DISEASE MANAGEMENT
`
`Drugs 1999 Aug; 58 (2): 283-296
`0012-6667/99/0008-0283/$14.00/0
`
`© Adis International Limited. All rights reserved.
`
`Management of Onychomycoses
`
`Markus Niewerth and Hans C. Korting
`
`Dermatologische Klinik und Poliklinik, Ludwig-Maximilians-Universit~t, Munich, Germany
`
`Contents
`.................................................. 283
`Abstract
`Definition and Epidemiology ....................................... 284
`1,
`Quality of Life ................................................ 284
`2,
`Clinical Types of Onychomycosis ..................................... 284
`3,
`Aetiology and Pathogenesis ....................................... 284
`4,
`Diagnosis .................................................. 285
`5,
`6,
`Treatment .................................................. 285
`6,1 Nail Removal ............................................. 285
`6,2 Drug Treatment ............................................ 286
`6,2,1 General Considerations ................................... 286
`6,2,2 Former Standard Antimycotics ............................... 287
`6,2,3 Itraconazole .......................................... 288
`6,2,4 Terbinafine ........................................... 288
`6,2,5 Fluconazole .......................................... 289
`6,2,6 Topical Therapy ........................................ 289
`Efficacy .................................................. 290
`Adverse Effects and Drug Interactions ................................. 291
`Cost Effectiveness ............................................. 292
`Conclusions ................................................. 292
`
`8,
`9,
`10,
`
`7,
`
`Abstract
`
`Onychomycoses~ infections of the nail caused by fungL are amongst the most
`common illnesses. Because of the high incidence of these infections and problems
`involved in their therapy~ they have received much attention~ particularly as con-
`cerns a better characterisation of the causative micro-organisms. Onychomycosis
`caused by dermatophytes (tinea unguium) is most common and is found
`more frequently on the feet than on the hands. The clinical presentation of ony-
`chomycosis is at best indicative of fungal infection~ and the growth of a credible
`pathogen is an indispensable prerequisite for definite diagnosis. The clinical ap-
`pearance is variable. Four major types of manifestation have been characterise&
`depending on localisation and spread.
`New antifungal agents for systemic or topical application based on novel
`active substances or vehicles are available~ and cure is feasible for the majority
`of cases. Therapy can and should be individualise& depending on the charac-
`teristics of the particular case.
`Currently~ continuous or intermittent oral treatment with itraconazole or ter-
`binafine exhibit a particularly favourable risk ¯ benefit ratio. Fluconazole might
`become an alternative in the near future. With respect to topical treatment~ ciclo-
`pirox or amorolfine lacquer and the bifonazole/urea combination deserve partic-
`ular interest. However~ cure cannot be expected for every case.
`
`ARGENTUM EX1026
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`284
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`Niewerth & Korting
`
`I. Definition and Epidemiology
`
`3. Clinical Types of Onychomycosis
`
`Onychomycosis is defined as an infection of the
`nail with fungi, whether dermatophytes, yeasts or
`moulds.
`It seems that the frequency of infections of the
`nail due to fungi has increased in recent decades.
`Although there are no comparative world-wide
`statistics on infections, there is an increasing num-
`ber of studies examining the frequency and caus-
`ative organisms ofonychomycoses from particular
`countries and groups of patients. In Europe, there
`seems to be an average prevalence of about 2 to
`5 %,[1,21 with the prevalence particularly increasing
`in older people. Important factors that influence the
`epidemiology comprise climatic conditions, geo-
`graphical location, degree of urbanisation and so-
`cial standards, in particular conditions of work and
`current footwear habits (onychomycosis of the feet
`is by and large restricted to populations wearing
`shoes). [3]
`Moreover, there are some individual risk factors
`promoting the manifestation of onychomycosis.
`These include mechanical alteration, for example
`onycholysis or onychodystrophy, respectively,
`caused by frequent recurrent trauma in athletes or
`a single injury of the nail organ resulting in life-
`long damage.[41 Even the application of cosmetic
`acrylic nail extensions can affect Candida nail bed
`infections and thus promote onychomycosis.[51
`
`2. Quality of Life
`
`Onychomycosis is not merely an aesthetic prob-
`lem, although this aspect must not be under-
`emphasised. For many patients it is a major prob-
`lem that interferes with their lifestyle. It has been
`proven repeatedly that this infection leads to psy-
`chological stress as well as to physical pain.[6-91
`Affected patients experience a decrease of self-
`confidence, reduction of leisure activities and, par-
`ticularly, a limitation of sports activities. Onycho-
`mycosis consequently compromises quality of life
`to a remarkable extent.
`
`The clinical spectrum ofonychomycosis is gen-
`erally represented by 4 different types of manifes-
`tation. According to localisation and spread, the
`classification differentiates between:1a°l
`¯ distal subungual onychomycosis
`¯ white superficial onychomycosis
`¯ proximal subungual onychomycosis
`¯ onychomycosis associated with chronic muco-
`cutaneous candidiasis.
`These clinical types can involve either toenails
`and/or fingernails. Recently, a new classification of
`onychomycosis has been published, differentiat-
`ing between distal and lateral subungual onycho-
`mycosis, superficial onychomycosis, proximal
`subungual onychomycosis, endonyx onychomyco-
`sis and total dystrophic onychomycosis.laal
`
`4. Aetiology and Pathogenesis
`
`Fungal infections of the nail involve toenails
`more often than fingernails, in a ratio of about
`5 : 1. With toenail onychomycosis, tinea pedis,
`especially of the intertriginous type, is responsible
`in most instances for the infection of the nail or-
`gan. 1a 21
`Onychomycoses can be caused by dermato-
`phytes, yeasts or moulds. However, dermatophytes
`are responsible for about 90 to 95% of infections.
`Among the dermatophytes, Trichophyton rubrum
`plays a major role as a pathogen.la31 In addition,
`Trichophyton mentagrophytes and Epidermophy-
`ton floccosum are regularly found as causative
`micro-organisms. Among the yeasts, Candida albi-
`cans plays the major, if not exclusive, role as a
`causative organism. Yeast infections of the nail or-
`gan are frequently associated with chronic paro-
`nychia or chronic mucocutaneous candidiasis, but
`yeast infection of the nail organ and chronic paro-
`nychia must clearly be differentiated. It is a matter
`of debate whether C. albicans is a primary patho-
`gen of nails or whether it can only directly invade
`nail tissue that is already abnormal.la41 Never-
`theless, onychomycoses due to C. albicans can
`show the same clinical picture as dermatophyte
`
`© Adis International Limited. All rights reserved.
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`Drugs 1999 Aug; 58 (2)
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`Management of Onychomycoses
`
`285
`
`onychomycoses. Among the moulds, Scopulariop-
`sis brevicaulis is currently considered to be the ma-
`jor pathogen. In some countries, infections due to
`Fusarium and Scytalidium spp. are also not infre-
`quent.[15-171 In overtly dystrophic nails, the rela-
`tive proportion of mould infections is clearly in-
`creased.[asl
`This distribution pattern applies to countries in
`climatically temperate zones. Under other condi-
`tions, other distributions of the frequency of patho-
`gens can be found. In tropical zones, for example,
`there is a higher proportion of yeast infections.
`In children, onychomycosis is seen at a lower
`frequency than in adults. The prevalence accord-
`ing to most studies world-wide is between 0% and
`6%. The majority of these infections are due to T.
`rubrum.~19,2°1 The lower frequency may be ex-
`plained by the faster growth of nails, a smaller sur-
`face to attack and structural differences.
`In immunosuppressed patients, particularly
`those with AIDS, onychomycosis is not an over-
`whelming problem. Although the prevalence in
`this group of patients seems to be slightly higher,
`severe manifestations of the disease, as seen for
`example with oral candidiasis, are uncommon.I211
`There are indications, however, of a shift of fre-
`quency of the clinical types towards proximal sub-
`ungual onychomycosis.[221
`
`5. Diagnosis
`
`In patients with nail disease indicative of ony-
`chomycosis, diagnostic proof of infection and
`identification of the pathogen is required before
`therapy starts. The first step in diagnosis is nor-
`mally microscopic examination of native material.
`The infected part of the nail must first be cleansed
`with a disinfectant such as 70% isopropanol to re-
`move contaminants such as bacteria.[231 The outer-
`most parts of the nail-plate to be examined should
`be removed as far as possible, and specimens
`should be taken from deeper layers. For this pur-
`pose, high speed abrasion using a special type of
`frais has proven particularly beneficial.[241 The
`material should be soaked in 15 to 20% potassium
`hydroxide solution and be examined by micros-
`
`copy after incubation for 1 hour in a wet chamber.
`In a positive case, mycelial material can be seen.
`Efforts can be made to differentiate between derm-
`atophytes, yeast and moulds; however, this will not
`generally be rewarding.I251 Potassium hydroxide
`preparations can be false-negative. If potassium
`hydroxide preparations are repeatedly negative but
`onychomycosis is still considered, a nail biopsy
`can be done. This approach is more sensitive but
`also more invasive, and for that reason it does not
`belong in the standard diagnostic procedures.[26,27]
`In addition to the native preparation, a proof of
`fungal nail disease by culture should be performed
`in every case. For this culture, media such as
`Kimmig’s agar or Sabouraud glucose agar can be
`used. For each specimen at least 2 cultures should
`be performed: one without any additive and the
`other with cycloheximide and/or chloramphenicol
`to prevent overgrowth by airborne bacteria or
`moulds present in the environment. The culture is
`time-consuming, taking at least 2 weeks and up to
`4 weeks. A clear differentiation of the pathogen at
`the species level can be made by growth form, sur-
`face and colour, and the microscopic appearance of
`macro- and microconidia, as well as further param-
`eters based on subcultures.[281 As yet, molecular
`approaches to diagnostics have not reached clinical
`practice. [29]
`
`6. Treatment
`
`6.1 Nail Removal
`
`Previously, nail removal by extraction was em-
`ployed not infrequently. Because of the high effi-
`cacy of the newer antifungal agents, surgical treat-
`ment by and large belongs to history. Surgery
`causes temporary disablement for work, intra- and
`postoperative complications, and in particular
`traumatisation of the nail matrix with possible
`permanent deformation. Therefore, its use must be
`approached very critically. A more recent alterna-
`tive is represented by atraumatic chemomechani-
`cal maceration of the diseased nail with urea oint-
`ment under occlusion, an option systematically
`developed in the context of the characterisation of
`
`© Adis International Limited. All rights reserved.
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`Drugs 1999 Aug; 58 (2)
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`286
`
`Niewerth & Korting
`
`Table I. Chemistry and route of administration of the most important
`antimycotics
`
`Drug
`Amorolfine
`Bifonazole
`Ciclopirox
`Clotrimazole
`Econazole
`Fluconazole
`Griseofulvin
`
`Itraconazole
`Ketoconazole
`Terbinafine
`Tioconazole
`
`Structural class
`Morpholine
`Imidazole
`Hydroxypyridone
`Imidazole
`Imidazole
`Triazole
`Dimethoxycoumarin
`derivative
`Triazole
`Imidazole
`Allylamine
`Imidazole
`
`Administration
`Topical
`Topical
`Topical
`Topical
`Topical
`Oral/intravenous
`Oral
`
`Oral
`Oral/topical
`Oral/topical
`Topical
`
`bifonazole/urea ointment which is commercially
`available in several countries.[30-331
`
`6.2 Drug Treatment
`
`6.2. I General Considerations
`For drug treatment of onychomycoses, the top-
`ical and systemic routes of application of antifun-
`gal agents are considered relevant (table I). Topical
`therapy might seem to be the treatment of choice,
`since it does not lead to systemic adverse effects or
`to any interactions with other systemic drugs taken
`by the patient. Unfortunately, at present topical
`treatment alone does not provide cure for more than
`a significant subgroup of patients.
`The reasons for the failure of topical treatment
`may be multiple. Apart from other factors, success
`depends on the type of infection. Success is con-
`sidered unlikely in the context of the most common
`type, pedal distal subungual onychomycosis, if
`more than 30 to 50% of the nail plate is affected.[341
`Moreover, cure seems to be particularly difficult if
`
`the lateral part of the nail plate is involved with the
`lesion reaching from the free margin to the nail
`matrix.[351 Additionally, the probability of cure de-
`pends on the number of infected nails. With more
`than 5 infected nails, cure is unlikely. A shorter
`period of therapy is commonly required for the
`treatment of fingernail onychomycosis and cure
`rates are slightly higher than with toenail onycho-
`mycosis. As topical antimycotics must, in most
`cases, diffuse through the horny material of the nail
`plate into deeper layers to reach the causative or-
`ganisms, the chance of cure seems to be particu-
`larly low with thickly keratinised, dystrophic, pre-
`damaged nails. Finally, a significant number of
`patients have problems with the application of the
`antifungal agent on toenails because of additional
`movement disorders.
`Topical therapy is particularly justified when
`less than 30% of the nail plate is affected and with
`white superficial onychomycosis.[341 With more
`extensive infections, or even in total dystrophic
`onychomycosis, topical treatment does not gener-
`ally lead to success and systemic therapy is neces-
`sary (table II). However, use of systemic therapy
`is limited by several factors, including possible
`severe adverse effects caused by the active com-
`pound itself or by its interaction with concomitant
`medication.
`Although there have been some important ad-
`vances in topical therapy in recent years, the most
`significant advances have been made in systemic
`therapy. This is particularly reflected by cure rates.
`A larger number of effective drugs are available
`today for drug therapy of onychomycosis than ever
`before. However, with this relative abundance of
`options, an informed choice of the correct anti-
`
`Table II. Therapeutic procedures for culture-proven onychomycoses[341
`
`Clinical type
`White superficial onychomycosis
`Distal subungual onychomycosis
`Distal subungual onychomycosis
`Proximal subungual onychomycosis
`Onychomycosis associated with chronic mucocutaneous candidiasis
`Total dystrophic onychomycosis
`a
`
`Degree of severitya
`
`I-III
`I-II
`III
`I1-111
`I-III
`
`Therapy
`Topical, possibly tangential removal
`Topical, possibly with nail plate removal
`Systemic
`Systemic
`Systemic
`Systemic
`
`I = <30% of the nail affected; II = 30 to 60% of the nail affected; III = >60% of the nail affected.
`
`© Adis International Limited. All rights reserved.
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`Management of Onychomycoses
`
`287
`
`mycotic agent for a given patient is even more im-
`portant. The different classes of agents have differ-
`ent targets (fig. 1) and thus differ considerably with
`respect to their therapeutic and adverse effect pro-
`files. Special consideration should be given to the
`risk : benefit ratio as well as to the cost : benefit
`ratio.
`It has become clear that griseofulvin as a thera-
`peutic agent has ceased to be the gold standard, and
`today it is rarely used in the therapy of onychomy-
`cosis in highly industrialised countries. Occasion-
`ally it still is used in studies as a comparative anti-
`fungal drag, because its action and effectiveness
`are well established. Another antifungal agent that
`has been removed from the therapeutic armamen-
`tarium is ketoconazole. Instead, the newer agents
`itraconazole, terbinafine and fluconazole are con-
`sidered for first-line systemic treatment; numerous
`studies of the effectiveness, optimal dosage, ad-
`verse effects and cost of these agents have been,
`and currently still are being, performed.
`
`6.2.2 Former Standard Antimycotics
`Griseofulvin is a compound synthesised by
`some species of Penicillium. It has been used for
`systemic treatment of dermal mycoses, including
`onychomycoses, since 1959. Its efficacy is limited
`to dermatophytes. The mechanism of action is
`fungistatic, due to interactions with microtubule-
`associated proteins and the ensuing inhibition of
`fungal cell mitosis. The gastrointestinal absorption
`of griseofulvin shows remarkable interindividual
`differences, and depends also on the drug formu-
`lation. The highest rates of absorption are found
`with the ultramicrosize preparation.1371 The route
`by which griseofulvin gets to the site of infection
`has not yet been fully elucidated; it is probably
`incorporated into newly formed keratinocytes.
`Griseofulvin undergoes hepatic metabolism to
`6-demethyl-griseofulvin, which is excreted in the
`urine.[381 In onychomycosis of the toenails, the
`rates of success ofgriseofulvin treatment are lower
`than 40% despite treatment periods of a year or
`more.[39]
`For some time at the beginning of the 1980s
`ketoconazole was used as an oral antifungal agent
`
`I Acetate I
`I Acety’OoA I
`I
`
`I Mevalonicacid ]
`
`I .~o,,.,.o. I
`
`Terbinafine --~ ~Squalene epoxidase
`
`I Squalene-2,3 oxide I
`
`I Lanoster°lI
`
`Triazoles/imidazoles --~ ~, 014 Demethylase
`
`I 14-Demethyllanosterol I
`
`I 4,4-Dimethylergosta-8,14,24,(28)-trien-3~-ol I
`
`Amorolfine --~ ~, A14-Reductase
`
`I 4,4-Dimethylergosta-8,24,(28)-dien-3~-ol I
`
`I Fecesterel I
`
`Amorolfine --~
`~,
`I epistero’
`
`A 8-A7-1somerase
`
`I
`
`I ergostero’ I
`I Fungal cell membrane synthesis I
`
`Griseofulvin --> ~, Microtubule-associated proteins
`
`[ Fungal cell replication ]
`
`Fig. 1. Molecular targets of relevant antimycotics (modified from
`Gupta et al.,[36] with permission).
`
`for systemic therapy ofonychomycoses and severe
`tinea of glabrous skin, with cure rates similar to
`those seen with griseofulvin. It was the forerunner
`of the more modem azoles itraconazole and flu-
`conazole. After some fatal cases of idiosyncratic
`drag-induced hepatitis, systemic ketoconazole is
`no longer generally approved for the treatment of
`onychomycoses. Nevertheless, it may be used with
`
`© Adis International Limited. All rights reserved.
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`Drugs 1999 Aug; 58 (2)
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`288
`
`Niewerth & Korting
`
`6.2.4 Terbinafine
`Terbinafine, an allylamine, also belongs to the
`newer antifungal agents.[47] It exhibits a primarily
`fungicidal mode of action. Its activity in vitro in-
`cludes dermatophytes as well as moulds, but it is
`less active against yeasts.[4s,49] Its activity against
`dermatophytes in vitro is higher by several orders
`of magnitude than those of the other antimycotics
`available (fig. 2). Terbinafine inhibits the biosyn-
`thesis of ergosterol by specific and selective inhi-
`bition of squalene epoxidase, leading to accumula-
`tion of toxic squalene and consequently destruction
`of the fungal cell. In contrast to the azoles, the af-
`finity ofterbinafine for CYP is low, and so it shows
`less interaction with other drugs as compared with
`the azoles.
`Maximal plasma concentrations of terbinafine
`are reached within 2 hours. Terbinafine is strongly
`
`Griseofulvin
`
`40
`
`30
`
`20
`
`10
`
`0
`
`40
`
`30
`
`20
`
`10
`
`0
`
`20
`
`10
`
`0
`
`2
`
`3 4
`
`10
`
`Itraconazole
`
`0.1
`
`0.5
`
`1
`
`2
`
`Terbinafine
`
`care for resistant mucocutaneous or fingernail dis-
`ease if topical treatment is not effective.
`
`6.2.3 Itraconazole
`Itraconazole is one of the most important drugs
`among the newer antifungal agents. It belongs to
`the triazoles, and is currently the only triazole ap-
`proved for oral administration in onychomycoses.
`At clinically achievable serum concentrations, itra-
`conazole is fungistatic. Its in vitro activity is di-
`rected against a variety of different fungi, including
`dermatophytes, yeasts and some moulds.[4°-421
`The affinity of itraconazole for fungal cyto-
`chrome P450 (CYP) isoenzymes is much higher
`than for their human congeners. After oral admin-
`istration it is distributed to a large apparent volume
`in the body.[42] It can be detected within 24 hours
`in sweat. The drug accumulates in stratum corn-
`eum, nail material, sebum and vaginal mucosa. The
`concentration in sebum is 10-fold higher than the
`corresponding plasma concentration.[43] In plasma,
`99.8% ofitraconazole is protein-bound. Because of
`its high affinity for keratin, itraconazole achieves
`high concentrations in the nail matrix and nail
`bed.[441 In the distal part of the nail plate, effective
`concentrations can be detected as early as 1 week
`after sttarting treatment. After termination of treat-
`ment, effective concentrations remain present in the
`nail for some months; this explains the further im-
`provement of the clinical state observed after dis-
`continuation of the drug. Consequently, pulse ther-
`apy is possible with administration of the drug for
`just 1 week per month. This results in a lower total
`dose with similar efficacy to continuous treatment.
`Itraconazole is processed to numerous metabo-
`lites by the liver. Within 1 week, 35% and 54%
`respectively are excreted in the urine and faeces.[451
`For management of onychomycosis, itracon-
`azole can either be given continuously at a dosage
`of 200 mg/day for 3 months or as a pulse therapy
`with 400 mg/day in 2 divided doses for 1 week per
`month for 3 to 4 months.[461 In fingernail onycho-
`mycosis, administration for 2 months may possibly
`be sufficient.
`
`0.001
`
`0.02
`0.01
`MIC (mg/L)
`Fig. 2. Distribution of the minimum inhibitory concentrations
`(MICs) of griseofulvin, itraconazole and terbinafine for dermato-
`phytes (from Niewerth et al.,[5°] with permission).
`
`0.1
`
`0.2
`
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`Management of Onychomycoses
`
`289
`
`and nonspecifically bound to plasma proteins.[47]
`It reaches the nail plate via the nail-bed by passive
`diffusion. Terbinafine can be detected in the distal
`part of the nail plate within 1 week.[Sa] Maximum
`effective concentrations in the nail are reached af-
`ter 18 weeks with a 6-week treatment. The phar-
`macokinetics ofterbinafine in affected nails do not
`differ substantially from those in healthy nails.[521
`Terbinafine has an average plasma half-life of
`about 3 weeks. In older patients or patients with
`hypertension, an increase of plasma concentrations
`can be found. Smokers show lower plasma concen-
`trations.[53]
`For the treatment of toenail onychomycosis,
`terbinafine 250 mg/day should be given for 12
`weeks;[54[ in fingernail onychomycosis a 6-week
`treatment is generally sufficient.
`
`6.2.5 Fluconazole
`The triazole fluconazole has been used for
`years with great success in oropharyngeal and oe-
`sophageal candidiasis and other indications in im-
`munocompromised patients with or without HIV
`infection. Fluconazole has only recently been eval-
`uated for therapy of onychomycosis.[55,56[ Conse-
`quently the experiences with this kind of therapy
`are limited.
`Because of its strongly hydrophilic character,
`fluconazole is well absorbed after oral administra-
`tion. In contrast to itraconazole, the absorption of
`fluconazole is not influenced by gastric acid, food
`and antacids or H2 receptor blocking agents.[57[
`Fluconazole is distributed in the total body water.
`In plasma, only 11% of fluconazole is protein-
`bound; the rest can be found as unbound free mol-
`ecules. Because of its long plasma half-life of 30
`hours, fluconazole can be given at 24-hour or even
`longer intervals (fig. 3). Nearly 80% offluconazole
`is excreted unchanged in urine. In toenails, flu-
`conazole can be detected for 4 to 5 months after
`termination of oral therapy (fig. 4).[581 In vitro,
`fluconazole shows sufficient activity against a va-
`riety of different fungi, including not only yeasts
`but also dermatophytes.[591
`So far, a consensus about the standard dosage
`of fluconazole for the treatment of onychomycosis
`
`has not been reached. Most often, 150 mg/day is
`given either once daily or once weekly for several
`months. In future, pulse therapy with 150, 300 or
`450mg once weekly for up to 12 months will prob-
`ably be recommended.[6°1
`
`6.2.6 Topical Therapy
`For topical therapy there are a number of alter-
`native approaches that differ in the mechanism of
`action of the antifungal compound and in the vehi-
`cle used. There are still agents for chemical re-
`moval of the nail plate alone as well as true anti-
`mycotics, and combinations of these approaches.
`For chemical removal, glutaraldehyde[6a[ and urea
`ointments,[621 among others, have been proposed.
`The clinical success with these agents, however, is
`poor. Better cure rates can be found with the com-
`bination of antifungal agent and nail removal, in
`particular with bifonazole 1% and urea ointment
`40%, which shows a mycological cure rate of 46%
`at 24-week follow-up,[63[ and propylene glycol/
`urea/lactic acid solution.[64[ Previously, tiocon-
`azole 28% nail solution alone had been suggested,
`and showed a cure rate of 22%.[651
`A better clinical outcome and higher microbio-
`logical cure rates can probably be reached with nail
`lacquer containing either the hydroxypyridone
`ciclopirox or the morpholine amorolfine. These
`drugs diffuse from the nail lacquer slowly into the
`
`[] Plasma (mg/L)
`¯ Stratum corneum (mg/Kg)
`
`L
`
`Day 10 Day 17
`
`Day 1
`(7h)
`
`Day 5
`(2h)
`
`Day 7
`
`Fig. 3. Fluconazole concentrations in plasma and stratum
`corneum of 9 healthy individuals atler daily administration of one
`200mg capsule for 5 days [time elapsed since previous applica-
`tion in brackets] (from Wildfeuer et a1.,[58] with permission).
`
`© Adis International Limited. All rights reserved.
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`Drugs 1999 Aug; 58 (2)
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`290
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`Niewerth & Korting
`
`1.0
`
`Hair
`(4 months after last administration)
`
`Toenails
`
`o
`--~
`
`0.8
`
`=8~ o.~
`
`._o .~ 0.4
`
`0.2
`
`3
`
`1 2 3 4 5 6 7 8 9 10 4 5
`
`Distance from the surface of the skin (cm) Time since last administration (months)
`
`!
`
`Fig. 4. Fluconazole concentrations in various segments of the scalp hair and toenails of 9 healthy individuals af(er daily administration
`of one 200mg capsule for 5 days (from Wildfeuer et al.,[58] with permission).
`
`nail plate and are active against dermatophytes,
`yeasts and moulds.[66-68]
`Amorolfine should be applied once weekly[691
`as a 5% lacquer, which provides clinical cure in
`46.1% of patients.[7°1 Ciclopirox 8% should be ap-
`plied every second day in the first month, at least
`twice weekly in the second month, and once weekly
`in the third month, possibly for longer.
`
`7. Efficacy
`
`Many studies have been performed to test the
`efficacy of different antifungal agents. In general,
`it is difficult to compare the cure rates established
`by the different studies, primarily because the end-
`points are defined differently, for example as clin-
`ical - either complete or partial - cure rates, myco-
`logical cure rates or combinations thereof. Another
`point that should be taken into account is disease
`relapse rate following successful treatment with
`different antifungal agents. Aknowledge of relapse
`rates is important for assessment of overall efficacy
`and cost effectiveness. Relapse rates vary to a large
`extent between the different studies, generally re-
`flecting cure rates, but in some studies follow-up
`was not performed. Thus, a final judgement on the
`relative merits of agents is only possible after direct
`comparative studies with an adequate follow-up.
`
`Ifgriseofulvin is compared with the newer anti-
`fungal agents itraconazole[7a] and terbinafine,[72-741
`lower efficacy rates can clearly be seen for the
`older agent even if the duration of therapy is up to
`3 times higher, possibly up to 18 months.
`The cure rates with terbinafine range from about
`60% to 80% for toenails at the usual daily dosage
`of 250mg for 3 months.[75-77] Extending the dura-
`tion of application to 12 months does not appear to
`improve the outcome,[78] whereas a shorter dura-
`tion of 6 weeks is insufficient.[79]
`The studies with itraconazole also show good
`efficacy rates, although the results, ranging from
`about 40% to 80%, differ more widely than with
`terbinafine.[8°,8a1 Itraconazole dosages of between
`5 0 and 100 mg/day have not been proven to be fully
`adequate,[821 and it seems that only dosages of 200
`mg/day or greater are sufficient. In addition to con-
`tinuous treatment with 200 mg/day for 3 months,
`pulse treatment with 400 mg/day as 2 divided doses
`for 1 week per month for 3 to 4 months has been
`proven sufficient.[83-86] In a direct comparison of
`continuous therapy and pulse therapy, almost equal
`cure rates were found,[87,88] pulse therapy excelling
`because of a lower frequency of adverse effects,
`lower costs and better compliance.[891 Thus, pulse
`therapy is considered an effective and well toler-
`ated approach.J9°]
`
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`Drugs 1999 Aug; 58 (2)
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`Management of Onychomycoses
`
`291
`
`In the majority of trials comparing terbinafine
`and the 2 alternative dosage regimens for itracon-
`azole, terbinafine tends to be slightly superior to
`itraconazole; with the latter drug, continuous ap-
`plication tends to be slightly more efficacious than
`intermittent application after a follow-up of 40
`weeks, 6 months and 8 months, respectively.[9a-931
`Some other studies show essentially similar results,
`with a slight trend towards a higher frequency of
`adverse effects with terbinafine.[941 In contrast
`with the older results, a recent study[95] indicates
`that terbinafine administered continuously for 12
`weeks is more effective for the treatment of toenail
`onychomycosis than intermittent therapy with
`itraconazole given for 1 week every 4 weeks for 12
`or 16 weeks.[951
`With fluconazole, the trials already published
`do not allow final judgement. Most of the recent
`data, however, suggest that pulse treatment with
`fluconazole might become a major alternative to
`established treatment options. According to recent
`US trials, cure rates between 77 and 86% have
`been found with fluconazole 150, 300 and 450mg
`given once weekly, without a clear-cut dose-de-
`pendency.[961
`We currently do not know what to do if an
`established treatment protocol has failed. Recalci-
`trant onychomycosis can still represent a therapeu-
`tic challenge. As such cases are by no means rare,
`this subpopulation of patients deserves to be the
`focus of research attention during the years to
`come. It might well turn out that combined topical
`and systemic treatment is a good idea in this con-
`text. The role of combined treatment still awaits
`definitive evaluation in placebo-controlled double-
`blind trials. [97-99]
`
`8. Adverse Effects and Drug Interactions
`
`Every effective drug applied systemically has
`adverse effects, and interactions with concomitant
`medication appear regularly.
`Ketoconazole is no longer used in the routine
`treatment of onychomycosis, because of rare events
`of life-threatening drug-induced hepatitis. Itracon-
`azole is also an azole derivative, but severe hepatic
`
`toxicity is not a major concern in this treatment
`setting.Ia°°] Single case reports refer to debilitating
`oedema[a°al and acute generalised exanthematic
`pustulosis.[a°21 In contrast to these individual case
`reports, itraconazole has been characterised in a
`report on the experience with 13 600 patients
`treated for various illnesses as virtually free from
`recognisable adverse effects.[a°31
`Drug interactions associated with itraconazole
`are generally related to an increase or decrease in
`the plasma concentrations of drugs. In particular,
`itraconazole on the one hand increases the plasma
`concentrations ofterfenadine, cyclosporin, digox-
`in, nifedipine and coumarin.~a°a-a°tl On the other
`hand, the plasma concentration of itraconazole is
`decreased by rifampicin (rifampin), isoniazid,
`phenytoin, carbamazepine, phenobarbital, antac-
`ids, H2 blockers and didanosine.
`Severe adver