Doctors and pharma-
cists should stress the importance of compliance
with the prescribed treatment schedule. A treatment
calendar would be useful to assist patients to com-
ply with the treatment schedule (including dates for
laboratory testing, follow-up visits and also to
record potential adverse drug reactions) (46).
COST OF TREATMENT INTERVENTIONS
Gupta and Lambert summarized the expected cost
(drug acquisition cost, medical management cost
and cost of managing adverse reactions) involved
per patient for mycological cures in the treatment of
pedal onychomycosis (147). The cost of the antifun-
gal regimen was as follows (1999 values): griseoful-
vin US$4917, itraconazole (continuous therapy)
US$2072, itraconazole (pulse therapy) US$1072,
terbinafine US$1042 and fluconazole US$1449 (147).
As the given values are nearly 10 years old, a follow-
up study would be informative.
Topical treatment has been shown to be less
expensive than oral treatments. Marty et al. esti-
mated treatment cost (2005 values) per cure of dif-
ferent antifungal nail lacquers (148). These costs did
not include the diagnostic cost and other medical
management costs associated with the treatment.
Treatment costs for the two widely recommended
nail lacquers were given as: amorolfine (applied
once weekly) 118 patient cured, whereas ciclopi-rox (applied once daily) cost 273 patient cured andit was shown to be more costly than amorolfine (148).
FINANCIAL IMPLICATIONS OF
ONYCHOMYCOSIS
In the majority of cases, foot infections start as a
minor dermatophytic infection. Superficial mycotic
infections can disrupt the skin integrity, thereby
leading to a point of entry for bacterial superin-
fection by Gram-positive cocci such as staphylo-
cocci and streptococci (15). As these complications
can result in hospitalization and even amputations,
prevention of complications and active treatment
of dermatophytic infections are essential. Diabetes
is the most common cause of non-traumatic
amputation in the United States, Australia and
Europe. Moreover, diabetic patients infected with
onychomycosis have a 3-fold higher risk for
developing lower extremity complications such as
foot ulcer and or gangrene compared to diabeticpatients without onychomycosis (149). Among the
120 000 non-traumatic amputations done each year
in the United States, 4583% are due to diabetes
(150, 151). In 2003, $2 billion was spent on lower
extremity (toe, leg and foot) amputations in the
United States, with a total of 112 551 amputations
costing $16 826 procedure (64). In 2001, in theUnited States, about $165 billion was spent on themanagement of diabetes-related lower extremity
amputations (152). In Australia, diabetes-related
foot problems and complications are the major
causes of hospitalizations in people with diabetes,
costing AUS$48 million year (151).The ageing population across the developed
countries is a concern; by 2030, in most of the
advanced economies, the fraction of the population
aged over 65 years will be about 1535% (153).
Approximately 50% of people aged >70 years have
onychomycosis (20, 62, 63). An increased prevalence
of onychomycosis has been observed in industrial-
ized nations during the past few decades. Compar-
ison of results from two US studies revealed a
remarkable increase in onychomycosis (approxi-
mately 6-fold increase between 1979 and 2000) (17,
2731, 33). This is presumably due to the ageing
population, use of immunosuppressant therapies,
involvement in fitness activities and increased use of
conventional occlusive footwear in comparison to
the open-toed type of footwear in third world
nations (4446). An American study illustrates the
potential financial burden of onychomycosis.
Elewski reported that $US43 million (as per 1997
values) was spent on onychomycosis management
over a 1-year period (19891990) on 13 milliontreatment visits by 662 000 subjects, aged > 65 years
(1). In 1999, in the United States approximately
US$250 million was spent on the debridement of
mycotic toenails alone (15). Furthermore, one-third
of Australias podiatry workload is considered to be
committed towards the management of onycho-
mycosis and related problems (154). These data
underline the health-related challenges ahead for
the vulnerable ageing population.
TREATMENT FAILURE OR RELAPSE
Onychomycosis has often been associated with
high recurrence rates (4070%) and many patients
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
Toenail onychomycosis: an important global disease burden 511
have a long history of disease recurrence (20, 155).
The term recurrence suggests both relapse and re-
infection. In treatment relapse, infection is not
completely cured and returns. This implies treat-
ment failure. In re-infection the ailment is com-
pletely cured and is followed by a new infection by
the same or a different organism (20, 125). Fungal-
free nails are the goal of antifungal therapy in
onychomycosis. Because of the slow growth pat-
tern of the toenails, up to 18 months is required for
the nail plate to grow out fully. Therapeutic success
of antifungal therapy of onychomycosis depends
on the newly grown-out nail plate, being fungus-
free (66, 155).
Onychomycosis is a deep-seated, recalcitrant
fungal infection. The in vitro activity of antifungal
drugs does not always correlate with their clinical
efficacy. This may be attributed to the carriage of
arthroconidia and chlamydoconidia (resting fungal
elements) in the nail plate (140, 156). Other nail
characteristics such as nail thickness (>2 mm), slow
outgrowth, severe onycholysis and dermatophy-
toma also contribute to the failure of antifungal
therapy (155). The resting fungal elements are
highly resistant to antifungal therapy and appear to
survive in the nail plate environment, and in foot-
wear for long periods of time, even contributing to
the recurrence of infection after therapy is stopped
(140, 157). The major risk factors for recurrence
include family history, co-existing ancillary clinical
conditions (diabetes, arterial and vascular diseases,
Down syndrome, Raynaud syndrome), immune
suppression and acquired or inherent immunode-
ficiency. Other previously implicated prognostic
factors are co-existing bacterial viral nail infec-tions, erroneous diagnosis, poor compliance, anti-
fungal resistance and poor choice of antifungal
therapy. Furthermore, the role of disease-causing
fungi is also critical. Generally, onychomycosis
caused by non-dermatophytic moulds does not
respond to oral antifungal therapy and current
effective management options are limited (34, 76,
136, 144).
RECOMMENDATIONS FOR PREVENTION
AND RECURRENCE
The nature of the infection requires careful man-
agement strategies to prevent re-infection. The
re-infection rate is often high. Given the influence
of predisposing factors, if an infection is not man-
aged carefully, re-infection may occur in virtually
every patient. Upon the completion of antifungal
therapy fungal-free nails may be achieved but
precautionary measures should be taken against re-
infection (20, 155). Numerous strategies have been
discussed (Table 3) for the efficient prevention of
recurrence. Regular prophylactic application of a
topical antifungal to the feet and toenails may be
beneficial. Therapeutic guidelines for the manage-
ment of onychomycosis have suggested that, at the
time of clinical assessment, marking a line with a
scalpel blade at the base of the nail dystrophy may
be helpful for treatment follow-up. If the newly
grown-out nail remains distal to the marking no
further treatment is needed, whereas if the dys-
trophy moves proximal to the scratch, a viable
infection that requires further medical manage-
ment, is likely (107).
CONCLUSION
Due to the high and increasing prevalence world-
wide, especially in some patient populations, ony-
chomycosis is a growing public health concern. It is
a significant medical disorder and can cause seri-
ous complications in some patient populations. The
patients affected harbour a fungal reservoir, with
Table 3. Recommended guidelines for the prevention
and recurrence of toenail onychomycosis
Protect toes from sources of infection
Treat tinea pedis (self and other household members)
Launder socks in hot water, after soaking in a
disinfectant solution
Avoid bare-footed walking through damp areas
Wear protective footwear at pool and gym
Avoid sharing of socks
Discard old shoes (they may have fungal
spores in them)
Use cotton socks and change them at regular intervals
Use aluminium hexahydrate solution powder tominimize sweating
Wear correctly fitting footwear
Wear shoes made of breathable material and
open toed footwear
Keep nails short and cut them straight
Use antifungal foot powders often
Modified from (20, 34, 76, 155, 173).
2010 The Authors. JCPT 2010 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 35, 497519
512 J. Thomas et al.
the potential to infect other subjects. In some
patients, such as those with diabetes, onychomy-
cosis can lead to foot ulcerations, local and sys-
temic bacterial infections and, in complicated cases,
amputations. Onychomycosis-induced foot com-
plications can contribute significant economic
costs, which weigh particularly heavily on devel-
oped nations.
Current medications are often ineffective in the
long-term management of the condition and are
often associated with high relapse rates. Compli-
ance to prescribed treatment regimens is critical to
achieving therapeutic success. Before commencing
the therapy, the patient must be educated about the
importance of adhering to the treatment protocol.
Currently, only oral medications are recommended
as first-line treatment for the management of ony-
chomycosis. Oral treatments have better cure rates
compared to the topical treatments. However, oral
medication may not be suitable for some groups
such as in children, the elderly, patients with liver
disease and individuals who are immunocompro-
mised. Currently available topical formulations are
costly and have mediocre therapeutic success.
Combination therapy is recommended as a useful
approach for the better management of the infec-
tion in non-responders and in difficult to treat
cases. Topical treatment can be used as an adjuvant
therapy along with oral medications to improve the
cure rate. The therapeutic utility of topical medi-
cations alone is limited. This warrants more
research into the development of a safe and inex-
pensive topical treatment for the management of
the infection in a broader range of patients. Such a
treatment may also be used to reduce treatment
recurrence relapse and may be useful as a pro-phylactic agent for populations such as diabetics,
with a high risk of extremity complications,
potentially leading to amputations. Furthermore, it
may help to improve the aesthetic appeal of the
nail plate(s) in onychomycosis patients, and it
could potentially improve individuals quality of
life, thereby reducing the embarrassment associ-
ated with the infection.
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