JEADV (2005) 19, 21–29

DOI: 10.1111/j.1468-3083.2004.00988.x
OR IG INAL AR T ICLE

Topical antifungal drugs for the treatment of onychomycosis: an
Blackwell Publishing, Ltd.

overview of current strategies for monotherapy and
combination therapy
R Baran,†* A Kaoukhov¶
†Nail Disease Center, 42, Rue des Serbes, 06400 Cannes, France, ¶Research & Development, Galderma Laboratories, 635, Route des Lucioles, BP 87, 06902
Sophia Antipolis Cedex, France. *Corresponding author, tel. +33 4 9339 9966; fax +33 4 9298 8030; E-mail: baran.r@club-internet.fr

ABSTRAC T
Background Onychomycosis is a relatively common disease accounting for up to 50% of all nail disorders
and its prevalence rises with age. As onychomycosis is an important medical disorder affecting both patient’s
health and quality of life, it requires prompt and effective treatment.
Objective Topical antifungal nail lacquers have been formulated to provide efficient delivery to the nail unit. As
both amorolfine and ciclopirox have proved useful as monotherapy for onychomycosis that does not involve the
nail matrix area, the purpose of this article is to check if, when combined with oral agents, the effectiveness and
scope of treatment can be improved further.
Methods Combining data for mycological cure with clinical success (nail morphology) provides a more
exacting efficacy measure.
Results Clinical investigations have shown that the combination of oral therapies with antifungal nail
lacquer can confer considerable advantage over monotherapy with either drug type.
Conclusion The improved effectiveness and economic advantages of combined topical/oral therapies
benefit both patients and health providers; these treatment regimens therefore have an important role to
play in the modern management of onychomycosis.
Key words: Onychomycosis, antifungal nail lacquers, combination therapy

Received: 4 July 2003, accepted 1 December 2003

Table 1 Risk factors for onychomycosis
Onychomycosis: the nature and causes of
the disease Predisposing factor
Onychomycoses are fungal infections of both the fingernails
Increased age
and toenails.1,2 Toenails are 4 –10 times more frequently affected Genetic and atopic tendencies
than fingernails, probably because of their slower growth and Family history
increased exposure to injury and infecting organisms.3,4 Ony- Poor general state of health
chomycosis is a relatively common disease accounting for up Frequent nail trauma
Environmental contact with pathogens
to 50% of all nail disorders.5,6 Typically, 2 – 3% of the adult
Warm and humid climates
population are affected but, in some countries, this figure appro- Sports activities
aches 10%.1– 4 The prevalence of onychomycosis rises with age, Shared bathing facilities
and as many as 14–28% of > 60-year-olds suffer from the Occlusive clothing and footwear
condition.1,7 Diabetes, psoriasis and other diseases may also Immunosuppression
Prevalence of tinea pedis (athlete’s foot)
increase the risk of infection.1,8,9 Even otherwise healthy indi-
Diabetes
viduals engaged in sporting activities, involving shared bathing
and changing facilities, are prone to the disease (Table 1).1–4 Modified from Ref. 1.

© 2004 European Academy of Dermatology and Venereology 21

034 µg/mg assumed that this condition is a minor and primarily cosmetic in the deepest layer. but. this new classification to deliver the drug. as is example.14 For older patients. also increased the risk of side-effects. Antifungal drugs provided more effective treatments. fungi (usually trichophyton Drug penetration as a factor in rubrum) invade the nail from beneath the proximal fold onychomycosis treatment resulting in nail discoloration. with mean concentrations obvious impact of onychomycosis is visual. although even with these treatments. and as such. are infections.19.22 The effectiveness of nail lacquer-formulated agents involvement of all tissues of the nail apparatus during chronic in penetrating the nail unit is outlined in the following sections. representing about 10% of all cases. five subjects both patients’ health and quality of life.2. DLSO. Epidermophyton and Microsporum. Early medications used for onychomycosis and other amounts of ciclopirox remained in the nail 14 days after superficial fungal infections were mainly non-specific oint. and Aspergillus spp. 21– 29 .20 The effectiveness of topical accommodate current advances in the study of the disease.17 In the first study. newer topical agents.17 After 24 h an antifungal concen- While it is evident from these descriptions that the most tration gradient was apparent. assessed in vitro following a single application to nails avulsed as cosis require combination therapy. is somewhat onychomycosis. primary depot and. evaporate leaving an occlusive film.e. but frequently occurs in AIDS patients and is impermeable.8 µg / mg in the uppermost layer to 0. although residual ments.21 Volatile vehicles.17. Recently. it is also important to clinically assess monotherapy for onychomycosis that does not involve the nail the degree and type of involvement. Thus. non-dermatophytic moulds such as safer. Acremonium. Interestingly.22 Baran and Kaoukhov Dermatophytes. mucocutaneous candidiasis. early treatment before disease lacquer removed once a week. Although care must be taken amorolfine. are the most likely used systemically. the effects can be The penetration of ciclopirox into and through the nail unit has considerable.13. Superficial white onychomycosis tively inaccessible and maintaining effective drug concentrations (SWO). thus restricting drug access to the organisms thus considered indicative of HIV infection. PSO. and by the cure rate and therefore avoid prescription of systemic treat.15. such as itraconazole and terbinafine. although fingernails are more the nail. onychomycosis. The most common type of fungal nail infection is distal lateral subungual onychomycosis (DLSO). it identifies endonyx onychomycosis.2 However. even the concentrations of ciclo- problem. notably Candida albicans. concentration (MIC) for most fungal organisms responsible for for example lower limb amputation in diabetics.10 Yeasts.12 Moreover. it requires prompt and applied ciclopirox nail lacquer 8% daily for 45 days. for antifungals can be enhanced when applied as a nail lacquer. which are related fungi of the genera Tricho. with the effective treatment. mean concentrations were reduced significantly. using a fourfold classification. The mean concentration of progression to total dystrophic onychomycosis can also increase ciclopirox increased throughout the treatment phase. In ments and disinfectants. there is a risk of serious complications or disability. With proximal subungual onychomycosis (PSO).2. have been formulated to provide efficient delivery to ensure that fungus is the cause of the nail dystrophy to avoid to the nail unit.13. This is the least common form of Nail keratin is both compact and hard. which is due to some proximity to the infection site.16 causes of onychomycosis. failure rates can be Scytalidium. even during the normal course of the disease. and those with other underly.19.2. Fusarium spp. topical solutions and creams are easily direct fungal invasion of the dorsal nail plate. some areas may still prove rela- moulds or Candida spp. thus con- system also introduces a novel distinction between primary centrating the drug on the nail surface.2. used of the nail plate is infected.15. mainly because of poor penetration into also give rise to nail infections. Moreover. and. treatment. a result of onychomycosis. may ceived as ineffective.19 Although topical agents allow greater may be associated with secondary PSO.8 µg /mg. by increasing hydration of the nail. a more removed by washing or wiping.1–3. when phyton. such as ciclopirox and likely to be affected than toenails.1. it should not be ranging from 7.11 Paronychia causing onychomycosis. nine healthy volunteers applied ciclopirox nail © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19. occurs following can be difficult.18 Both these agents have proved useful as unnecessary treatment. The penetration of C14-labelled ciclopirox nail lacquer was and both primary and secondary totally dystrophic onychomy.10 and scope of treatment can be improved further. together with the mode and matrix.9 Furthermore. This film then acts as a drug and secondary total dystrophic onychomycosis. when combined with oral agents. and are responsible for 90% of toenail Newer systemic agents.14 also been investigated in preliminary studies involving small As onychomycosis is an important medical disorder affecting numbers of healthy volunteers.16 Topical agents have generally been per- can also cause the disease. Moreover. the effectiveness site of invasion. However. as high as 30 – 50%. enhances drug total dystrophic onychomycosis constitutes the simultaneous diffusion.1. white superficial onychomycosis (WSO) or endonyx onychomycosis). where the core the case with amorolfine and ciclopirox. which further reduces delivery comprehensive classification scheme has been proposed to of the drug to the subungual tissue. Crucially. day 45 had reached 6. whereas secondary total dys- trophic onychomycosis is the culmination of any of the different Penetration of ciclopirox types of destructive nail dystrophy (i. which proved relatively ineffective. pirox achieved in the nail bed exceeded the minimal fungicidal ing disease.15 a similar study.

the mean concentration of demonstrate whether these agents subsequently achieve clinical ciclopirox increased throughout the treatment phase.7 µg/mg nail tissue. these studies do not each fresh application.26 mg nail. Again. effective con- centrations of ciclopirox nail lacquer 8% can be achieved Limitations of clinical trials throughout the nail unit. 7. but may be a nail that is Penetration of amorolfine mycologically cured. open study involving 27 patients with © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19. Overall. Results from a study in which 5% amorolfine. Furthermore. In a further in vitro study by Franz.9 and 1. and tested for both mycological cultures and Although these problems have been overcome to some extent its ability to inhibit growth of fresh T. the deepest layer. Indeed.4 µg /mg after 30 days. in either ethanol clinical success could be assessed as a 90 –100% clear nail. or as or methylene chloride. terbinafine cosis. Importantly. investigated the efficacy of topical tioconazole 28% trations of amorolfine have been shown to persist for up to solution in a small-scale. peaking cures. Epstein concluded that for the newer oral agents. but the development of novel agents and of subungual samples taken between 3 and 10 days inhibited formulations offers the prospect of more successful topical growth of T. clearly a place for topical agents in the management of fungal 94% of samples had negative cultures. Topical agents have generally been regarded as 82% of samples still had negative cultures. Cure does not always indicate a disease-free normal nail.25 Topical monotherapy for onychomycosis Two groups of patients applied 5% amorolfine lacquer in without matrix involvement ethanol or methylene chloride to infected nails twice weekly for Oral antifungals often give rise to side-effects and may interact 4 weeks. In addition. concentrations of morphology) provides a more exacting efficacy measure. such as itraconazole and terbinafine.23 Drug levels in the uppermost layer ranged Combining data for mycological cure with clinical success (nail from 1 to 6.e. These results demon. which can reduce patient compliance. there is cating the presence of active drug). Complete replacement of a fingernail takes 4–6 months and ments that amorolfine in ethanol or methylene chloride that of a toenail 12–18 months. provided that the affected nail area is restricted to the 15 days after discontinuing treatment. with newer drugs.2 µg drug / achieved in only 35–50% and 25–40% of cases. slowly. by the treatment. active concen. that. with the old lacquer removed before 2 weeks in subungual debris. imidazoles are generally given systemically. The overall efficacy and wider applications of antifungal at 3. had fallen below the limit of detection (0.16 strate that amorolfine lacquer not only penetrates into subungual debris but also maintains effective antifungal drug concentra- Imidazoles tions for at least 2 weeks after termination of treatment. Hay et al. even after 14 days at least nail diseases. prevent the growth of most fungi responsible for onychomy. for severe 100 ng /cm2/ h and peaking between 5 and 25 h. 10 and 14 days. > 97% rather ineffective.e.04 µg/ mg). These results indicate that. varying criteria used to define clinical cure or improvement (sometimes called clinical success). rubrum cultures and 91% still prevented growth therapies. respectively. amorolfine and ciclopirox but some have been used topically as monotherapy. with other medications. following termination of difficult. Three days after treatment. The effectiveness of penetration of amorolfine into subungual tissues has been confirmed in patients with onychomycosis. Antifungal combined therapies 23 lacquer daily for 45 days. during the treatment phase. amorolfine achieved at the nail bed exceeded those needed to following extensive analysis of several published clinical studies. when formulated as lacquers. results from these in vitro and in vivo studies indicate In onychomycosis. was applied to a range of nail types of one that simply shows marked improvement. However. disease-free toenails (i. the mean concentration of ciclopirox in the nail lowing sections. even if it is still malformed. 21–29 .24 These data indicate that amorolfine lacquers should be Even longer follow-up periods are warranted for recurrence able to deliver effective levels of antifungal drug to onychomycosis assessment. Similarly. In the four subjects assessed 14 days lacquers and other topical agents are considered in the fol- after treatment. infection sites. a 48-h treatment with and itraconazole. A residual varying hardness and morphology for 24 h demonstrated that affected area smaller than 10% may correspond to residual exponential penetration kinetics were followed. concentrations onychomycosis not yet completely cured but is more likely of the drug in the uppermost layer were 100-fold higher than in to include previous nail dystrophy of unknown aetiology. clinically normal 3H-labelled 5% amorolfine in methylene chloride and ethanol nails with negative microscopy and fungal culture) were lacquers resulted in concentrations of 2. requires further investigation. Whether effective concentrations Judging the efficacy of treatments for onychomycosis is made of ciclopirox persist within the nail. Subungual material was subsequently removed after 3. can effectively penetrate nail tissue.24 Franz also demonstrated in several experi. Although studies involving penetrates rapidly into the nail. rubrum inocula (i. indi. especially when comparing different studies.15. respectively. For example. distal two-thirds. with rates ranging from 20 to only distal onychomycosis can be relatively short. before declining onychomycosis a study length of 6 months is not sufficient.

vehicle-controlled.34 In fact. Throughout the 6-month Ciclopirox has proven effective in the treatment of superficial treatment period there was a steady clinical improvement. in a number of clinical trials. with no serious adverse events reported in tions. Another multicentre. In some of these studies topical tioconazole. Whether less frequent ciclopirox applica- combination with chemomechanical nail avulsion. Mycological cure rates fingernails − involved patients). Six months after treatment. once the clinical studies with overall encouraging results. Safety profiles in the two cured in 46% of assessments following once-weekly applica- studies were similar.e. many are used in the treatment phase. and dermatomycoses. combined mycological multicentre studies have recently demonstrated the efficacy and and clinical response data showed that onychomycosis had safety of ciclopirox nail lacquer 8% monotherapy in the improved or was cured in 67% and 70% of assessments follow- treatment of a total of 460 patients with mild to moderate ing application of the 2% and 5% formulations. At treatment end (48 weeks). multicentre trial. 3 months after stopping medication. onychomycosis.24 Baran and Kaoukhov Table 2 Nail lacquer monotherapy for mild to Active ingredient Dosing Mycological cure Overall cure* moderate onychomycosis: effect of strength and Study concentration frequency (%) (%) frequency Lauharanta37 Amorolfine 2% Once weekly 55 12 Amorolfine 5% Once weekly 60 38 Reinel and Clarke38 Amorolfine 5% Once weekly 71 46 Amorolfine 5% Twice weekly 76 52 Gupta and Joseph35 Ciclopirox 8% Once daily 32 9 Ciclopirox vehicle Once daily 10 1 *Cure = mycological cure with a normal nail or a nail with ≤ 10% still affected.g. combined results parallel group study compared once. followed by 1% bifonazole cream alone (i. 42% of treated nails were cured (cure Amorolfine was defined as no subungual hyperkeratosis. particularly towards the end of penetration of the nail unit. Indeed. 21– 29 .29–33 with amorolfine nail lacquer 5% (80 patients) for the treatment of onychomycosis (predominantly the toenail) in a double- blind. has. respectively. onycho- Clinical assessments also demonstrated the efficacy of ciclopirox mycosis had improved or was cured in 69% of assessments and nail lacquer over vehicle (Table 2). higher in the 5% amorolfine group. once daily to all (even unaffected) toenails and any affected 38% vs.and twice-weekly applica- showed that patients treated with ciclopirox had significantly tions of 5% amorolfine lacquer for 6 months.27 The results suggested that topical tioconazole Europe. Three months after cessation of therapy. in both studies the medications were higher incidence of erythema in the skin adjacent to the nail plate. fingernails. randomized. randomized. It was subsequently suggested of 47–67% were reported. but this was generally mild in severity. however. © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19.36 Patients with mild to achieved a cure (defined as a completely normal nail and negative moderate onychomycosis were treated with ciclopirox nail direct microscopy) in 22% of patients (six − five having only lacquer 8% for periods of 6–12 months. Consequently. tions are as effective as the recommended once-daily regimen Rollman demonstrated the efficacy of a topical miconazole needs confirmation with more strictly controlled studies. South America and Asia. two double-blind.a Importantly. ‘clinical improvement’ was defined as a nail with ≥ of clinical trials (most of which were open-label) conducted in 20% reduction of total affected area compared with baseline.27 As mentioned previously. and toenails). negative micro- scopy and negative fungal culture). no data was available regarding clin- that combination therapy might improve the cure rate with ical success or clinical cure rates. 12% (Table 2). the efficacy of ciclopirox nail lacquer was applied less frequently (e. solution following nail avulsion in 13 patients with DLSO. nail is removed). results for the twice-weekly dosing regimen were similar any patient. three topical solutions and creams may be hindered by their poor times a week instead of once a day).37 Lacquers were applied Ciclopirox weekly on affected nails only. The ciclopirox-treated patients did show a slightly (Table 2).38 A total of 317 higher mycological cure rates (defined as the percentage of patients were included in the efficacy analysis with 326 assess- patients with negative culture and negative KOH microscopy) ments performed (nine patients had both affected fingernails compared with those treated with the vehicle lacquer (Table 2).28 Similarly. For example. repeatedly Lauharanta compared amorolfine nail lacquer 2% (77 patients) shown efficacy in the treatment of onychomycosis. onychomycosis.35 Ciclopirox or vehicle lacquers were applied The cure rate was. topical treatment The efficacy and safety of amorolfine lacquer for the treatment of onychomycosis with a combination of 1% bifonazole and of fungal nail infections has been assessed in a number of 40% urea.35 a ‘Clinical cure’ was defined as a normal nail or a nail with ≤ 10% The efficacy of ciclopirox has also been assessed in a variety still affected.

and enhanced tolerability and (n = 727) treated with amorolfine lacquer once. suc. but when mycological and clinical (31 nails) and the results showed a clinical and mycological evaluations were assessed together. presumably therapy.15. a less severe problem because of its high cure rate alone (73% in this trial). especially as antifungal drugs are often combined with isoconazole cream. Additionally. Potential advantages of confined to the application site. However. Hay et al. Moreover.43 Similarly. amorolfine should also be considered as a first step. necessary to confirm the effect of such a combination. However. itchiness. which usually precedes and the recommended doses where clinical cure / improvement accompanies toenail onychomycosis. against a number of dermatophytes involving a combination of a topical and an oral antifungal. (definition as in footnote) with associated negative culture was Chances of clinical success are increased with combination observed in 56% of assessments. encouraging results have been some patients may not show any improvement despite clearing reported from a recent open study in which 117 onychomycosis of infection owing to pre-existing nail dystrophy. fungal ergosterol biosynthesis. Indeed.4%) for ciclopirox and 35.39 A total of 379 assessments were made with oral therapy against tinea pedis. the use of ciclopirox nail trations in the infected tissue.or twice-weekly safety. these example. improved fungicidal activity. open-label single-blind study of 90 patients with onycho- Limitations with monotherapy mycosis. spectrum. As a relatively new formulation. although both itraconazole and amorolfine block included burning. which is a for combinations of amorolfine with griseofulvin. or redness near the application site. 21–29 .44 The activity of itraconazole was not several factors can influence the success of the chosen mono. increased cure rates.35 remission of 69% in the combination group compared with 41% in the oral griseofulvin group.45 At the end of the on the toe. documented. However. compared with antibacterial resistance. however. Randomized. Importantly. in a comparative. itraconazole or fluconazole. wider antifungal Similar findings were reported in a more detailed and com. grow very slowly.42 recent pharmacoeconomic meta-analysis. a infection site from different directions. a particular problem with more lacquer in combination with oral antifungals has not been well severe forms of onychomycosis (dermatophytoma). Finally. particularly those combination with itraconazole for 3 months. especially from the surrounding tissue (other 100% clearance of the nail plate) and 47% had therapeutic superficial fungal diseases often accompany nail infections). Nevertheless. demonstrated the efficacy of tioconazole used cess rates fell to 31. using the more exacting measure of cure alone. the clinician Improvements in fungistatic activity have been demonstrated should recommend the second therapeutic stage.3% (SE 2. suppression of resistant prehensive analysis of a large number of onychomycosis patients mutants. with all reported side-effects being minor and proximal third of the nail is involved. improved in combination with these topical agents. Combination therapies for onychomycosis with matrix involvement Amorolfine in combination When presented with non-responders who have received 6 months of monotherapy with topical treatment. For (7 / 727) reported adverse events linked to medication. cure rates fell to < 10%.9%) for amorolfine.41 In addition. implicated in superficial infections.2. Antifungal combined therapies 25 well tolerated. double-pronged therapy. a keratolytic cream.10 success (negative mycology with incomplete clearance of the nail plate). antifungal resistance. particularly when the has been combined with several oral drugs used to treat nail © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19. they have different target When evaluating results from these clinical trials it is important enzymes. terbinafine.40 Furthermore.16 There may also be advantages in using drugs with to consider that the criteria used to gauge efficacy can also separate administration routes because they can access the influence estimates of success with topical agents. performed using ciclopirox and amorolfine treatments for onychomycosis as Imidazoles in combination examples. failure of patients were treated with ciclopirox nail lacquer 8% in monotherapy may be due to the fact that nails. clearance of infecting fungi from toenail onychomycoses The reasons why monotherapy for onychomycosis may fail are by oral griseofulvin rose from 27% to 46% when it was not completely understood. monotherapy may fail because of the difficulty in achieving biologically effective drug concen. < 1% of patients therapies if the drugs have distinct mechanisms of action. initially found both agents to be > 70% successful. controlled comparative studies are.8% topically in combination with oral griseofulvin.46 In clinical trials. 41% of patients were cured (negative mycology with to reinfection. combination of treatments. For example. which can make them vulnerable study. this approach include: antimicrobial synergy. a recent study reported receiving 1 g oral griseofulvin daily over 1 year were treated a mycological cure rate of 34% following treatment with topically with tioconazole 28% nail solution (29 nails) or placebo ciclopirox nail lacquer 8%. combination therapy provides effective for 6 months. and to 43% when given with very active against the causative organisms in vitro.43 Ten patients (SE 1. may result in some fungi that cause nail infections falling outside the spectrum Ciclopirox in combination of any one drug.

infections. Mycological cure rates (P < 0. respectively). matrices in most cases).001) (Table 3). 2 months. accompanied by patients to evaluate combined amorolfine/oral itraconazole twice-daily griseofulvin 500 mg for the first 2 months. lacquer has been compared in an open-comparative 15-month study of patients with severe onychomycosis (affecting lunulae / Amorolfine with itraconazole. mycologyd. randomized multicentre study recruited 131 fine nail lacquer twice weekly for 12 months. Another The efficacy of amorolfine combined with oral terbinafine has study assessed a combination of 3-months’ itraconazole pulse been investigated in an open. respectively. micorscopy. 21– 29 . A further open. changes or ≥ 95% reduction in diseased nail surface. multicentre study enrolling 147 therapy with 6 months’ amorolfine once weekly in patients with patients with toenail onychomycosis with matrix involvement.8%) with extensive onychomycosis and in 12 / 16 12 weeks (groups AT6 and AT12. but adverse events were more frequent in the first 2 months.16 related) and decreased after the first 6 weeks indicating that they Its activity alone and in combination with 5% amorolfine nail were most probably caused by terbinafine. such as for all treatment groups (overall. are fairly common.47– 49 and lowest after T12 monotherapy (66%) (Table 3).1 84‡ Itraconazole 3 months 6 months ≥ 90 100 94‡ *Combined clinical response and negative mycology at 18 months. compared with < 69% of those receiving monotherapy fulvin treatment groups. 22% were assessed as drug headache and gastrointestinal upset.49 other group were given griseofulvin 500 mg twice daily for Patients applied 5% amorolfine lacquer once a week for 6 months. Cure was achieved in 21/ 27 were given 250 mg of terbinafine daily for either the first 6 or patients (77. but cure rates tend to be low.26 Baran and Kaoukhov Table 3 Combined amorolfine/oral antifungal therapy for severe onychomycosis: responses at last reported visit Oral drug and duration ±5% Amorolfine Mycological cure Clinical response Overall cure Study of dose for (%) (%) (%) Zaug47 Griseofulvin 12 months – 50 42 – Griseofulvin 2 months 12 months 63 45 – Baran et al. Both cure rates were considerably higher than the 69% rate suggesting an association with the higher griseofulvin dose. and 84% for 6-week combination therapy. At the last visit. clinical and mycological or 12 weeks. ‡Global cure assessment at 6 months. ‘clinical cure’ was defined as the disappearance of all visible ‘mycological cure’ was defined as negative culture and micorscopy.47 observed with itraconazole alone. Three accompanied by itraconazole 200 mg daily for either the first 6 months after the end of treatment. similar. respectively.48 extensive dermatophyte onychomycosis and a group of patients Subjects applying 5% amorolfine once a week for 15 months with recurrent onychomycosis. end-point global cure rates (clinical cure plus mycological Amorolfine with griseofulvin cure)c were much higher for the AT12 group (72%) than either Griseofulvin has been widely used in antifungal therapy for over the AT6 (44%) or T12 groups (38%). for 12 weeks. and the distribution and number Amorolfine with terbinafine of events were similar for the three treatment groups. Similarly. †Unpublished data.47 One set of patients applied amorol. a further group received itraconazole monotherapy assessments were performed on 59 and 57 patients in the com. and once daily for the following 10 months. The combined mycological–clinical cure4 were 63% in the combination and 50% in the griseofulvin group rate at 6 months for the amorolfine /12-week itraconazole (Table 3). with the aim of improving both the efficacy and the cure was highest following AT12 combination therapy (89%) cost-effectiveness of the single agents (Table 3). a group taking c ‘Mycological cure’ was defined as negative culture and negative terbinafine alone for 12 weeks served as controls (T12). ‘clinical cure’ was defined as the disappearance of all were followed for up to 18 months. © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19. b ‘Clinical cure’ was defined as intact lunulae/matrix and complete d ‘Mycological cure’ was defined as negative culture and negative clearing of each nail or residuum not exceeding 5% of the nail surface. The therapy for the treatment of severe toenail onychomycosis. No serious adverse events were reported during the trial.15.b Safety profiles for the two treatment groups were regimen was 94%. ≥ 90% of patients treated with bination and griseofulvin alone groups. By 6 months. mycological lesions on each nail or residual disease of no more than 10% of the original disease surface.2. Subjects microscopy.5 months 15 months 73 46† 44* Terbinafine 3 months 15 months 89 75† 72* Lecha49 Itraconazole 3 months – < 69 90 69‡ Itraconazole 1. and side-effects.5 months 6 months ≥ 90 88. Clinical either of the amorolfine and itraconazole regimens had negative cure rates were 45% and 42% in the combination and griseo. Side-effects were similar 40 years.48 Terbinafine 3 months – 66 42† 38* Terbinafine 1.

A study was also cosmetically convenient. The com. References looking part of the nail keratin. combined topical/oral therapies benefit both patients and When there is a risk of failure because of interruption in the health providers. amorolfine lacquer 8% was started once weekly. compared with oral therapy alone. as it remains in nail keratin (up to 14 days) patients started with fluconazole 150 mg once weekly and. Prevalence of dermatophyte onychomycosis in the bination will result in increased cure rates. Br J Dermatol 1999.51 nails assessed. as some fungi may be left 1 Zaias N. although current monotherapy conducted in 157 patients treated with amorolfine once weekly recommendations suggest applying ciclopirox to all nails. Onychomycosis: current treatment and future established whether it is possible to formulate a combination challenges. Arch Dermatol 1972.54 tion of oral therapies with a topical agent. with Amorolfine with fluconazole approximately 20% of terbinafine-treated patients and 50% of A small study was performed by Sergeev and Sergeev to assess itraconazole-treated patients. as after the weekly active therapy has been interrupted. appreciable cost siderations often dictate prescribing practices as much as clinical savings can be made by using oral and topical agents together.40 combined therapy is clearly an attractive option The improved effectiveness and economic advantages of from more than one viewpoint. 141 (Suppl 56): 1 – 4. 2 Elewski BE. © 2004 European Academy of Dermatology and Venereology JEADV (2005) 19. 21–29 . beneath its lateral margin and on the newly growing nail. with an oral antifungal drug can result in dose-sparing effects and The use of combination therapy of onychomycosis might can increase the number of patients cured from onychomycosis also decrease costs per cure by 16–23%. once for 12 months and an oral antifungal of the investigator’s daily. mens in which drugs are prescribed in parallel from the start. normal. Clin Microbiol Rev 1998.6%). ive in the treatment of onychomycosis. management. Br J Dermatol 1992. smaller study (n = 12) was used Although several topical agents can be prescribed as mono- to test the effectiveness of fluconazole/amorolfine combination. The patients were divided into two groups with group I (32 patients) receiving itraconazole according to a pulse regime over 3 –4 months and group II (41 patients) receiving a Long-term therapy combination of itraconazole with amorolfine lacquer. A 5 Meinhof W. Co-administration of amorolfine benefits for the treatment of onychomycosis. In: Korting G. 11: 415 –429.55 As financial con. can confer considerable advantages over mono- therapy using amorolfine nail lacquer offers significant clinical therapy with either drug type. onychomycosis.53 therapy for mild to moderate onychomycosis. In addition. 4 Roberts DT. Onychomycosis. ed. Germany. such as amorolfine or The data from these trials therefore suggest that combination ciclopirox. Another.4 –19.52 Complete clinical and mycological cure was noted in Summary and conclusions 19 patients (82. Antifungal combined therapies 27 patients (75%) with recurrent onychomycosis. 1980: 19. of different antimycotics in a single lacquer. All the studies described above assessed combination regi. In addition. 105: 263 –274.1. Thieme. efficacy. with itraconazole therapy showed recurrent dystrophy in 17% of all patients demonstrating clinical and mycological recovery. mechanical or chemical removal of the diseased nail is com- bined with oral and topical antifungal therapy. amorolfine nail lacquer has an advantage in that only choice: either terbinafine once daily for 3 months. and convenient twice a month) appears to be a logical and safe method for pre- because of its once-weekly application. Onychomycosis: pathogenesis. amorolfine and In this study. Dermatologic in different approach has been suggested recently in which oral Klinik and Praxis. Cure rates were similar in all groups (71 – 73%). soon as the Scoring Clinical Index for Onychomycosis scores had decreased to 3 – 6. and was found to be well tolerated. periodic use of amorolfine (for instance.5. Assessment of disease recurrence in patients 2 years after bination treatment was highly effective and well tolerated. In triple therapy. reinfection. immediate important role to play in the modern management of eradication of the pathogen is indicated. United Kingdom: results of an omnibus survey. and Although current combination therapies have proven effect.52 This com. pulse therapy for 3 months or fluconazole once weekly for Recent clinical investigations have shown that the combina- 6 months. Tinea unguium. nine patients (75%) achieved complete clinical ciclopirox nail lacquers are generally considered the most cure and all patients showed mycological cure. However. with the topical study was conducted in 73 patients with onychomycosis of the prescribed immediately after the oral treatment is stopped.57 Long-term results from a recent 5-year blinded follow-up study also show significant recurrence rates. it also remains to be 3 Roberts DT. Stuttgart. Another study in 23 venting recurrences. diagnosis. the re-establishment of tinea pedis and limit the possibility of bination was preferred over a terbinafine/amorolfine combination. itraconazole once-weekly applications to affected nails are required.56 fingers and toes. and if such a com. effective. 126 (Suppl 39): 23 – 27.50 A further and topical agents are prescribed sequentially. Application of antifungal nail lacquer is continued on the remaining. these treatment regimens therefore have an transport of the drug from the nail into the nail bed.58 the combination of fluconazole 150 mg once weekly with Long-term intermittent traditional therapy should prevent amorolfine nail lacquer applied once weekly.

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