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Continuing professional development

Treatment of fungal nail infections
Amorolfine nail lacquer will soon be available over the counter for the treatment of fungal nail infection. In this article, Alan Nathan
provides the background to the causes of fungal nail infections and types of infection, and looks at the treatment options

DISTAL END
Nail root Nail body
Free edge

Hyponychium Nail body

Epidermis
Phalanx (finger bone) Lunula
Cuticle
Nail root
Nail bed
Nail matrix PROXIMAL END

Figure 1: Nail anatomy

ungal nail infection (onychomycosis) is a

F more common condition than is some-

times realised. Prevalence in adults is esti-
mated at between 3–8 per cent and there are
more than one million sufferers in the UK.1
Onychomycosis is often considered to be a
trivial disease with only cosmetic implications
but it can cause embarrassment and under-
mine self-esteem. Moreover, if left untreated
it can lead to pain and discomfort and spread
to surrounding tissues.
Onychomycosis presents as a discoloured
nail (white, yellow or brown), which is thick
or brittle, or both. It is important to recognise
that the appearance of fungal nail infections
can vary.
Nail anatomy and growth
Nails are plates of tightly packed, keratinised
epidermal cells. The nail is made up of three
parts (see Figure 1):
■ The nail body (the visible part of the nail)
■ The free edge (the part extending past the
end of the digit)
■ The nail root (the portion buried at the
base in a fold of skin)
Most of the nail appears pink due to blood
in the capillaries beneath. The free edge
appears whitish because there are no underly-
ing capillaries. The lunula, the half-moon
shaped area at the base of the nail also has
a whitish appearance because the vascular
tissue does not show through the thickened
stratum basale, the deepest layer of the
epidermis.
At the tip of the finger beneath the free
edge is a thickened region of stratum
corneum, called the hyponychium.This band
of tissue is made up of layers of flattened, dead
keratinocytes, and secures the nail to the
fingertip. The cuticle (eponychium) is a nar-
rower band of stratum corneum that attaches
the sides and base of the nail to the skin.
Identify knowledge gaps
Dermatophytes 1. Can you describe the anatomy of the nail?
are responsible 2. What conditions are sometimes mistaken for
fungal nail infections?
for 90 per cent 3. What are the treatment options for fungal nail
infections?
of toenail and
Before reading on, think about how this article may
more than 50 help you to do your job better. The Royal
per cent of Pharmaceutical Society’s areas of competence for
pharmacists are listed in “Plan and record”,
fingernail (available at: www.rpsgb.org/education). This
article relates to “common disease states and
infections their drug therapies”.
Nail growth occurs from the nail matrix,
the epithelium beneath the nail root, through
the transformation of superficial cells into nail
cells. Growth rate is determined by the rate of
mitosis in matrix cells, which, in turn, is influ-
enced by age, health and nutritional status.
Growth rate also varies according to season,
time of day and temperature. The rate of
growth increases with the length of the digit
Alan Nathan, BPharm, and the amount of use it has — the fastest
FRPharmS, is a growing nail is that of the middle finger on
freelance pharmacy writer the dominant hand. Fingernails grow at a rate
and consultant of 2 to 3mm per month and toenails grow at

www.pjonline.com 20 May 2006 The Pharmaceutical Journal (Vol 276) 597


Panel 1: Types of onychomycosis
Distal and lateral onychomycosis (DLSO)
DLSO is mainly caused by Trichophyton rubrum. It
can develop on fingernails but infection of toenails is
20–30 times more common. Infections often begin
as tinea pedis, accounting for the higher frequency of
toenail infections. Infection begins by invasion of the
nail bed and underside of the nail, beginning at the
hyponychium. The fungus migrates down the nail
through the underlying nail matrix. Mild inflammation
Epidermophyton, Trichophyton and Microsporum.
The most common cause of tinea unguium
(and tinea pedis — athlete’s foot) is
Trichophyton rubrum, followed by T mentagro-
phytes and Epidermophyton floccosum.
Downward Onychomycosis accounts for one-third of
invasion all fungal skin infections. Infection rates in
children are about 30 times lower than in
adults, and in patients with diabetes about
three times higher. Immunosuppressed indi-
viduals (eg, as a result of disease or drug ther-
apy) have a high susceptibility to infection.

Galderma (UK) Ltd

develops, resulting in areas of deformed nail and Predisposing factors for onychomycosis
hypertrophy of the stratum corneum (subungual include: increasing age, male gender, diabetes,
hyperkeratosis), with two consequences: nail trauma, excessive sweating, peripheral
detachment of the nail from the nail bed vascular disease, poor hygiene, athlete’s foot,
(onycholysis) and thickening of the subungual region. Distal and lateral immunodeficiency and chronic exposure of
This subungual space can then serve as a reservoir for onychomycosis the nails to water (this presents a particular
superinfecting bacteria and moulds, giving the nail a risk of candidal onychomycosis).
yellowish-brown appearance. Subungual debris accumulates. There are several types of onychomycosis,
differentiated by clinical presentation and
Proximal subungual onychomycosis (PSO) route of invasion. Panel 1 presents four
PSO is mainly caused by T rubrum. It is uncommon. main types. “Total dystrophic onychomyosis”
It mainly presents in patients with HIV infection. PSO describes late-stage nail infection, where the
is about 10 times more frequent in toenails than entire nail has become thick and deformed as
fingernails. Organisms invade the nail through the a result of any of the four types.
cuticle area at the base of the nail where they Invasion through
penetrate the newly formed nail and migrate cuticle Diagnosis It is important that pharmacists
upwards. The clinical presentation includes are able to distinguish distal or lateral subun-
subungual hyperkeratosis, onycholysis beginning at Galderma (UK) Ltd gual onychomycosis (DLSO) from other nail
the free edge, white spotting, streaking or conditions because the over-the-counter
discolouration (leukonychia) and destruction of the amorolfine lacquer is only licensed for the
proximal nail plate. treatment of mild (not more than two nails)
DLSO.
White superficial onychomycosis (WSO) Proximal subungual Ideally, the diagnosis of onychomycosis
WSO accounts for about 10 per cent of onychomycosis onychomycosis should be confirmed by both microscopic
cases. It occurs primarily in the toenails when certain analysis and culture of a specimen because
fungi invade the surface layers of the nail directly. WSO is characterised by the presence of only about 50 per cent of nail dystrophies are
well-delineated opaque “white islands” on the nail which join and spread as the disease caused by fungal infections. There are,
progresses. Eventually, the nail becomes rough, soft and crumbly. Inflammation is usually however, several difficulties in doing so in a
minimal because viable tissue is not involved but the infection may later move through the community pharmacy:
nail to infect the nail bed and hyponychium.
■ Pharmacists are not trained to take sam-
Candidal onychomycosis ples and it is, in any case, difficult to get a
Candidal nail infections can occur in patients with chronic candidiasis of the skin and good sample of nail clippings and subun-
mucous membranes. Candida albicans invades the entire nail. Candida spp can cause gual scrapings (eg, for suspected DLSO,
other syndromes, including onycholysis and inflammation of the tissues adjacent to the samples must be taken from the nail bed
nail (paronychia or whitlows). Candidal nail infections occur more commonly in women and as close to the cuticle as possible).
than in men. They can begin as paronychia, appearing as an oedematous, reddened pad ■ Microscopy and culture results can take
surrounding the nail, before penetrating it. After infection of the nail matrix occurs, up to six weeks (although this is not long
transverse depressions (“Beau’s lines”) can appear in the nail plate, which becomes in the context of the length of develop-
irregular, rough and, ultimately, deformed. ment of the condition and its treatment).
■ There is also the question of who would
pay for the microscopy and culture —
around 1mm per month. It takes about six patients are likely to be reluctant to.
months for a cell at the base of a fingernail to
reach the tip (12–18 months for toenails). Indeed, many GPs depend on clinical fea-
tures alone for diagnosis of onychomycosis
Onychomycosis and do not take samples. Moreover, if results
Nails can be infected by a dermatophyte (a of tests come back as negative (eg, with direct
fungus that obtains nutrients from keratin), a microscopy there is a 5 to 15 per cent possi-
yeast (eg, Candida spp), or a mould. bility of a false negative result), some doctors
Dermatophytes are responsible for 90 per cent will still institute antifungal treatment if the
of toenail and more than 50 per cent of fin- clinical signs clearly point to an infection. In
gernail infections. “Tinea unguium” is the the case of OTC sale of amorolfine lacquer it
term used specifically to describe dermato- is recognised that there could be occasional
phytic onychomycosis. inappropriate use, but this is relatively harm-
The dermatophytes comprise three genera less and the licensing conditions require reg-
that can cause pathogenic infections of the ular monitoring and referral to a doctor if
skin and nails in humans and animals: treatment does not improve the condition.

598 The Pharmaceutical Journal (Vol 276) 20 May 2006 www.pjonline.com

 Continuing professional development
The main diagnostic features of DLSO
are:

■ The nail is thickened and has turned

yellow or white
■ These changes appear to have started at
the top of the nail but may have spread
down towards the nail base
■ Debris (created as a result of the infec-
tion) has accumulated under the nail
(“subungual debris”)
■ Scaling and distortion of the nail has
occurred
■ The nail may have become brittle and
some or all of it may have broken off.
Other conditions that may be confused
with DLSO are described in Panel 2. These
require treatment by a podiatrist, GP or
dermatologist.
Treating onychomycosis
Onychomycosis is one of the most difficult
fungal infections to treat because of the time
it takes for the nail to grow, the hardness of
the nail plate and location of the infectious
process (between the nail bed and plate). For
many years, griseofulvin was the only oral an-
tifungal agent available, but its effectiveness
was restricted by its limited antifungal spec-
trum and poor pharmacokinetic profile. In
addition, topical agents were generally inef-
fective due to their inability to penetrate the
entire nail. In recent years, however, more
effective agents have become available. Oral
antifungals are recommended unless the
infection is mild and limited to two nails.
Panel 2: Conditions confused with onychomycosis
Psoriasis* Psoriasis of the nails may appear similar to DLSO but it is also usually
present at other skin sites. There is usually fine pitting on the nail surface, small
salmon-coloured “oil drops”, and fingernails on
both hands are affected.
Squalene Lanosterol Ergosterol
Terbinafine Azoles Amorolfine
Figure 2: Site of action of antifungals for nail infections
Oral therapies Terbinafine and itraconazole
are now considered to be the treatments of
choice for the systemic treatment of ony-
chomycosis.
Oral antifungals Evidence from several trials supports the
effectiveness of itraconazole in onychomyco-
are sis,2–4 but a systematic review5 has found good
recommended evidence that a continuous regimen of the al-
lylamine terbinafine (250mg daily for three
unless the months) is the most effective oral treatment
for fungally infected toenails.
infection is mild Terbinafine inhibits ergosterol formation
and limited to earlier in the synthesis pathway than the azoles
(see Figure 2), at the point where squalene is
two nails converted to squalene epoxide, the precursor
of lanosterol. This step does not require cy-
tochrome P450, so side effects associated with
cytochrome P450-mediated actions do not
occur (see below). The resulting intracellular
accumulation of squalene exerts a disruptive
effect on the fungal cell membrane, a step that
is likely to be fungicidal, whereas the ergos-
terol deficiency caused by azole antifungals is
probably fungistatic.
Azole antifungals inhibit cytochrome P450-
dependent enzymes in the fungal cells, impair-
ing the formation of ergosterol, an essential
component of the fungal cell wall. High doses
of the imidazoles, such as ketoconazole, are
required to effect this inhibition, leading to an
unacceptable level of adverse effects, which
include gastrointestinal effects and, rarely, hepa-
totoxicity. Patients on long-term ketoconazole
require regular liver function tests.
Mike Wyndham Medical Picture Library

In addition, there are potentially serious

Lichen planus* The main features of lichen planus drug interactions between the imidazoles and
are itchy, flat-topped papules most commonly seen drugs metabolised by cytochrome P450.
on the inner surfaces of the wrists and the lower Triazole antifungals (eg, fluconazole and itra-
legs. Involvement of the nails occurs in about 10 per conazole) bind less strongly to mammalian
cent of patients (usually in more serious cases) and cytochrome P450 enzymes than the older
fine ridging or grooving can be seen, with severe imidazoles but retain a high affinity for fungal
dystrophy or even complete destruction of the nail P450 enzyme sites, resulting in a decreased
bed. Pitting and oncholysis probability of side effects.
in psoriasis Itraconazole reaches the site of infection
Contact dermatitis Contact dermatitis occasionally within 24 hours of administration. It can be
resembles onychomycosis. Asking the patient about contact with possible irritants and detected in the nail plate within a month of
finding the presence of contact dermatitis elsewhere on the body should differentiate the beginning therapy and persists in the nail for
condition from DLSO. longer than fluconazole or terbinafine. A
200mg dose can be taken od continuously for
Nail trauma Repeated damage to the nail can cause distal onycholysis, leading to three months but, because of its rapid penetra-
colonisation by micro-organisms and pigmentation of the area. If the onycholytic nail is tion into and prolonged presence in the nail,
clipped and the nail bed examined, however, it will appear normal (eg, no subungual treatment can be reduced to one-week
debris). courses at intervals, with advantages in terms
of cost and a greater likelihood of adherence.
Yellow nail syndrome Yellow nail syndrome is characterised by yellow nails and is This is known as “pulse therapy”, where the
commonly associated with lung disorders. The nails lack a cuticle, grow slowly and are itraconazole is taken bd for seven days, with
loose or detached. All nails are affected. subsequent courses after a 21-day interval.Two
courses are prescribed for fingernails and three
* Usually, not only the nails will be affected and patients will have accompanying signs of disease for toenails.

www.pjonline.com 20 May 2006 The Pharmaceutical Journal (Vol 276) 599

 Panel 3: Over-the-counter amorolfine nail lacquer for fungal nail infection
Amorolfine Amorolfine is a morpholine derivative which is used
topically as an antifungal. It has a broad spectrum of activity, against
dermatophytes, other fungi and yeasts. Its fungicidal action is based on
ergosterol depletion and the accumulation of ignosterol in fungal
cytoplasmic membrane, which causes the fungal cell wall to thicken and
chitin to be deposited.
The nail lacquer formulation builds a non-water soluble film on the
nail plate which remains at the application site for a week, acting as a
depot for the drug.
Efficacy and safety In a randomised clinical trial6 involving 456
patients, 46 per cent had an overall cure rate after weekly treatment for
six months with amorolfine 5 per cent lacquer and a further 24 per cent
of patients had overall improvement. Almost no adverse effects were
reported. The manufacturers report7 minor adverse reactions in about
one in 200,000. This is usually a slight burning sensation or irritation in
the area after application. Amorolfine is not systematically absorbed and
there are no known interactions with other drugs.
Compliance is vital for treatment success.

Indication OTC amorolfine 5 per cent nail lacquer for pharmacy sale is
licensed for treatment of mild cases of distal and lateral onychomycosis,
affecting up to two nails, in those aged18 years or over.
Application The lacquer is used once a week. Before application, the
surface of the infected nail must be filed and cleaned using the file and
cleaning pad provided. These are disposable and should not be reused.
The pack size is 3ml, which is sufficient for about three months, after
which the condition should be reviewed.
Patients must be encouraged to use the treatment regularly,
according to the manufacturer’s directions, and to persist with
treatment until the infected section of nail has completely grown out.
Continuous use (six months for fingernails and at least nine months for
toe nails) is usually required.
Review Pharmacists recommending OTC amorolfine should ask patients
to return for reviews at three-monthly intervals. There is an aid for
monitoring treatment progress in the patient information leaflet and
patients should be advised to use this.
Whom to refer The following people should be referred:
■ Those with conditions that predispose them to fungal infections (eg,
immunosuppression, diabetes, peripheral circulatory disorders).
■ Pregnant or breast-feeding women
■ Those under 18 years of age
■ Those with nail conditions other than DLSO
■ Those with more than two infected nails
■ Those with nail dystrophy or a destroyed nail
■ Those with no improvement after three-months’ treatment

Topical treatments Three preparations are ■ Visit a podiatrist regularly.

licensed in the UK for topical treatment of
onychomycosis: amorolfine 5 per cent nail
Action: practice The infection can be passed to others
lacquer, tioconazole 28 per cent cutaneous points through contamination of shared facilities so
solution and a paint containing undecanoates. Reading is only one way to patients should be advised not to go barefoot
There is little clinical evidence for the undertake CPD and the in the family bathroom or public places.
effectiveness of tioconazole or undecanoates Society will expect to see
in onychomycosis and both products require various approaches in a
twice daily application to the affected pharmacist’s CPD portfolio. Resources References
nail. Use of OTC amorolfine lacquer is cov- 1. Read the Royal ■ Elewski BE. Onychomycosis: pathogenesis, diagnosis, and
ered in Panel 3. Pharmaceutical Society management. Clinical Microbiological Review.
guidance on OTC 1998;11:415–29. This article contains information about
taking nail specimens and their analysis.
Advice for patients amorolfine (available at
Although the newer antifungal treatments have www.rpsgb.org/members/
References
considerably increased treatment success rates in practice). Answer the 1. Roberts DT. Prevalence of dermatophyte onychomycosis in
recent years, one in five onychomycosis patients following questions: the United Kingdom: results of an omnibus survey. British
is still not cured.The reasons include inaccurate ■ Can the applicator be put Journal of Dermatology. 1992;126 (Suppl):23–7.
diagnosis, misidentification of the pathogen and back in the bottle straight 2. De Doncker P, Decroix J, Pierard GE, Roelant D,
the presence of a second disorder. It is impor- after use? Woesternborghs R, Jacqmin et al. Antifungal pulse therapy
tant, therefore, for pharmacists to refer patients ■ What if the patient also for onychomycosis: a pharmacokinetic and
to a podiatrist or to their GP if they are in any has athlete’s foot? pharmacodynamic investigation of monthly cycles of one-
doubt over the diagnosis or if there appears to ■ Can nail varnish be worn week pulse therapy with itraconazole. Archives of
be no improvement after treatment. when amorolfine is used? Dermatology. 1996;132:34–41.
3. Havu V, Brandt H, Heikkilä H, Hollne A, Oksman R, Rantanen
To assist treatment and prevent recurrence, 2. Train your staff on OTC
T et al. A double-blind, randomized study comparing
pharmacists can provide the following addi- amorolfine. itraconazole pulse therapy with continuous dosing for the
tional advice: 3. Think about how to let treatment of toenail onychomycosis. British Journal of
people know pharmacists Dermatology 1997;136:230–4.
■ A cure cannot be achieved overnight. It is can now treat DLSO. 4. Odom R, Daniel C R, Aly R. A double-blind, randomised
important that treatment is continued and comparison of itraconazole capsules and placebo in the
directions are followed. Evaluate treatment of onychomycosis of the toenail. Journal of the
■ Wash and thoroughly dry feet everyday. For your work to be presented American Academy of Dermatology 1996;35:110–1.
■ To try to prevent the infection spreading as CPD, you need to evaluate 5. Crawford F, Young P, Godfrey C, Bell-Syer SE, Hart R, Brunt E
et al. Oral treatments for onychomycosis: a systematic
to other toes, avoid tight fitting or occlu- your reading and any other
review. Archives of Dermatology 2002;138:811–6.
sive shoes. activities. Answer the following 6. Reinel D. Topical treatment of onychomycosis with
■ Rest shoes periodically to limit exposure questions: What have you amorolfine 5 per cent nail lacquer: comparative efficacy and
to infectious fungi. learnt? How has it added value tolerability of once and twice weekly use. Dermatology
■ Use antifungal powders once a week to to your practice? What will you 1992;184 (Suppl):21–4.
help keep shoes free from pathogens do now and how will this be 7. Medicines and Healthcare products Regulatory Agency.
■ Exercise good nail care and be alert for achieved? Consultation document: ARM 31. Available at:
infection recurrence. www.mhra.gov.uk/home (accessed 9 May 2006).

600 The Pharmaceutical Journal (Vol 276) 20 May 2006 www.pjonline.com