treatment of fungal nail infections

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

For personal use only. Not to be reproduced without permission of the editor(permissions@pharmj.org.uk)

Continuing professional development

Dermatophytesare responsiblefor 90 per centof toenail andmore than 50per cent offingernailinfections

Alan Nathan, BPharm,FRPharmS, is afreelance pharmacy writerand consultant

Treatment of fungal nail infectionsAmorolfine 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

Fungal nail infection (onychomycosis) is amore common condition than is some-times realised. Prevalence in adults is esti-

mated at between 3–8 per cent and there aremore than one million sufferers in the UK.1

Onychomycosis is often considered to be atrivial disease with only cosmetic implicationsbut it can cause embarrassment and under-mine self-esteem. Moreover, if left untreatedit can lead to pain and discomfort and spreadto surrounding tissues.

Onychomycosis presents as a discolourednail (white, yellow or brown), which is thickor brittle, or both. It is important to recognisethat the appearance of fungal nail infectionscan vary.

Nail anatomy and growthNails are plates of tightly packed, keratinisedepidermal cells.The nail is made up of threeparts (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 bloodin the capillaries beneath. The free edge appears whitish because there are no underly-ing capillaries. The lunula, the half-moonshaped area at the base of the nail also has a whitish appearance because the vascular tissue does not show through the thickenedstratum basale, the deepest layer of the epidermis.

At the tip of the finger beneath the freeedge is a thickened region of stratumcorneum, called the hyponychium.This bandof tissue is made up of layers of flattened, deadkeratinocytes, and secures the nail to the fingertip.The cuticle (eponychium) is a nar-rower band of stratum corneum that attachesthe sides and base of the nail to the skin.

Nail growth occurs from the nail matrix,the epithelium beneath the nail root, throughthe transformation of superficial cells into nailcells. Growth rate is determined by the rate ofmitosis 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 ofgrowth increases with the length of the digitand the amount of use it has — the fastestgrowing nail is that of the middle finger onthe dominant hand. Fingernails grow at a rateof 2 to 3mm per month and toenails grow at

Figure 1: Nail anatomy

Identify knowledge gaps1. Can you describe the anatomy of the nail?2. What conditions are sometimes mistaken for

fungal nail infections?3. What are the treatment options for fungal nail

infections?

Before reading on, think about how this article mayhelp you to do your job better. The RoyalPharmaceutical Society’s areas of competence forpharmacists are listed in “Plan and record”,(available at: www.rpsgb.org/education). Thisarticle relates to “common disease states andtheir drug therapies”.

Free edge

Nail bodyHyponychium

Phalanx (finger bone)

DISTAL END

PROXIMAL END

Lunula

CuticleNail root

Nail root Nail body

Epidermis

Nail matrixNail bed

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

around 1mm per month. It takes about sixmonths for a cell at the base of a fingernail toreach the tip (12–18 months for toenails).

OnychomycosisNails can be infected by a dermatophyte (afungus that obtains nutrients from keratin), ayeast (eg, Candida spp), or a mould.Dermatophytes are responsible for 90 per centof toenail and more than 50 per cent of fin-gernail infections. “Tinea unguium” is theterm used specifically to describe dermato-phytic onychomycosis.

The dermatophytes comprise three generathat can cause pathogenic infections of theskin and nails in humans and animals:

Epidermophyton, Trichophyton and Microsporum.The most common cause of tinea unguium(and tinea pedis — athlete’s foot) isTrichophyton rubrum, followed by T mentagro-phytes and Epidermophyton floccosum.

Onychomycosis accounts for one-third ofall fungal skin infections. Infection rates inchildren are about 30 times lower than inadults, and in patients with diabetes aboutthree times higher. Immunosuppressed indi-viduals (eg, as a result of disease or drug ther-apy) have a high susceptibility to infection.Predisposing factors for onychomycosis include: increasing age, male gender, diabetes,nail trauma, excessive sweating, peripheralvascular disease, poor hygiene, athlete’s foot,immunodeficiency and chronic exposure ofthe nails to water (this presents a particularrisk of candidal onychomycosis).

There are several types of onychomycosis,differentiated by clinical presentation androute of invasion. Panel 1 presents four main types. “Total dystrophic onychomyosis”describes late-stage nail infection, where theentire nail has become thick and deformed asa result of any of the four types.

Diagnosis It is important that pharmacistsare able to distinguish distal or lateral subun-gual onychomycosis (DLSO) from other nailconditions because the over-the-counteramorolfine lacquer is only licensed for thetreatment of mild (not more than two nails)DLSO.

Ideally, the diagnosis of onychomycosisshould be confirmed by both microscopicanalysis and culture of a specimen becauseonly about 50 per cent of nail dystrophies arecaused by fungal infections. There are,however, several difficulties in doing so in acommunity pharmacy:

■ Pharmacists are not trained to take sam-ples and it is, in any case, difficult to get agood sample of nail clippings and subun-gual scrapings (eg, for suspected DLSO,samples must be taken from the nail bedand as close to the cuticle as possible).

■ Microscopy and culture results can takeup to six weeks (although this is not longin the context of the length of develop-ment of the condition and its treatment).

■ There is also the question of who wouldpay for the microscopy and culture — patients are likely to be reluctant to.

Indeed, many GPs depend on clinical fea-tures alone for diagnosis of onychomycosisand do not take samples. Moreover, if resultsof tests come back as negative (eg, with directmicroscopy there is a 5 to 15 per cent possi-bility of a false negative result), some doctorswill still institute antifungal treatment if theclinical signs clearly point to an infection. Inthe case of OTC sale of amorolfine lacquer itis recognised that there could be occasionalinappropriate use, but this is relatively harm-less and the licensing conditions require reg-ular monitoring and referral to a doctor iftreatment does not improve the condition.

Panel 1: Types of onychomycosisDistal and lateral onychomycosis (DLSO)DLSO is mainly caused by Trichophyton rubrum. Itcan develop on fingernails but infection of toenails is20–30 times more common. Infections often beginas tinea pedis, accounting for the higher frequency oftoenail infections. Infection begins by invasion of thenail bed and underside of the nail, beginning at thehyponychium. The fungus migrates down the nailthrough the underlying nail matrix. Mild inflammationdevelops, resulting in areas of deformed nail andhypertrophy of the stratum corneum (subungualhyperkeratosis), with two consequences:detachment of the nail from the nail bed(onycholysis) and thickening of the subungual region.This subungual space can then serve as a reservoir forsuperinfecting bacteria and moulds, giving the nail ayellowish-brown appearance. Subungual debris accumulates.

Proximal subungual onychomycosis (PSO)PSO is mainly caused by T rubrum. It is uncommon.It mainly presents in patients with HIV infection. PSOis about 10 times more frequent in toenails thanfingernails. Organisms invade the nail through thecuticle area at the base of the nail where theypenetrate the newly formed nail and migrateupwards. The clinical presentation includessubungual hyperkeratosis, onycholysis beginning atthe free edge, white spotting, streaking ordiscolouration (leukonychia) and destruction of theproximal nail plate.

White superficial onychomycosis (WSO)WSO accounts for about 10 per cent of onychomycosiscases. It occurs primarily in the toenails when certainfungi invade the surface layers of the nail directly. WSO is characterised by the presence ofwell-delineated opaque “white islands” on the nail which join and spread as the diseaseprogresses. Eventually, the nail becomes rough, soft and crumbly. Inflammation is usuallyminimal because viable tissue is not involved but the infection may later move through thenail to infect the nail bed and hyponychium.

Candidal onychomycosisCandidal nail infections can occur in patients with chronic candidiasis of the skin andmucous membranes. Candida albicans invades the entire nail. Candida spp can causeother syndromes, including onycholysis and inflammation of the tissues adjacent to thenail (paronychia or whitlows). Candidal nail infections occur more commonly in womenthan in men. They can begin as paronychia, appearing as an oedematous, reddened padsurrounding the nail, before penetrating it. After infection of the nail matrix occurs,transverse depressions (“Beau’s lines”) can appear in the nail plate, which becomesirregular, rough and, ultimately, deformed.

Proximal subungualonychomycosis

Distal and lateralonychomycosis

Galde

rma (

UK) L

tdGa

lderm

a (UK

) Ltd

Downwardinvasion

Invasion throughcuticle

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

Continuing professional development

The main diagnostic features of DLSOare:

■ The nail is thickened and has turned yellow or white

■ These changes appear to have started atthe top of the nail but may have spreaddown 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 andsome or all of it may have broken off.

Other conditions that may be confusedwith DLSO are described in Panel 2. Theserequire treatment by a podiatrist, GP or dermatologist.

Treating onychomycosisOnychomycosis is one of the most difficultfungal infections to treat because of the timeit takes for the nail to grow, the hardness ofthe nail plate and location of the infectiousprocess (between the nail bed and plate). Formany years, griseofulvin was the only oral an-tifungal agent available, but its effectivenesswas restricted by its limited antifungal spec-trum and poor pharmacokinetic profile. Inaddition, topical agents were generally inef-fective due to their inability to penetrate theentire nail. In recent years, however, more effective agents have become available. Oralantifungals are recommended unless the infection is mild and limited to two nails.

Oral therapies Terbinafine and itraconazoleare now considered to be the treatments ofchoice for the systemic treatment of ony-chomycosis.

Evidence from several trials supports theeffectiveness of itraconazole in onychomyco-sis,2–4 but a systematic review5 has found goodevidence that a continuous regimen of the al-lylamine terbinafine (250mg daily for threemonths) is the most effective oral treatmentfor fungally infected toenails.

Terbinafine inhibits ergosterol formationearlier in the synthesis pathway than the azoles(see Figure 2), at the point where squalene isconverted to squalene epoxide, the precursorof lanosterol. This step does not require cy-tochrome P450, so side effects associated withcytochrome P450-mediated actions do notoccur (see below). The resulting intracellularaccumulation of squalene exerts a disruptiveeffect on the fungal cell membrane, a step thatis likely to be fungicidal, whereas the ergos-terol deficiency caused by azole antifungals isprobably fungistatic.

Azole antifungals inhibit cytochrome P450-dependent enzymes in the fungal cells, impair-ing the formation of ergosterol, an essentialcomponent of the fungal cell wall. High dosesof the imidazoles, such as ketoconazole, are required to effect this inhibition, leading to anunacceptable level of adverse effects, which include gastrointestinal effects and, rarely, hepa-totoxicity. Patients on long-term ketoconazolerequire regular liver function tests.

In addition, there are potentially seriousdrug interactions between the imidazoles anddrugs metabolised by cytochrome P450.Triazole antifungals (eg, fluconazole and itra-conazole) bind less strongly to mammalian cytochrome P450 enzymes than the older imidazoles but retain a high affinity for fungalP450 enzyme sites, resulting in a decreasedprobability of side effects.

Itraconazole reaches the site of infectionwithin 24 hours of administration. It can bedetected in the nail plate within a month ofbeginning therapy and persists in the nail forlonger than fluconazole or terbinafine. A200mg dose can be taken od continuously forthree months but, because of its rapid penetra-tion into and prolonged presence in the nail,treatment can be reduced to one-weekcourses at intervals, with advantages in termsof cost and a greater likelihood of adherence.This is known as “pulse therapy”, where theitraconazole is taken bd for seven days, withsubsequent courses after a 21-day interval.Twocourses are prescribed for fingernails and threefor toenails.

Panel 2: Conditions confused with onychomycosis

Psoriasis* Psoriasis of the nails may appear similar to DLSO but it is also usuallypresent at other skin sites. There is usually fine pitting on the nail surface, small salmon-coloured “oil drops”, and fingernails onboth hands are affected.

Lichen planus* The main features of lichen planusare itchy, flat-topped papules most commonly seenon the inner surfaces of the wrists and the lowerlegs. Involvement of the nails occurs in about 10 percent of patients (usually in more serious cases) andfine ridging or grooving can be seen, with severedystrophy or even complete destruction of the nailbed.

Contact dermatitis Contact dermatitis occasionallyresembles onychomycosis. Asking the patient about contact with possible irritants andfinding the presence of contact dermatitis elsewhere on the body should differentiate thecondition from DLSO.

Nail trauma Repeated damage to the nail can cause distal onycholysis, leading tocolonisation by micro-organisms and pigmentation of the area. If the onycholytic nail isclipped and the nail bed examined, however, it will appear normal (eg, no subungualdebris).

Yellow nail syndrome Yellow nail syndrome is characterised by yellow nails and iscommonly associated with lung disorders. The nails lack a cuticle, grow slowly and areloose or detached. All nails are affected.

Oral antifungalsare

recommendedunless the

infection is mildand limited to

two nails

* Usually, not only the nails will be affected and patients will have accompanying signs of disease

Pitting and oncholysisin psoriasis

Figure 2: Site of action of antifungals for nail infections

Squalene Lanosterol Ergosterol

Terbinafine Azoles Amorolfine

Mike

Wyn

dham

Med

ical P

ictur

e Libr

ary

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

Topical treatments Three preparations arelicensed in the UK for topical treatment ofonychomycosis: amorolfine 5 per cent naillacquer, tioconazole 28 per cent cutaneous solution and a paint containing undecanoates.There is little clinical evidence for the effectiveness of tioconazole or undecanoatesin onychomycosis and both products requiretwice daily application to the affected nail. Use of OTC amorolfine lacquer is cov-ered in Panel 3.

Advice for patientsAlthough the newer antifungal treatments haveconsiderably increased treatment success rates inrecent years, one in five onychomycosis patientsis still not cured.The reasons include inaccuratediagnosis, misidentification of the pathogen andthe presence of a second disorder. It is impor-tant, therefore, for pharmacists to refer patientsto a podiatrist or to their GP if they are in anydoubt over the diagnosis or if there appears tobe no improvement after treatment.

To assist treatment and prevent recurrence,pharmacists can provide the following addi-tional advice:

■ A cure cannot be achieved overnight. It isimportant that treatment is continued anddirections are followed.

■ Wash and thoroughly dry feet everyday.■ To try to prevent the infection spreading

to other toes, avoid tight fitting or occlu-sive shoes.

■ Rest shoes periodically to limit exposureto infectious fungi.

■ Use antifungal powders once a week tohelp keep shoes free from pathogens

■ Exercise good nail care and be alert for infection recurrence.

■ Visit a podiatrist regularly.

The infection can be passed to othersthrough contamination of shared facilities sopatients should be advised not to go barefootin the family bathroom or public places.

Resources References■ Elewski BE. Onychomycosis: pathogenesis, diagnosis, and

management. Clinical Microbiological Review.1998;11:415–29. This article contains information abouttaking nail specimens and their analysis.

References1. Roberts DT. Prevalence of dermatophyte onychomycosis in

the United Kingdom: results of an omnibus survey. BritishJournal of Dermatology. 1992;126 (Suppl):23–7.

2. De Doncker P, Decroix J, Pierard GE, Roelant D,Woesternborghs R, Jacqmin et al. Antifungal pulse therapyfor onychomycosis: a pharmacokinetic andpharmacodynamic investigation of monthly cycles of one-week pulse therapy with itraconazole. Archives ofDermatology. 1996;132:34–41.

3. Havu V, Brandt H, Heikkilä H, Hollne A, Oksman R, RantanenT et al. A double-blind, randomized study comparingitraconazole pulse therapy with continuous dosing for thetreatment of toenail onychomycosis. British Journal ofDermatology 1997;136:230–4.

4. Odom R, Daniel C R, Aly R. A double-blind, randomisedcomparison of itraconazole capsules and placebo in thetreatment of onychomycosis of the toenail. Journal of theAmerican Academy of Dermatology 1996;35:110–1.

5. Crawford F, Young P, Godfrey C, Bell-Syer SE, Hart R, Brunt Eet al. Oral treatments for onychomycosis: a systematicreview. Archives of Dermatology 2002;138:811–6.

6. Reinel D. Topical treatment of onychomycosis withamorolfine 5 per cent nail lacquer: comparative efficacy andtolerability of once and twice weekly use. Dermatology1992;184 (Suppl):21–4.

7. Medicines and Healthcare products Regulatory Agency.Consultation document: ARM 31. Available at:www.mhra.gov.uk/home (accessed 9 May 2006).

Action: practicepointsReading is only one way toundertake CPD and theSociety will expect to seevarious approaches in apharmacist’s CPD portfolio.1. Read the Royal

Pharmaceutical Societyguidance on OTCamorolfine (available atwww.rpsgb.org/members/practice). Answer thefollowing questions:

■ Can the applicator be putback in the bottle straightafter use?

■ What if the patient alsohas athlete’s foot?

■ Can nail varnish be wornwhen amorolfine is used?

2. Train your staff on OTCamorolfine.

3. Think about how to letpeople know pharmacistscan now treat DLSO.

EvaluateFor your work to be presentedas CPD, you need to evaluateyour reading and any otheractivities. Answer the followingquestions: What have youlearnt? How has it added valueto your practice? What will youdo now and how will this beachieved?

Amorolfine Amorolfine is a morpholine derivative which is usedtopically as an antifungal. It has a broad spectrum of activity, againstdermatophytes, other fungi and yeasts. Its fungicidal action is based onergosterol depletion and the accumulation of ignosterol in fungalcytoplasmic membrane, which causes the fungal cell wall to thicken andchitin to be deposited.

The nail lacquer formulation builds a non-water soluble film on thenail plate which remains at the application site for a week, acting as adepot for the drug.

Indication OTC amorolfine 5 per cent nail lacquer for pharmacy sale islicensed 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, thesurface of the infected nail must be filed and cleaned using the file andcleaning pad provided. These are disposable and should not be reused.The pack size is 3ml, which is sufficient for about three months, afterwhich the condition should be reviewed.

Patients must be encouraged to use the treatment regularly,according to the manufacturer’s directions, and to persist withtreatment until the infected section of nail has completely grown out.Continuous use (six months for fingernails and at least nine months fortoe nails) is usually required.

Efficacy and safety In a randomised clinical trial6 involving 456patients, 46 per cent had an overall cure rate after weekly treatment forsix months with amorolfine 5 per cent lacquer and a further 24 per centof patients had overall improvement. Almost no adverse effects werereported. The manufacturers report7 minor adverse reactions in aboutone in 200,000. This is usually a slight burning sensation or irritation inthe area after application. Amorolfine is not systematically absorbed andthere are no known interactions with other drugs.

Compliance is vital for treatment success.

Review Pharmacists recommending OTC amorolfine should ask patientsto return for reviews at three-monthly intervals. There is an aid formonitoring treatment progress in the patient information leaflet andpatients 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

Panel 3: Over-the-counter amorolfine nail lacquer for fungal nail infection