Dermatologic Therapy, Vol.

25, 2012, 582593 Printed in the United States All rights reserved

2012 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

INVITED ARTICLE

Update: medical treatment of onychomycosis

Avner Shemer
Dermatology, Sheba Medical Cenet-Tel Hashomer, Tel-Aviv University, Tel Hashomer, 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 or veried presence of molds and/or yeasts. Dermatophytes are usually considered as pathogens, whereas non-dermatophyte molds and yeasts are saprophytes. Basic anamnesis and close inspection should be performed to eliminate combined diseases (e.g., onychomycosis and trauma). The gold standard treatment for onychomycosis is basically systemic. Combination with topical agents, such as nail lacquer and/or chemical nail avulsion, produces better results than systemic treatment alone. Topical treatment as monotherapy is not efcient, excluding minor cases. Terbinane is superior to itraconazole for dermatophyte onychomycosis. Evaluation of the outcome of clinical cure, mycological cure and total cure should be based on the well-dened worldwide criteria; otherwise, comparison of results is impossible due to lack of uniformity in different studies. In case of treatment failure, the reasons for each failure should be carefully considered. KEYWORDS: combined diseases, diagnosis of onychomycosis, onychomycosis, treatment failure, unied criteria for cure

Introduction
Onychomycosis is a common fungal infection of the toenails and/or ngernails and may be due to dermatophytes, yeasts, and nondermatophyte molds (1,2). In about 90% of the cases, the cause of onychomycosis is the anthropophilic dermatophytes: Trichophyton rubrum and Trichophyton mentagrophytes. Nondermatophyte molds and yeasts are much less common (3). The rates of onychomycosis worldwide are not clear enough. Different studies show a very wide range of 240%. Many factors contribute to this wide range: age, race, country, other nail/s, and/or
Address correspondence and reprint requests to: Avner Shemer, MD, Professor of Dermatology, Sheba Medical Cenet-Tel Hashomer, Tel-Aviv University, Tel Hashomer 52621, Israel, or email: ashemer1@gmail.com.

systemic diseases, and of course the way of the calculation, namely from the general population or a specic population that comes to be examined due to foot problems. Within subgroups such as elderly patients, patients with diabetes mellitus, and HIV positive patients, the prevalence of onychomycosis could be as high as 60 and 30%, respectively (4). Different studies show onychomycosis prevalence of 2.1813% (5), whereas among elderly patients, it may reach up to 28% (6). Onychomycosis is 425 times more widespread in toenails than in nger nails (4,7). The results of the Achilles Project in Europe regarding the prevalence of onychomycosis (in 16 European countries) is 3540% (4). Predisposing factors for onychomycosis are as follows: old age, sex, genetic susceptibility, tinea pedis (moccasin type), nail psoriasis (controversy), peripheral arterial disease, smoking, diabetes

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mellitus, different nail trauma/s, inactivity, family background of onychomycosis, different causes of immune deciency, hyperhidrosis, and inappropriate nail hygiene (4,5,8). Onychomycosis is very rarely found in young children. Several studies show that the incidence of onychomycosis in young children is less than 0.5% (9). Scher (8) showed that the estimation of onychomycosis in children is 30 times less than in the adult population. In addition, young children lack the risk factors for onychomycosis, which are well known in playing a role in the development of onychomycosis. Young children also have smaller nail surfaces and faster nail growth (10). The very low incidence of onychomycosis in children is due to rapid nail growth, which occurs faster than the retrograde progression of the fungus from the distal part of the nail to the matrix region.

7. Secondary onychomycosisAnother subtype represents the end stage of the progression of all the above subtypes. The term for this end-stage subtype is TDO total dystrophic onychomycosis, which is secondary to one of four subtypes. TDO can primarily be due to a chronic mucocutaneous candidiasis.

DLSO distal and lateral subungual onychomycosis

DLSO is the most common type of onychomycosis. The infected fungus begins with the invasion of the hyponychium. The fungus penetrates the horny layer of the hyponychium and then the distal and the ventral parts of the nail plate and at the same time or thereafter to the nail bed. The rst clinical picture of this subtype is variable. Usually, the distal portion of the infected nail becomes thickened and opaque. This minor deformation starts to progress distally, causing a separation between the nail plate and the nail bed (FIG. 1). The direction of the fungus pathway is toward the proximal nail fold, and on the other hand, the direction of the nail growth is distal. The equilibrium of these two contrary progressions usually tends to move to the fungus pathway, and as a result, the nail plate becomes more and more deformed, opaque, and thickened. The most common pathogens for DLSO are dermatophytes. T. rubrum is the most common pathogen, whereas T. mentagrophytes var. interdigitalis and Epidermophyton occosum are relatively uncommon especially the latter.

Onychomycosis denition
Onychomycosis is a fungal infection of the toenails and/or ngernails. The meaning of onychomycosis is derived from the Greek language, namely onyx a nail, mykes a fungus. It may involve any component of the nail unit, namely the nail plate, the nail bed, and the nail matrix (7). Tinea unguium refers to the dermatophyte infection of the nails, whereas onychomycosis 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 and the location of the fungus penetration into the nail plate.

Subtypes
There are seven subtype clinical patterns of onychomycosis (11): 1. DLSO distal and lateral subungual onychomycosis. 2. SO supercial onychomycosis (white or black) 3. EO endonyx onychomycosis 4. PSO proximal subungual onychomycosis 5. MPO mixed pattern Onychomycosis 6. TDO total dystrophic onychomycosis

FIG. 1. Distal and lateral subungual onychomycosis.

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The spread of T. rubrum on the nail bed is from the plantar area of the toes. The infection usually begins with the involvement of the distal corner of the big toenail and progresses along the nail bed and the ventral part of the nail plate toward the nail matrix. Sometimes, the progression is located only in the corner and then continues proximally by creating a yellow spike. The yellow spike (also called yellow streak) is a variant of DLSO and this subtype is very difcult to get rid of when attempting medical treatment.

the absence of the classical picture onychomycosis and subungual hyperkeratosis. The most common pathogenic dermophyte is Trichophyton soudanense and Trichophyton violaceum (FIG. 3). TDO total dystrophic onychomycosis Total dystrophic onychomycosis is the end stage of all the above subtypes. All the nail plate is deformed, opaque. This type is considered as a secondary form. Primary TDO may be seen in patients suffering from chronic mucocutaneous candidiasis or in other immune-compromised patients (FIG. 4). PSO proximal subungual onychomycosis PSO could be presented as patches or transverse striate patterns. The infection starts under the proximal nail fold and continues distally. The most common pathogens in this subtype are T. rubrum and Fusarium spp.

SO supercial onychomycosis (white or black)

This clinical type could be patchy or transverse, which originates from beneath the proximal nail fold or with deep penetration through the nail plate. Supercial white onychomycosis is a supercial infection of the outer part of the nail plate (FIG. 2). SWO is usually located in the toe nails, but it can also occur in the ngernails. The most common cause for this type of onychomycosis is T. mentagrophytes var. interdigitalis (90%). Other pathogens causing SO are T. rubrum, Scytalidium, Aspergillus spp., Fusarium spp., and Acremonium spp. The clinical picture of SWO appears as white patches located on the supercial portion of the nail plate, which may coalesce and cover all or almost all the nail plate. Extensive SWO is usually seen together with vesiculobullous tinea pedis, which is also caused by the same pathogen T. mentagrophytes var. interdigitalis. Supercial black onychomycosis: the dark (black) discoloration of the nail plate is caused by the invention of T. rubrum var. nigricans or the mold Scytalidium dimidiatum. Endonyx onychomycosis (EO) is a rare type of onychomycosis (a variant of distal and lateral subungual onychomycosis). EO is characterized by a massive nail plate invasion with no involvement of the nail bed. The nail plate is opaque and white in

FIG. 3. Endonyx onychomycosis.

FIG. 2. Supercial white onychomycosis.

FIG. 4. Total dystrophic onychomycosis.

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MPO mixed pattern onychomycosis MPO is a combination of the above subtypes in the same patient or even in the same nail, such as DLSO + SO and DLSO + PSO.

Secondary onychomycosis
Secondary onychomycosis is the invasion of the fungal agent to a deformed nail due to trauma or disease such as psoriasis.

Laboratory analysis
The diagnosis of onychomycosis may be detected via a clinical examination, but a denitive diagnosis is made by the gold standard direct microscopy and mycological culture.
FIG. 5. Collection of subungual debris using drilling
methods.

The collection of the specimen technique

After obtaining the clinical diagnosis of onychomycosis, the second step before treatment is a mycological conrmation or a negation of the diagnosis. It is very important for the laboratory to dene the type of the onychomycosis. The mycological technician collecting the specimen must do it correctly according to the type of onychomycosis otherwise, it can be misinterpreted. In case of negative results, a reevaluation should be performed (12). The most common type of onychomycosis is distal and lateral onychomycosis DLSO. In this case, it is important to take the specimen from the subungual area under the nail plate and from the nail bed with a curette and/or use a drill (13) (FIG. 5). In supercial white onychomycosis, the specimen should be taken from the upper supercial part of the nail plate, with a scalpel blade number 10 or 15. In PSO proximal subungual onychomycosis the specimen should be taken from the proximal subungual part of the nail by curette, scalpel blade number 15 or by drilling (14). Before systemic treatment of onychomycosis, a mycological diagnosis is essential in order to determine the fungi type and so as to provide the right treatment. After collecting the mycological specimen from the relevant location, a direct smear and culture with and without cycloheximide should be carried out in order to nd out the type of the fungus.

Denition of cure (clinical/mycological) rates

There are several parameters in determining the total cure in onychomycosis a clinical cure 80100%, combined with a positive or negative direct smear and a negative mycological culture. These different parameters cause variations among different studies worldwide. In the absence of clear, consistent criteria in total cure rates, the different results observed prevent precise conclusions (15). The variation may be even greater as different studies examine results for treatment given for different lengths of time. These varying results may even be found when the same drug and dosage are given for the same length of time (16). Although one might expect research results to vary, such a great variation is implausible (16).

Bad prognostic factors for the total cure of antifungal agent/s (1719)
Nail characteristics: 1. thickened nail plate >2 mm 2. slow growth of the nail plate 3. more than 75% of the nail plate/bed involved 4. matrix involvement 5. longitudinal spike/streak 6. lateral nail disease 7. onychomycosis with severe onycholysis 8. subungual dermatophytoma 9. high nail severity index (19) Patient characteristics: 1. immuno-compromised individuals 2. family history of onychomycosis

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3. poor hygiene 4. old patients 5. Downs syndrome 6. Severe onychomycosis 7. poor compliance 8. poor vascularization 9. diabetes mellitus 10. severe tinea pedis 11. major and/or recurrent minor traumas Laboratory characteristics: 1. incorrect diagnosis (misdiagnosed moulds and/or yeast due to the presence of cycloheximide in the fungal culture media which prevents the growth of different molds and yeasts) 2. misinterpretation of the fungus in the culture 3. technical mistakes in the laboratory Antifungal agents: 1. poor bioavailability 2. drug interactions 3. incorrect dosage 4. drugs and food (e.g., itraconazole with empty stomach decreasing the efcacy) 5. incorrect length of time using the antifungal agent 6. incorrect antifungal agent (e.g., griseofulvin for Candida and/or molds)

nail/s in the same patient, and/or contamination of other healthy people. All of the above are good reasons to start treatment. Onychomycosis causes deformation of the involved nail (big/thick nails). When it comes to toenails, this deformation may cause a retrograde pressure from the shoes an uncomfortable sensation while walking/running (20). Other reasons are medically related, e.g., recurrent erysipelas/cellulites, ingrown nail/s, and a secondary infection. Patient expectation The patients expectation as a rule is to achieve a normal looking nail, although some of the patients would like to be sure that there is no more fungus existing in the nail after the successful treatment, which is as important as a good clinical appearance of the nail. In case of combined disorders such as nail trauma and onychomycosis, treatment with systemic antifungal medication will diminish or conceal the fungus only and is not supposed to make any changes in the deformation, which is not directly related to the fungus itself. However, the patients expectation in the case above is to achieve a total cure regardless of the other cause the traumatic deformation. From the patients point of view, a total mycological cure is the goal. Negative mycological results a direct smear and culture after the end of the treatment from the nail with the combined disorder (trauma and onychomycosis), which do not achieve a total cure in contrast to the other neighboring nails that are totally cured (clinically and mycologically), do not really interest the patient, whose goal is the good healthy appearance of the nail (FIG. 6). Expectation of treatment Realistic expectation can be achieved by basic anamnesis, careful inspection of the involved nails, and in this way, we can decrease the possibility of overexpectation. In the case of combined nail disorders, two types exist: 1. localized traumatic onychodystrophy reversible or irreversible nail unit trauma (to the nail bed and/or nail matrix) 2. systemic disorders that involve the nails psoriasis, lichen planus, chronic dermatitis, idiopathic onycholysis, 20 nail dystrophy, onychogryphosis, pachyonychia congenita, yellow

Prediction of treatment results

The dermatologist should include and exclude his ndings carefully not only by anamnesis but also by a very close inspection. If any nails are not purely infected by onychomycosis, the patient has to be notied that there may be a chance that the nail will not be totally cured. In some cases, the visual state of the deformed nail can be wrongly perceived as onychomycosis, whereas a laboratory test will nd the presence of some molds and/or yeasts, 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 problem and that is a good enough reason to have it treated. Onychomycosis of the nger nails causes different functional disabilities besides the cosmetic inconvenience. On one hand, nonspontaneous remission of the onychomycosis, and on the other hand, a risk of contamination of the other

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FIG. 6. Onychomycosis and trauma.

nail syndrome, Dariers disease, etc.When a localized disorder is the case traumatic onychodystrophy and other neighboring nails suffer from pure onychomycosis, the caregiver can predict that the nail suffering from irreversible traumatic onychodystrophy will not be totally cured, even though the mycological analysis was positive, whereas other neighboring pure onychomycosis cases are totally cured. When systemic disorders of the nails with onychomycosis are the case combined disorders the caregiver should not expect a total cure because the antifungal medication may not be able to treat the other disorder. As a matter of fact, it depends on the degree of the relationship between the two disorders. If the majority of the deformation is due to the fungal infection, a greater part of the nail will improve. On the other hand, in the case of minimal involvement of fungal infection in the diseased nail, no impressive involvement can be predicted (except for cases where other diseases produce the Kbner phenomenon/the isomorphic phenomenon) to the nail itself (e.g., psoriasis, lichen planus) by the fungus and the elimination of the fungus can reduce or even eliminate the basic disorder of the nail.

Treatment
Further treatment is based on the severity of the patients onychomycosis, the other drugs used concomitantly, and ones compliance with the treatment. Hence, the new antimycotic treatment is prolonged by a few months (in contrast to the old

drugs griseofulvin and ketoconazole, which were given for up to 1824 months or until total replacement of the nail plate). The new antimycotic drugs remain in the nail matrix for more than 6 months, depending on the drug, after cessation of the systemic treatment, in a concentration (i.e., above the minimal inhibitory concentration) that is needed for the majority of dermatophytes. The clinical and mycological success will be judged after 1218 months, depending on the basic clinical feature (mild onychomycosis needs less time to replace the infected nail plate and severe cases need longer periods of time). Another parameter that should be taken into account is the growth rate of the nail plate, which is related to race and age. The patient has to be informed that although the treatment is over, the antimycotic drug in the nail continues working and the results will be seen within several months or more. Without knowing this very important parameter, the patient will misinterpret the outcome. The management options are variable and basically depend on the clinical severity of the onychomycosis. Choosing the correct treatment will depend on the clinical pattern of the fungus type and the severity of the onychomycosis. In general, the onychomycosis management includes systemic antifungal agents, topical antifungal agents, chemical debridement, medical devices, palliative treatment, and the combinations between the above options. The results of the treatment of onychomycosis are often a disappointment for various reasons. The most common cause for these failures is incorrect diagnosis. Most physicians and some dermatologists might nd looking at the clinical signs sufcient and will only perform the onychomycosis diagnosis. In those cases, where the physicians take a mycological analysis from nails that do not present clinical signs of onychomycosis, they get a result of nondermatophyte molds, which are not necessarily pathogenic and will give a systemic and/or topical treatment, which is irrelevant to the nail condition. Among the conditions that might be falsely perceived as onychomycosis are prior nail traumas, psoriasis, contact dermatitis, thick nails, 20 nail dystrophy, etc. Therefore, it is very important to choose suitable onychomycosis cases for the mycological analysis. It is important to take a clinical look at the onychomycosis; otherwise, we might wrongly perceive molds or yeasts, which are often irrelevant to the clinical analysis.

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In addition, we need to check if it is indeed a dermatophyte or a mold, which could be a saprophyte (21). In this chapter, the systemic and topical antifungal will be discussed. The newer topical antifungal is based on the ability to penetrate the nail plate through to the nail bed. Medical devices will be discussed in another chapter.

Systemic treatment gold standard

Systemic antifungal agents are considered to date as the gold standard for all types of onychomycosis. These agents achieve the highest cure rate clinically and mycologically. Griseofulvin was the rst oral systemic antifungal agent. For about three to four decades, griseofulvin was the only oral antifungal agent available. The very low cure rate of griseofulvin for onychomycosis led doctors to look for a better solution. For many years, griseofulvin has not been the drug of choice for onychomycosis worldwide, but this old drug should be mentioned at least for historical reasons. The newer drugs, such as terbinane and itreaconazole, are the leading antimycotic agents worldwide. Fluconazole is not approved for the treatment of onychomycosis in the majority of countries, although several studies show that this drug is effective for onychomycosis. Other systemic antimycotic agents are not routinely available for the treatment of onychomycosis. These newest agents will be discussed in short further ahead.

The mechanism of griseofulvin is brought about by affecting nucleic acid synthesis and arresting fungal cell mitosis in metaphase. The low cure rate of onychomycosis is commonly as a result of the long time use of the drug up to almost 2 years in severe cases causing low patient compliance. Another reason is that a group of dermatophytes and yeasts and molds are well known to accompany the pathogenic fungus. The ineffectiveness of griseofulvin for yeasts and molds and the lengthy time of treatment play a critical role for the low cure rate of griseofulvin for onychomycosis. The cure rate of griseofulvin is low and is estimated at 2060%, with an average of 30%. A combination therapy of griseofulvin with 40% urea was better than griseofulvin alone (22). A combination therapy of griseofulvin or other systemic drugs with 5% amorolne nail lacquer was better than systemic drug only griseofulvin (23). Adverse events Adverse events associated with griseofulvin are usually mild and reversible. The most common side effects are gastrointestinal disturbance and headaches, which occur in 15% of the patients treated. Hypersensitivity (skin rash, urticaria, angioneurotic edema, and toxic epidermal necrolysis) is rarely observed. Serious adverse events such as hepatotoxicity, leucopenia, thrombocytopenia, or anemia are rarely reported. Griseofulvin increases the metabolism of warfarin by its action on the cytochrome P-450 and may reduce the efcacy of several oral contraceptive pills. Several studies have shown that the azoles and the allylamine terbinane are more effective than griseofulvin. As a result, the use of griseofulvin has decreased in the last 20 years.

Griseofulvin
As mentioned before, griseofulvin was the rst antimycotic drug specically approved for onychomycosis. For many years, terbinane and less commonly itraconazole were used as the drug of choice for onychomycosis. It should be stressed that griseofulvin is not effective against different types of molds and yeasts, but only for dermatophytes. The acceptable dosage of griseofulvin for onychomycosis in healthy adults is 500-1000 mg/day, for up to 1218 months. The treatment with griseofulvin is continued until the complete regrowth of the whole new nail plate.

Ketoconazole
Ketoconazole is a broad-spectrum antifungal agent that was the rst orally active imidazole (3). The use of this agent in onychomycosis was limited even before recent developments as it has many disadvantages. Unlike recent treatments, the medicine has to be consumed until a full cure is visible and the nail has completely regrown. As a result, the treatment takes a long period of time, same as griseofulvin. In addition, there is an occurrence of side effects such as hypersensitivity reactions, nausea,

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vomiting, headaches, abdominal pain, pruritus, and fever. The most signicant side affect is hepatotoxicity, which has a range of 1 in 10,000 incidences reported (3).

Terbinane
Terbinane is an antifungal agent fungicidal and fungistatic which belongs to the allylamine class. This medication was developed in 1979 and was approved for the treatment of onychomycosis in 1991 in the United Kingdom. Currently, it is the only fungicidal oral antimycotic and it is highly effective against fungi, dermatophytes, and some yeasts; terbinane has low efcacy against nondermatophyte molds. Terbinane penetrates the nail through the nail matrix and the nail bed. The metabolism of terbinane goes through the cytochrome (CY) P450 enzymes. The acceptable dosage for onychomycosis is 250 mg on a daily basis for 34 months. The mechanisms of terbinane Terbinane has a dual inhibition of sterol biosynthesis. The actions of inhibition are fungicidal and fungistatic. Terbinane exhibits its fungicidal activity by inhibiting the production of squalene epoxidase, causing the accumulation of squalene in cell cytoplasm, leading to lipid droplets within the cell, the release of lytic enzymes, and the disruption of cell physiology, and as a result, the rapid death of the fungal cell. Subsequently, the fungistatic action is via the biosynthesis inhibition of the ergosterol. Pharmacokinetics of terbinane More than 70% of terbinane is absorbed when the drug is taken orally (after food or on empty stomach) and 19% of oral terbinane binds with plasma proteins. Terminal half-life of terbinane is as much as 200400 hours, which supplies dermatological effectiveness for several weeks after the cessation of the treatment. After 2 hours of oral intake of 250 mg terbinane, the plasma concentration may reach 0.8 mg/L. In case of a liver or kidney disorder, about 50% of terbinane is discharged from the kidney. Terbinane 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 terbinane in addition to the mechanism of the other azoles may account for its higher efcacy compared with the other systemic antifungal. Many reviews and many meta-analysis studies have shown some differences among the studies. Using the metaanalysis technique has shown the superiority of terbinane compared with other available systemic antifungal agents. A meta-analysis review, which was performed by Gupta et al., shows the variation in results in different research (24). A meta-analysis of 36 studies of systemic monotherapy of terbinane for onychomycosis found that terbinane had higher mycological cure rates (76%; n = 18 studies, 993 patients) than either griseofulvin (60%; n = 3 studies, 131 patients), uconazole (48%, n = 3 studies, 167 patients), continuous itraconazole (59%; n = 7 studies, 1131 patients), or pulse itraconazole (63%; n = 6 studies, 318 patients) (24). A prospective, random, double-bind, doubledummy, multicenter, parallel-group study to compare the efcacy and tolerability of continuous terbinane with intermittent itraconazole in the treatment of toenail onychomycosis was carried out. Four hundred ninety-six patients with a clinical diagnosis of dermatophyte toenail onychomycosis, conrmed by a positive mycological culture and microscopy (KOH), were recruited from 35 centers in six European countries. At week 72, the clinical efcacy (dened as mycological cure and at least 5 mm of new clear toenail growth from baseline) was 65.7% (67/102) for terbinane at 3 months, 70.5% (67/95) for terbinane at 4 months, 28.4% (29/102) for itraconazole at 3 months, and 33.7% (35/104) for itraconazole at 4 months. All comparisons at week 72 were again statistically in favor of the terbinane regimens, p < 0.0001. Continuous terbinane was signicantly more effective than intermittent itraconazole in the treatment of toenail dermatophyte onychomycosis. Adverse effects The most commonly reported adverse effects of terbinane include gastrointestinal effects, such as taste disturbance, nausea, diarrhea, and mild abdominal pain. The overall frequency of adverse effects is about 10% (3). In rare cases, terbinane has been associated with hepatotoxicity, comprising a prodrome of asthenia, anorexia, and abdominal pain about 1 week prior to the onset of jaundice, pale white stools, and dark urine that can progress to a mixed hepatocellular and cholestatic

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dysfunction. Although terbinane-induced hepatotoxicity is rare, it is recommended that patients on terbinane therapy have liver function tests performed before treatment and at 46 weeks. Drug interactions In interaction with rifampin (a CYP450 inducer), terbinanes clearance is increased, whereas in interaction with cimetidine (a CYP450 inhibitor), nortriptyline, paroxetine, amitriptyline, and desipramine, its clearance is decreased. Thus, avoid combination or adjust dosages accordingly. Terbinane increases metabolism of cyclosporine by 15% thus, there is a need to monitor the cyclosporine levels (25). Itraconazole Itraconazole is a triazole antifungal that rapidly penetrates the nail plate (3). It was developed in the late 1980s and was approved for the treatment of onychomycosis in 1995. Itraconazole can be detected at the distal nail plate within 7 days from the beginning of the treatment and has a wide spectrum of antifungal activity, namely dermatophytes, nondermatophyte molds, and yeasts. There are two different regimens of itraconazole. The rst-continuous regimen which is approved by Food and Drugs Administration (FDA) is 200 mg/day for 3 months, and the other regimen is pulse regimen 400 mg/day for 1 week, monthly for 34 months. A meta-analysis of 318 patients who were treated 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 pulse regimen. As mentioned in the LI ON study (26) and other studies, the total cure of itraconazole continuous or pulse regimens is about 3050%, depending on the denition of the cure. Regarding the adverse events of itraconazole, the most common is a minor gastrointestinal upset or headaches. The reversible elevation of liver function tests may occur (27). Therefore, liver function tests should be monitored. Itraconazole inhibits the fungal cell CYP450 enzyme, 14-a demethylase, which prevents the production of ergosterol, which is a very important component in the fungal cell wall. Itraconazole is well absorbed when taken with food and low acid pH. Itraconazole is not recommended and some-

times contraindicated with the coadministration of oral cisapride, midazolam, pimozide, triazolam, and different types of statins. The absorption of itraconazole is decreased by coadministration with gastric acid suppressors. Coadministration of cyclosporine and/or tacrolimus with itraconazole raises the levels of cyclosporine and tacrolimus. Severe hypoglycemia may occur when coadministered with some hypoglycemic agents. Thus, avoid combination or adjust dosages accordingly (25).

Fluconazole
Fluconazole is a bis-triazole drug, which was developed in the 1990s (3). Its mechanism of action is like the other triazoles, inhibiting the synthesis of ergosterol. Fluconazole is dependent on the CYP450 system. It can be taken regardless of food intake. Fluconazole is effective against dermatophytes and other types of Candida spp. Fluconazole is authorized in some countries for the treatment of onychomycosis, whereas in other countries, it is only used for the treatment of tinea corporis of the skin. The uconazole cure rate varies and is considered low compared with itraconazole and terbinane. Side effects are similar to itraconazole, including headaches, nausea, and gastrointestinal upsets. As uconazole is metabolized by the CYP450 enzyme system, coadministration with phenytoin, hypoglycemic agents, cyclosporine, rifampin, terfenadine, and theophylline is contraindicated. There are new azoles that are not yet widely distributed. We shall describe them briey.

Voriconazole
Voriconazole is a triazole structurally similar to uconazole. 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 may be elevated as a result of voriconazole, but this is usually reversible. Voriconazole is effective against Scopulariopsis brevicaulis, Fusarium spp., and Scytalidium dimidiatum, which are well known to be effective against stubborn conditions of onychomycosis. There are not enough controlled data regarding the outcome

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of the cure rate of onychomycosis with voriconazole in clinical studies (28).

Posaconazole
Posaconazole like the other azoles inhibits CYP450, 14-a demethylase, which blocks the synthesis of ergosterol. Posaconazole is effective against different types of non dermatophyte molds (NDM), such as Aspergillus, some yeasts (Candida spp.), and zygomycete infections (28). Posaconazole has similar side effects as other azoles, including headaches, skin rashes, dry skin, dizziness, nausea, ushing, abdominal pain, and taste disturbance (as in terbinane). Liver function tests may be elevated by posaconazole but is usually reversible. Posaconazole 200 mg/day for 24 weeks cure rate is 54.1%, whereas the mycological cure rate is 59% (29).

and seborrheic dermatitis (32). The drug was well tolerated in Phase 1 and 2 clinical trials and can be given in a once-daily dose due to its long halflife. It reduces the growth of Malassezia globosa, Candida albicans, T. rubrum, T. mentagrophytes, and Microsporum canis. There are not enough controlled data regarding the outcome of the cure rate of onychomycosis with pramiconazole in clinical studies (32). Albaconazole Albaconazole is a broad-spectrum antifungal agent. This drug was effective against candidiasis, systemic aspergillosis and cryptococcosis. In Phase 2 studies, this drug showed better efcacy than uconazole in tinea pedis and toenail onychomycosis when administered once weekly. There are no enough controlled data regarding the outcome of the cure rate of onychomycosis with albaconazole in clinical studies (33).

Ravuconazole
Ravuconazole, as the other azoles, blocks the synthesis of ergosterol by inhibition of the 14-a demethylase enzyme. Ravuconazole is effective against species of Candida, Cryptococcus neoformans, dermatophytes, and dematiaceous fungi. There are similar side effects to other azoles, including headaches, abdominal pain, liver function tests elevation, rash, etc. The effective cure of ravuconazole 200 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 terbinane, but further comparative studies are needed to assess the effectiveness of isavuconazole for the treatment of onychomycosis. In vitro there is an activity against Zygomycetes, Cryptococcus, Aspergillus spp., Scedosporium spp., Fusarium spp., and Candida spp. In vitro activity was reduced against Histoplasma capsulatum. It has been shown to be effective in vivo against candidiasis and invasive Aspergillosis. Drug interactions were described. The drug is currently in Phase 3 clinical trials. There are not enough controlled data regarding the outcome of the cure rate of onychomycosis with isavuconazole in clinical studies (31). Pramiconazole Pramiconazole can be administered orally for the treatment of dermatomycosis, onychomycosis,

Topical treatment
The topical treatment for onychomycosis can be divided into three sub-chapters: Topical antifungal creams/ointments/ solutions/lotions/foams All the above topical forms of antifungals are basically not used as a monotherapy for onychomycosis but can be used as an adjuvant to the systemic antifungal agents. Topical antifungal treatment. Topical antifungal treatment including creams, gels, ointments, and solutions are usually not effective against onychomycosis (except for a very mild case of onychomycosis). This is due to their inability to penetrate through the nail plate. Therefore, these topical treatments are effective against dermatomycosis and have a limited effectiveness against onychomycosis. Among them are azoles bifonazole, butoconazole, clomidazole, clotrimazole, econazole, fenticonazole, ketoconazole, isoconazole, miconazole, neticonazole, omoconazole, oxiconazole, sertaconazole, sulconazole, and Tioconazole and allylamines/benzylamines butenane, naftine, and terbinane. Nail lacquers and solutions for onychomycosis There are four available nail lacquers/solutions for onychomycosis:

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1. amorolne (Loceryl, Laboratories Galderma S.A., France) 2. ciclopirox olamin (Batrafen, Sano -Aventis, Deutschland GmbH; Penlac, Dermik Laboratories, Bridgewater, NJ, USA) 3. tioconazole 28% 4. terbinane nail lacquer. Amorolne (Loceryl). Amorolne nail lacquer is a broad-spectrum antifungal agent. The amorolne molecule inhibits two enzymes (delta-14reductase and delta-7,8-isomerase) (28). These two enzymes block the production of ergosterol and have fungistatic and fungicidal properties. The amorolne molecule is lypophilic and unionized (depends on the pH of the nail plate, which is usually 7.4). The amorolne molecule tends to be unionized due to the basic pH of the nail plate. These two characteristics (lipophilic and unionized) are important for the penetration through the nail plate to the nail bed, and the penetration into the fungal membrane. The onychomycosis case rate of amorolne as a monotherapy is 1271% (23) and it acts as topical lacquer. Ciclopirox olamine. Ciclopirox olamine 8% is a broad-spectrum antifungal agent. Its exact mechanism is unknown. Ciclopirox may inhibit the transport of certain essential substrates into fungal cells. Ciclopirox may inuence the production of different proteins. Ciclopirox nail lacquer penetrates the nail plate to the nail bed. The fungicidal effect of ciclopirox is based on its inhibition of the cellular uptake of vital cell ingredients. The onychomycosis case rates of ciclopirox olamine are around 931.3% (23) and it acts as a topical lacquer.

parative clinical studies, and the nail lacquer is not available in the market yet. Nail avulsion Chemical nail avulsion is a painless method of onychomycotic thickened/deformed nail dissolving. Using this method in addition to the relevant systemic treatment supplies better results than the systemic treatment alone. This is due to the fact that the systemic drug is acting against lower amount of fungal elements; hence, the chemical debridement itself eliminates a large amount of fungal elements and deformed keratin. Three different types of nail avulsion are known: 1. chemical avulsion 2. surgical avulsion 3. laser avulsionIn this article, chemical avulsion will be discussed in short. The chemical avulsion can be divided into two parts: keratinolytic agents and keratinoplastic agents. The keratinolytic agents crack the interconnecting disulde bridges of keratin. The lattice-like polymerization of the keratin is broken up and the protein structure undone at the molecular level. Chief members of this group are as follows:

Thioglycolic acid, alkali suldes, earth alkali suldes

The keratinoplastic agents act on the cementing substances located between the individual keratin strands. These agents chemically break the hydrophobic bonds such as parallel arrangement of the molecular chains. Chief members of this group are as follows:

Tioconazole nail solution

Tioconazole (28%) nail solution is a topical preparation for onychomycosis. Tioconazole is a substituted imidazole that has antimicrobial and antifungal properties, and has a broad spectrum of activity in vitro against dermatophytes and yeasts. The cure rate of the treatment with tioconazole nail solution is 22% (34). Terbinane nail lacquer Terbinane nail lacquer is a new product. This nail lacquer has a penetration enhancer, which helps the terbinane molecules penetrate the nail plate to the nail bed. So far, there are not enough com-

Urea, salicylic acid, and resorcin

Both keratinolytic and keratinoplastic agents alter the keratin structure, facilitating the penetration of the antimycotic agents in and through the skin and nails. Application of 40% urea results in change in the bound intermolecular water alteration of the ratio between the water enveloping the proteins and the intramolecular water deposit expulsion of water and replacement of other water molecules, causing changes in the nail elasticity, extreme loosening of keratin, and easy removal of the nail material. Urea is indicated in higher concentrations for local use in the removal of keratin masses without

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completely destroying the barrier function. Chemical ablation debridement probably facilitates the attachment of the nail plate to the nail bed. Healthy (compact) nail does not respond well to urea debridement (35).

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