INVITED ARTICLE

Update: medical treatmentof onychomycosis

Avner ShemerDermatology, Sheba Medical Cenet-Tel Hashomer, Tel-Aviv University, TelHashomer, Israel

ABSTRACT: The diagnosis of onychomycosis should be made clinically and mycologically: clinically,by one of seven subtypes of onychomycosis, and mycologically, by evidence of dermatophytes orverified presence of molds and/or yeasts. Dermatophytes are usually considered as pathogens, whereasnon-dermatophyte molds and yeasts are saprophytes. Basic anamnesis and close inspection should beperformed to eliminate combined diseases (e.g., onychomycosis and trauma). The gold standard treat-ment for onychomycosis is basically systemic. Combination with topical agents, such as nail lacquerand/or chemical nail avulsion, produces better results than systemic treatment alone. Topical treat-ment as monotherapy is not efficient, excluding minor cases. Terbinafine is superior to itraconazole fordermatophyte onychomycosis. Evaluation of the outcome of clinical cure, mycological cure and totalcure should be based on the well-defined worldwide criteria; otherwise, comparison of results is impos-sible due to lack of uniformity in different studies. In case of treatment failure, the reasons for eachfailure should be carefully considered.

KEYWORDS: combined diseases, diagnosis of onychomycosis, onychomycosis, treatment failure,unified criteria for cure

Introduction

Onychomycosis is a common fungal infection ofthe toenails and/or fingernails and may be dueto dermatophytes, yeasts, and nondermatophytemolds (1,2). In about 90% of the cases, the causeof onychomycosis is the anthropophilic dermato-phytes: Trichophyton rubrum and Trichophytonmentagrophytes. Nondermatophyte molds andyeasts are much less common (3).

The rates of onychomycosis worldwide are notclear enough. Different studies show a very widerange of 2–40%. Many factors contribute to thiswide range: age, race, country, other nail/s, and/or

systemic diseases, and of course the way of the cal-culation, namely from the general population or aspecific population that comes to be examined dueto foot problems. Within subgroups such as elderlypatients, patients with diabetes mellitus, and HIVpositive patients, the prevalence of onychomycosiscould be as high as 60 and 30%, respectively (4).Different studies show onychomycosis prevalenceof 2.18–13% (5), whereas among elderly patients, itmay reach up to 28% (6).

Onychomycosis is 4–25 times more widespreadin toenails than in finger nails (4,7).

The results of the Achilles Project in Europeregarding the prevalence of onychomycosis (in 16European countries) is 35–40% (4).

Predisposing factors for onychomycosis are asfollows: old age, sex, genetic susceptibility, tineapedis (moccasin type), nail psoriasis (controversy),peripheral arterial disease, smoking, diabetes

Address correspondence and reprint requests to: AvnerShemer, MD, Professor of Dermatology, Sheba MedicalCenet-Tel Hashomer, Tel-Aviv University, Tel Hashomer 52621,Israel, or email: ashemer1@gmail.com.

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Dermatologic Therapy, Vol. 25, 2012, 582–593Printed in the United States · All rights reserved

© 2012 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPYISSN 1396-0296

mellitus, different nail trauma/s, inactivity, familybackground of onychomycosis, different causes ofimmune deficiency, hyperhidrosis, and inappro-priate nail hygiene (4,5,8).

Onychomycosis is very rarely found in youngchildren. Several studies show that the incidenceof onychomycosis in young children is less than0.5% (9). Scher (8) showed that the estimation ofonychomycosis in children is 30 times less than inthe adult population. In addition, young childrenlack the risk factors for onychomycosis, which arewell known in playing a role in the development ofonychomycosis. Young children also have smallernail surfaces and faster nail growth (10).

The very low incidence of onychomycosis inchildren is due to rapid nail growth, which occursfaster than the retrograde progression of the fungusfrom the distal part of the nail to the matrix region.

Onychomycosis – definition

Onychomycosis is a fungal infection of the toenailsand/or fingernails.

The meaning of onychomycosis is derived fromthe Greek language, namely onyx – a nail, mykes – afungus. It may involve any component of the nailunit, namely the nail plate, the nail bed, and thenail matrix (7). Tinea unguium refers to the der-matophyte infection of the nails, whereas onycho-mycosis refers to any fungal infection of the nails(dermatophytes and/or molds and/or yeasts).

Subtypes

Clinical types of onychomycosis

There are several clinical types of onychomycosis.The clinical subtype is derived from the way andthe location of the fungus penetration into thenail plate.

Subtypes

There are seven subtype clinical patterns of ony-chomycosis (11):1. DLSO – distal and lateral subungual onychomy-

cosis.2. SO – superficial onychomycosis (white or black)3. EO – endonyx onychomycosis4. PSO – proximal subungual onychomycosis5. MPO – mixed pattern Onychomycosis6. TDO – total dystrophic onychomycosis

7. Secondary onychomycosisAnother subtype rep-resents the end stage of the progression of allthe above subtypes. The term for this end-stagesubtype is TDO – total dystrophic onychomyco-sis, which is secondary to one of four subtypes.TDO can primarily be due to a chronic mucocu-taneous candidiasis.

DLSO – distal and lateral subungualonychomycosis

DLSO is the most common type of onychomycosis.The infected fungus begins with the invasion of thehyponychium. The fungus penetrates the hornylayer of the hyponychium and then the distal andthe ventral parts of the nail plate and – at the sametime or thereafter – to the nail bed.

The first clinical picture of this subtype is vari-able. Usually, the distal portion of the infectednail becomes thickened and opaque. This minordeformation starts to progress distally, causing aseparation between the nail plate and the nail bed(FIG. 1).

The direction of the fungus pathway is towardthe proximal nail fold, and on the other hand, thedirection of the nail growth is distal. The equilib-rium of these two contrary progressions usuallytends to move to the fungus pathway, and as aresult, the nail plate becomes more and moredeformed, opaque, and thickened.

The most common pathogens for DLSO aredermatophytes. T. rubrum is the most commonpathogen, whereas T. mentagrophytes var. inter-digitalis and Epidermophyton floccosum are rela-tively uncommon – especially the latter.

FIG. 1. Distal and lateral subungual onychomycosis.

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The spread of T. rubrum on the nail bed is fromthe plantar area of the toes. The infection usuallybegins with the involvement of the distal corner ofthe big toenail and progresses along the nail bedand the ventral part of the nail plate toward the nailmatrix. Sometimes, the progression is located onlyin the corner and then continues proximally by cre-ating a yellow spike. The yellow spike (also calledyellow streak) is a variant of DLSO and this subtypeis very difficult to get rid of when attemptingmedical treatment.

SO – superficial onychomycosis(white or black)

This clinical type could be patchy or transverse,which originates from beneath the proximal nailfold or with deep penetration through the nail plate.

Superficial white onychomycosis is a superficialinfection of the outer part of the nail plate (FIG. 2).

SWO is usually located in the toe nails, but it canalso occur in the fingernails. The most commoncause for this type of onychomycosis is T. menta-grophytes var. interdigitalis (90%). Other pathogenscausing SO are T. rubrum, Scytalidium, Aspergillusspp., Fusarium spp., and Acremonium spp.

The clinical picture of SWO appears as whitepatches located on the superficial portion of thenail plate, which may coalesce and cover all or al-most all the nail plate. Extensive SWO is usually seentogether with vesiculobullous tinea pedis, which isalso caused by the same pathogen – T. mentagro-phytes var. interdigitalis. Superficial black onycho-mycosis: the dark (black) discoloration of the nailplate is caused by the invention of T. rubrum var.nigricans or the mold Scytalidium dimidiatum.

Endonyx onychomycosis (EO) is a rare type ofonychomycosis (a variant of distal and lateral sub-ungual onychomycosis). EO is characterized by amassive nail plate invasion with no involvement ofthe nail bed. The nail plate is opaque and white in

the absence of the classical picture onychomycosisand subungual hyperkeratosis. The most commonpathogenic dermophyte is Trichophyton soudan-ense and Trichophyton violaceum (FIG. 3).

TDO – total dystrophic onychomycosis

Total dystrophic onychomycosis is the end stageof all the above subtypes. All the nail plate isdeformed, opaque. This type is considered as a sec-ondary form.

Primary TDO may be seen in patients sufferingfrom chronic mucocutaneous candidiasis or inother immune-compromised patients (FIG. 4).

PSO – proximal subungual onychomycosis

PSO could be presented as patches or transversestriate patterns. The infection starts under theproximal nail fold and continues distally. The mostcommon pathogens in this subtype are T. rubrumand Fusarium spp.

FIG. 2. Superficial white onychomycosis.

FIG. 3. Endonyx onychomycosis.

FIG. 4. Total dystrophic onychomycosis.

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MPO – mixed pattern onychomycosis

MPO is a combination of the above subtypes inthe same patient or even in the same nail, such asDLSO + SO and DLSO + PSO.

Secondary onychomycosis

Secondary onychomycosis is the invasion of thefungal agent to a deformed nail due to trauma ordisease such as psoriasis.

Laboratory analysis

The diagnosis of onychomycosis may be detectedvia a clinical examination, but a definitive diagnosisis made by the “gold standard” – direct microscopyand mycological culture.

The collection of thespecimen technique

After obtaining the clinical diagnosis of onychomy-cosis, the second step before treatment is a myco-logical confirmation or a negation of the diagnosis.

It is very important for the laboratory to definethe type of the onychomycosis. The mycologicaltechnician collecting the specimen must do itcorrectly according to the type of onychomycosis –otherwise, it can be misinterpreted. In case ofnegative results, a reevaluation should be per-formed (12).

The most common type of onychomycosis isdistal and lateral onychomycosis –DLSO. In thiscase, it is important to take the specimen fromthe subungual area under the nail plate and fromthe nail bed with a curette and/or use a drill (13)(FIG. 5).

In superficial white onychomycosis, the speci-men should be taken from the upper superficialpart of the nail plate, with a scalpel blade number10 or 15.

In PSO – proximal subungual onychomycosis –the specimen should be taken from the proximalsubungual part of the nail by curette, scalpel bladenumber 15 or by drilling (14).

Before systemic treatment of onychomycosis, amycological diagnosis is essential in order to deter-mine the fungi type and so as to provide the righttreatment.

After collecting the mycological specimen fromthe relevant location, a direct smear and culturewith and without cycloheximide should be carriedout in order to find out the type of the fungus.

Definition of cure(clinical/mycological) rates

There are several parameters in determiningthe total cure in onychomycosis – a clinical cure80–100%, combined with a positive or negativedirect smear and a negative mycological culture.These different parameters cause variations amongdifferent studies worldwide. In the absence of clear,consistent criteria in “total cure” rates, the differentresults observed prevent precise conclusions (15).The variation may be even greater as differentstudies examine results for treatment given for dif-ferent lengths of time. These varying results mayeven be found when the same drug and dosage aregiven for the same length of time (16).

Although one might expect research results tovary, such a great variation is implausible (16).

Bad prognostic factors for the totalcure of antifungal agent/s (17–19)

Nail characteristics:1. thickened nail plate >2 mm2. slow growth of the nail plate3. more than 75% of the nail plate/bed involved4. matrix involvement5. longitudinal spike/streak6. lateral nail disease7. onychomycosis with severe onycholysis8. subungual dermatophytoma9. high nail severity index (19)Patient characteristics:

1. immuno-compromised individuals2. family history of onychomycosis

FIG. 5. Collection of subungual debris using drillingmethods.

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3. poor hygiene4. old patients5. Down’s syndrome6. Severe onychomycosis7. poor compliance8. poor vascularization9. diabetes mellitus

10. severe tinea pedis11. major and/or recurrent minor traumasLaboratory characteristics:1. incorrect diagnosis (misdiagnosed moulds

and/or yeast – due to the presence of cyclohex-imide in the fungal culture media which pre-vents the growth of different molds and yeasts)

2. misinterpretation of the fungus in the culture3. technical mistakes in the laboratoryAntifungal agents:1. poor bioavailability2. drug interactions3. incorrect dosage4. drugs and food (e.g., itraconazole with empty

stomach – decreasing the efficacy)5. incorrect length of time using the antifungal

agent6. incorrect antifungal agent (e.g., griseofulvin for

Candida and/or molds)

Prediction of treatment results

The dermatologist should include and exclude hisfindings carefully not only by anamnesis but alsoby a very close inspection. If any nails are notpurely infected by onychomycosis, the patient hasto be notified that there may be a chance that thenail will not be totally cured. In some cases, thevisual state of the deformed nail can be wronglyperceived as onychomycosis, whereas a laboratorytest will find the presence of some molds and/oryeasts, which are irrelevant to the nail condition.Onychomycosis may be mistakenly diagnosed,thus resulting in irrelevant treatment.

Decision of treatment

Why is it necessary to treat onychomycosis?

Onychomycosis is basically a cosmetic problemand that is a good enough reason to have it treated.

Onychomycosis of the finger nails causesdifferent functional disabilities besides the cos-metic inconvenience. On one hand, nonspontane-ous remission of the onychomycosis, and on theother hand, a risk of contamination of the other

nail/s in the same patient, and/or contaminationof other healthy people. All of the above are goodreasons to start treatment.

Onychomycosis causes deformation of theinvolved nail (big/thick nails). When it comes totoenails, this deformation may cause a retrogradepressure from the shoes – an uncomfortable sensa-tion while walking/running (20).

Other reasons are medically related, e.g.,recurrent erysipelas/cellulites, ingrown nail/s, anda secondary infection.

Patient expectation

The patient’s expectation – as a rule – is to achievea normal looking nail, although some of thepatients would like to be sure that there is no morefungus existing in the nail after the successful treat-ment, which is as important as a good clinicalappearance of the nail.

In case of combined disorders such as nailtrauma and onychomycosis, treatment with sys-temic antifungal medication will diminish orconceal the fungus only and is not supposed tomake any changes in the deformation, which is notdirectly related to the fungus itself.

However, the patient’s expectation – in the caseabove – is to achieve a total cure regardless of theother cause – the traumatic deformation. From thepatient’s point of view, a total mycological cure isthe goal.

Negative mycological results – a direct smearand culture – after the end of the treatment fromthe nail with the combined disorder (trauma andonychomycosis), which do not achieve a total curein contrast to the other neighboring nails that aretotally cured (clinically and mycologically), do notreally interest the patient, whose goal is the goodhealthy appearance of the nail (FIG. 6).

Expectation of treatment

Realistic expectation can be achieved by basicanamnesis, careful inspection of the involved nails,and in this way, we can decrease the possibility ofoverexpectation.

In the case of combined nail disorders, two typesexist:1. localized – traumatic onychodystrophy – revers-

ible or irreversible nail unit trauma (to the nailbed and/or nail matrix)

2. systemic disorders that involve the nails –psoriasis, lichen planus, chronic dermatitis,idiopathic onycholysis, 20 nail dystrophy, ony-chogryphosis, pachyonychia congenita, yellow

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nail syndrome, Darier’s disease, etc.When alocalized disorder is the case – traumatic ony-chodystrophy – and other neighboring nailssuffer from pure onychomycosis, the caregivercan predict that the nail suffering from irrevers-ible traumatic onychodystrophy will not betotally cured, even though the mycologicalanalysis was positive, whereas other neighbor-ing pure onychomycosis cases are totally cured.When systemic disorders of the nails with ony-

chomycosis are the case – combined disorders –the caregiver should not expect a total curebecause the antifungal medication may not be ableto treat the other disorder.

As a matter of fact, it depends on the degree ofthe relationship between the two disorders. If themajority of the deformation is due to the fungalinfection, a greater part of the nail will improve.On the other hand, in the case of minimal involve-ment of fungal infection in the diseased nail, noimpressive involvement can be predicted (exceptfor cases where other diseases produce the Köbnerphenomenon/the isomorphic phenomenon) tothe nail itself (e.g., psoriasis, lichen planus) by thefungus and the elimination of the fungus canreduce or even eliminate the basic disorder of thenail.

Treatment

Further treatment is based on the severity of thepatient’s onychomycosis, the other drugs usedconcomitantly, and one’s compliance with thetreatment.

Hence, the new antimycotic treatment is pro-longed by a few months (in contrast to the old

drugs griseofulvin and ketoconazole, which weregiven for up to 18–24 months or until total replace-ment of the nail plate). The new antimycotic drugsremain in the nail matrix for more than 6 months,depending on the drug, after cessation of the sys-temic treatment, in a concentration (i.e., above theminimal inhibitory concentration) that is neededfor the majority of dermatophytes. The clinical andmycological success will be judged after 12–18months, depending on the basic clinical feature(mild onychomycosis needs less time to replace theinfected nail plate and severe cases need longerperiods of time). Another parameter that should betaken into account is the growth rate of the nailplate, which is related to race and age. The patienthas to be informed that although the treatment isover, the antimycotic drug in the nail continuesworking and the results will be seen within severalmonths or more. Without knowing this very impor-tant parameter, the patient will misinterpret theoutcome.

The management options are variable and basi-cally depend on the clinical severity of the onycho-mycosis. Choosing the correct treatment willdepend on the clinical pattern of the fungus typeand the severity of the onychomycosis.

In general, the onychomycosis managementincludes systemic antifungal agents, topical anti-fungal agents, chemical debridement, medicaldevices, palliative treatment, and the combina-tions between the above options.

The results of the treatment of onychomycosisare often a disappointment for various reasons.The most common cause for these failures is incor-rect diagnosis.

Most physicians and some dermatologists mightfind looking at the clinical signs sufficient and willonly perform the onychomycosis diagnosis.

In those cases, where the physicians take amycological analysis from nails that do not presentclinical signs of onychomycosis, they get a resultof nondermatophyte molds, which are not neces-sarily pathogenic and will give a systemic and/ortopical treatment, which is irrelevant to the nailcondition.

Among the conditions that might be falsely per-ceived as onychomycosis are prior nail traumas,psoriasis, contact dermatitis, thick nails, 20 naildystrophy, etc.

Therefore, it is very important to choose suitableonychomycosis cases for the mycological analysis.It is important to take a clinical look at the onycho-mycosis; otherwise, we might wrongly perceivemolds or yeasts, which are often irrelevant to theclinical analysis.

FIG. 6. Onychomycosis and trauma.

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In addition, we need to check if it is indeeda dermatophyte or a mold, which could be asaprophyte (21).

In this chapter, the systemic and topical antifun-gal will be discussed.

The newer topical antifungal is based on theability to penetrate the nail plate through to thenail bed.

Medical devices will be discussed in anotherchapter.

Systemic treatment – gold standard

Systemic antifungal agents are considered – to date– as the gold standard for all types of onychomyco-sis. These agents achieve the highest cure rate –clinically and mycologically.

Griseofulvin was the first oral systemic antifun-gal agent. For about three to four decades, griseof-ulvin was the only oral antifungal agent available.The very low cure rate of griseofulvin for onycho-mycosis led doctors to look for a better solution.For many years, griseofulvin has not been the drugof choice for onychomycosis worldwide, but thisold drug should be mentioned at least for historicalreasons.

The newer drugs, such as terbinafine anditreaconazole, are the leading antimycotic agentsworldwide. Fluconazole is not approved for thetreatment of onychomycosis in the majority ofcountries, although several studies show that thisdrug is effective for onychomycosis.

Other systemic antimycotic agents are not rou-tinely available for the treatment of onychomyco-sis. These newest agents will be discussed in shortfurther ahead.

Griseofulvin

As mentioned before, griseofulvin was the firstantimycotic drug specifically approved for ony-chomycosis. For many years, terbinafine and –less commonly – itraconazole were used as thedrug of choice for onychomycosis. It should bestressed that griseofulvin is not effective againstdifferent types of molds and yeasts, but only fordermatophytes.

The acceptable dosage of griseofulvin for ony-chomycosis in healthy adults is 500-1000 mg/day,for up to 12–18 months. The treatment with griseof-ulvin is continued until the complete regrowth ofthe whole new nail plate.

The mechanism of griseofulvin is brought aboutby affecting nucleic acid synthesis and arrestingfungal cell mitosis in metaphase.

The low cure rate of onychomycosis is com-monly as a result of the long time use of the drug –up to almost 2 years in severe cases – causinglow patient compliance. Another reason is that agroup of dermatophytes and yeasts and molds arewell known to accompany the pathogenic fungus.The ineffectiveness of griseofulvin for yeasts andmolds and the lengthy time of treatment play acritical role for the low cure rate of griseofulvin foronychomycosis.

The cure rate of griseofulvin is low and is esti-mated at 20–60%, with an average of 30%.

A combination therapy of griseofulvin with40% urea was better than griseofulvin alone (22). Acombination therapy of griseofulvin or other sys-temic drugs with 5% amorolfine nail lacquer wasbetter than systemic drug only– griseofulvin (23).

Adverse events

Adverse events associated with griseofulvin areusually mild and reversible. The most common sideeffects are gastrointestinal disturbance and head-aches, which occur in 15% of the patients treated.Hypersensitivity (skin rash, urticaria, angioneuroticedema, and toxic epidermal necrolysis) is rarelyobserved.

Serious adverse events such as hepatotoxi-city, leucopenia, thrombocytopenia, or anemia arerarely reported.

Griseofulvin increases the metabolism of war-farin by its action on the cytochrome P-450 andmay reduce the efficacy of several oral contracep-tive pills.

Several studies have shown that the azoles andthe allylamine – terbinafine – are more effectivethan griseofulvin. As a result, the use of griseofulvinhas decreased in the last 20 years.

Ketoconazole

Ketoconazole is a broad-spectrum antifungal agentthat was the first orally active imidazole (3). The useof this agent in onychomycosis was limited evenbefore recent developments as it has many disad-vantages. Unlike recent treatments, the medicinehas to be consumed until a full cure is visible andthe nail has completely regrown. As a result, thetreatment takes a long period of time, same asgriseofulvin.

In addition, there is an occurrence of sideeffects such as hypersensitivity reactions, nausea,

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vomiting, headaches, abdominal pain, pruritus,and fever. The most significant side affect is hepa-totoxicity, which has a range of 1 in 10,000 inci-dences reported (3).

Terbinafine

Terbinafine is an antifungal agent – fungicidal andfungistatic – which belongs to the allylamine class.This medication was developed in 1979 and wasapproved for the treatment of onychomycosis in1991 in the United Kingdom. Currently, it is theonly fungicidal oral antimycotic and it is highlyeffective against fungi, dermatophytes, and someyeasts; terbinafine has low efficacy against nonder-matophyte molds.

Terbinafine penetrates the nail through thenail matrix and the nail bed. The metabolismof terbinafine goes through the cytochrome (CY)P450 enzymes.

The acceptable dosage for onychomycosis is250 mg on a daily basis for 3–4 months.

The mechanisms of terbinafine

Terbinafine has a dual inhibition of sterol biosyn-thesis. The actions of inhibition are fungicidal andfungistatic. Terbinafine exhibits its fungicidal activ-ity by inhibiting the production of squalene epoxi-dase, causing the accumulation of squalene in cellcytoplasm, leading to lipid droplets within the cell,the release of lytic enzymes, and the disruption ofcell physiology, and as a result, the rapid death ofthe fungal cell.

Subsequently, the fungistatic action is via thebiosynthesis inhibition of the ergosterol.

Pharmacokinetics of terbinafine

More than 70% of terbinafine is absorbed whenthe drug is taken orally (after food or on emptystomach) and 19% of oral terbinafine binds withplasma proteins.

Terminal half-life of terbinafine is as muchas 200–400 hours, which supplies dermatologicaleffectiveness for several weeks after the cessationof the treatment.

After 2 hours of oral intake of 250 mg ter-binafine, the plasma concentration may reach0.8 mg/L. In case of a liver or kidney disorder,about 50% of terbinafine is discharged from thekidney.

Terbinafine is strongly lipophilic, and as a result,it binds with the adipose tissue and the skin,leading to its slow elimination from the body.

The unique mechanism of action of terbinafine– in addition to the mechanism of the other azoles– may account for its higher efficacy comparedwith the other systemic antifungal. Many reviewsand many meta-analysis studies have shown somedifferences among the studies. Using the meta-analysis technique has shown the superiority ofterbinafine compared with other available sys-temic antifungal agents.

A meta-analysis review, which was performed byGupta et al., shows the variation in results in differ-ent research (24).

A meta-analysis of 36 studies of systemic mono-therapy of terbinafine for onychomycosis foundthat terbinafine had higher mycological cure rates(76%; n = 18 studies, 993 patients) than eithergriseofulvin (60%; n = 3 studies, 131 patients),fluconazole (48%, n = 3 studies, 167 patients),continuous itraconazole (59%; n = 7 studies, 1131patients), or pulse itraconazole (63%; n = 6 studies,318 patients) (24).

A prospective, random, double-bind, double-dummy, multicenter, parallel-group study tocompare the efficacy and tolerability of continuousterbinafine with intermittent itraconazole in thetreatment of toenail onychomycosis was carriedout. Four hundred ninety-six patients with a clini-cal diagnosis of dermatophyte toenail onychomy-cosis, confirmed by a positive mycological cultureand microscopy (KOH), were recruited from 35centers in six European countries. At week 72, theclinical efficacy (defined as mycological cure andat least 5 mm of new clear toenail growth frombaseline) was 65.7% (67/102) for terbinafine at 3months, 70.5% (67/95) for terbinafine at 4 months,28.4% (29/102) for itraconazole at 3 months, and33.7% (35/104) for itraconazole at 4 months. Allcomparisons at week 72 were again statistically infavor of the terbinafine regimens, p < 0.0001.

Continuous terbinafine was significantly moreeffective than intermittent itraconazole in the treat-ment of toenail dermatophyte onychomycosis.

Adverse effects

The most commonly reported adverse effects ofterbinafine include gastrointestinal effects, such astaste disturbance, nausea, diarrhea, and mildabdominal pain. The overall frequency of adverseeffects is about 10% (3). In rare cases, terbinafinehas been associated with hepatotoxicity, compris-ing a prodrome of asthenia, anorexia, and abdo-minal pain about 1 week prior to the onset ofjaundice, pale white stools, and dark urine that canprogress to a mixed hepatocellular and cholestatic

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dysfunction. Although terbinafine-induced hepa-totoxicity is rare, it is recommended that patientson terbinafine therapy have liver function testsperformed before treatment and at 4–6 weeks.

Drug interactions

In interaction with rifampin (a CYP450 inducer),terbinafine’s clearance is increased, whereas ininteraction with cimetidine (a CYP450 inhibitor),nortriptyline, paroxetine, amitriptyline, and desi-pramine, its clearance is decreased. Thus, avoidcombination or adjust dosages accordingly.

Terbinafine increases metabolism of cyclospo-rine by 15% – thus, there is a need to monitor thecyclosporine levels (25).

Itraconazole

Itraconazole is a triazole antifungal that rapidlypenetrates the nail plate (3). It was developed in thelate 1980s and was approved for the treatment ofonychomycosis in 1995.

Itraconazole can be detected at the distal nailplate within 7 days from the beginning of the treat-ment and has a wide spectrum of antifungal activ-ity, namely dermatophytes, nondermatophytemolds, and yeasts.

There are two different regimens of itraconazole.The first-continuous regimen – which is approvedby Food and Drugs Administration (FDA) – is200 mg/day for 3 months, and the other regimen ispulse regimen – 400 mg/day for 1 week, monthlyfor 3–4 months.

A meta-analysis of 318 patients who weretreated with continuous itraconazole 200 mg/day,and 1131 patients on pulse itraconazole 400 mg/day shows similar clinical results, 63% vs. 59%,respectively. It is twice as cheap to use the pulseregimen.

As mentioned in the LI ON study (26) and otherstudies, the total cure of itraconazole continuousor pulse regimens is about 30–50%, depending onthe definition of the cure.

Regarding the adverse events of itraconazole,the most common is a minor gastrointestinal upsetor headaches. The reversible elevation of liver func-tion tests may occur (27). Therefore, liver functiontests should be monitored.

Itraconazole inhibits the fungal cell CYP450enzyme, 14-a demethylase, which prevents theproduction of ergosterol, which is a very importantcomponent in the fungal cell wall. Itraconazole iswell absorbed when taken with food and low acidpH. Itraconazole is not recommended and some-

times contraindicated with the coadministrationof oral cisapride, midazolam, pimozide, triazolam,and different types of statins. The absorption ofitraconazole is decreased by coadministrationwith gastric acid suppressors. Coadministration ofcyclosporine and/or tacrolimus with itraconazoleraises the levels of cyclosporine and tacrolimus.Severe hypoglycemia may occur when coadminis-tered with some hypoglycemic agents.

Thus, avoid combination or adjust dosagesaccordingly (25).

Fluconazole

Fluconazole is a bis-triazole drug, which wasdeveloped in the 1990s (3).

Its mechanism of action is like the other triaz-oles, inhibiting the synthesis of ergosterol. Flu-conazole is dependent on the CYP450 system. Itcan be taken regardless of food intake. Fluconazoleis effective against dermatophytes and other typesof Candida spp.

Fluconazole is authorized in some countries forthe treatment of onychomycosis, whereas in othercountries, it is only used for the treatment of tineacorporis of the skin. The fluconazole cure ratevaries and is considered low compared with itra-conazole and terbinafine. Side effects are similarto itraconazole, including headaches, nausea, andgastrointestinal upsets. As fluconazole is metabo-lized by the CYP450 enzyme system, coadmini-stration with phenytoin, hypoglycemic agents,cyclosporine, rifampin, terfenadine, and theophyl-line is contraindicated.

There are new azoles that are not yet widelydistributed. We shall describe them briefly.

Voriconazole

Voriconazole is a triazole structurally similar tofluconazole. It was approved by the FDA in 2002(26). Among the side effects are fever, rash, nausea,vomiting, abdominal pain, diarrhea, headaches,peripheral edema, sepsis, respiratory disorders,and visual disturbances. Liver function tests maybe elevated as a result of voriconazole, but this isusually reversible.

Voriconazole is effective against Scopulariopsisbrevicaulis, Fusarium spp., and Scytalidium dimid-iatum, which are well known to be effective againststubborn conditions of onychomycosis. There arenot enough controlled data regarding the outcome

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of the cure rate of onychomycosis with voricona-zole in clinical studies (28).

Posaconazole

Posaconazole like the other azoles inhibits CYP450,14-a demethylase, which blocks the synthesis ofergosterol. Posaconazole is effective against differ-ent types of non dermatophyte molds (NDM), suchas Aspergillus, some yeasts (Candida spp.), andzygomycete infections (28).

Posaconazole has similar side effects as otherazoles, including headaches, skin rashes, dry skin,dizziness, nausea, flushing, abdominal pain, andtaste disturbance (as in terbinafine). Liver functiontests may be elevated by posaconazole but isusually reversible. Posaconazole 200 mg/day for 24weeks cure rate is 54.1%, whereas the mycologicalcure rate is 59% (29).

Ravuconazole

Ravuconazole, as the other azoles, blocks the syn-thesis of ergosterol by inhibition of the 14-a dem-ethylase enzyme. Ravuconazole is effective againstspecies of Candida, Cryptococcus neoformans, der-matophytes, and dematiaceous fungi. There aresimilar side effects to other azoles, including head-aches, abdominal pain, liver function tests eleva-tion, rash, etc. The effective cure of ravuconazole200 mg/day for 12 weeks in onychomycosis is 56%,whereas the mycological cure rate is 59% (30).

Isavuconazole

This azole has shown similar activity as terbinafine,but further comparative studies are needed toassess the effectiveness of isavuconazole for thetreatment of onychomycosis. In vitro there isan activity against Zygomycetes, Cryptococcus,Aspergillus spp., Scedosporium spp., Fusariumspp., and Candida spp. In vitro activity was reducedagainst Histoplasma capsulatum. It has beenshown to be effective in vivo against candidiasisand invasive Aspergillosis. Drug interactions weredescribed.

The drug is currently in Phase 3 clinical trials.There are not enough controlled data regarding theoutcome of the cure rate of onychomycosis withisavuconazole in clinical studies (31).

Pramiconazole

Pramiconazole can be administered orally forthe treatment of dermatomycosis, onychomycosis,

and seborrheic dermatitis (32). The drug was welltolerated in Phase 1 and 2 clinical trials and canbe given in a once-daily dose due to its long half-life. It reduces the growth of Malassezia globosa,Candida albicans, T. rubrum, T. mentagrophytes,and Microsporum canis. There are not enough con-trolled data regarding the outcome of the cure rateof onychomycosis with pramiconazole in clinicalstudies (32).

Albaconazole

Albaconazole is a broad-spectrum antifungalagent. This drug was effective against candidiasis,systemic aspergillosis and cryptococcosis. In Phase2 studies, this drug showed better efficacy than flu-conazole in tinea pedis and toenail onychomyco-sis when administered once weekly. There are noenough controlled data regarding the outcome ofthe cure rate of onychomycosis with albaconazolein clinical studies (33).

Topical treatment

The topical treatment for onychomycosis can bedivided into three sub-chapters:

Topical antifungal creams/ointments/solutions/lotions/foams

All the above topical forms of antifungals are basi-cally not used as a monotherapy for onychomyco-sis but can be used as an adjuvant to the systemicantifungal agents.

Topical antifungal treatment. Topical antifungaltreatment including creams, gels, ointments, andsolutions are usually not effective against onycho-mycosis (except for a very mild case of onychomy-cosis). This is due to their inability to penetratethrough the nail plate. Therefore, these topicaltreatments are effective against dermatomycosisand have a limited effectiveness against onycho-mycosis. Among them are azoles – bifonazole,butoconazole, clomidazole, clotrimazole, econa-zole, fenticonazole, ketoconazole, isoconazole,miconazole, neticonazole, omoconazole, oxicona-zole, sertaconazole, sulconazole, and Tioconazole –and allylamines/benzylamines – butenafine,naftifine, and terbinafine.

Nail lacquers and solutions for onychomycosis

There are four available nail lacquers/solutions foronychomycosis:

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1. amorolfine (Loceryl, Laboratories GaldermaS.A., France)

2. ciclopirox olamin (Batrafen, Sanofi -Aventis,Deutschland GmbH; Penlac, Dermik Laborato-ries, Bridgewater, NJ, USA)

3. tioconazole 28%4. terbinafine nail lacquer.

Amorolfine (Loceryl). Amorolfine nail lacquer is abroad-spectrum antifungal agent. The amorol-fine molecule inhibits two enzymes (delta-14-reductase and delta-7,8-isomerase) (28). These twoenzymes block the production of ergosterol andhave fungistatic and fungicidal properties. Theamorolfine molecule is lypophilic and unionized(depends on the pH of the nail plate, which isusually 7.4). The amorolfine molecule tends to beunionized due to the basic pH of the nail plate.These two characteristics (lipophilic and union-ized) are important for the penetration through thenail plate to the nail bed, and the penetration intothe fungal membrane. The onychomycosis caserate of amorolfine as a monotherapy is 12–71% (23)and it acts as topical lacquer.

Ciclopirox olamine. Ciclopirox olamine 8% is abroad-spectrum antifungal agent. Its exact mecha-nism is unknown. Ciclopirox may inhibit the trans-port of certain essential substrates into fungal cells.Ciclopirox may influence the production of differ-ent proteins.

Ciclopirox nail lacquer penetrates the nail plateto the nail bed. The fungicidal effect of ciclopirox isbased on its inhibition of the cellular uptake of vitalcell ingredients. The onychomycosis case rates ofciclopirox olamine are around 9–31.3% (23) and itacts as a topical lacquer.

Tioconazole nail solution

Tioconazole (28%) nail solution is a topical pre-paration for onychomycosis. Tioconazole is asubstituted imidazole that has antimicrobial andantifungal properties, and has a broad spectrum ofactivity in vitro against dermatophytes and yeasts.The cure rate of the treatment with tioconazole nailsolution is 22% (34).

Terbinafine nail lacquer

Terbinafine nail lacquer is a new product. This naillacquer has a penetration enhancer, which helpsthe terbinafine molecules penetrate the nail plateto the nail bed. So far, there are not enough com-

parative clinical studies, and the nail lacquer is notavailable in the market yet.

Nail avulsion

Chemical nail avulsion is a painless method of ony-chomycotic thickened/deformed nail dissolving.Using this method in addition to the relevant sys-temic treatment supplies better results than thesystemic treatment alone. This is due to the factthat the systemic drug is acting against loweramount of fungal elements; hence, the chemicaldebridement itself eliminates a large amount offungal elements and deformed keratin.

Three different types of nail avulsion are known:1. chemical avulsion2. surgical avulsion3. laser avulsionIn this article, chemical avulsion

will be discussed in short.The chemical avulsion can be divided into

two parts: keratinolytic agents and keratinoplasticagents.

The keratinolytic agents crack the interconnect-ing disulfide bridges of keratin. The lattice-likepolymerization of the keratin is broken up and theprotein structure undone at the molecular level.

Chief members of this group are as follows:

Thioglycolic acid, alkali sulfides,earth alkali sulfides

The keratinoplastic agents act on the cementingsubstances located between the individual keratinstrands. These agents chemically break the hydro-phobic bonds such as parallel arrangement of themolecular chains.

Chief members of this group are as follows:

Urea, salicylic acid, and resorcin

Both keratinolytic and keratinoplastic agents alterthe keratin structure, facilitating the penetration ofthe antimycotic agents in and through the skin andnails. Application of 40% urea results in change inthe bound intermolecular water alteration of theratio between the water enveloping the proteinsand the intramolecular water deposit expulsionof water and replacement of other water mol-ecules, causing changes in the nail elasticity,extreme loosening of keratin, and easy removal ofthe nail material.

Urea is indicated in higher concentrations forlocal use in the removal of keratin masses without

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completely destroying the barrier function. Chemi-cal ablation debridement probably facilitates theattachment of the nail plate to the nail bed. Healthy(compact) nail does not respond well to urea debri-dement (35).

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