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British Journal of Dermatology 2003; 149 (Suppl. 65): 15–18.
J . H . O L A F S S O N , B . S I G U R G E I R S S O N * A N D R . B A R A N †Department of Dermatology, Landspitali University Hospital, Tverholt 18, 105 Reykjavik, Iceland*Hudlaeknastodin, Smaratorg 1, 200 Kopavogur, Iceland†Nail Disease Centre, Le Grand Palais, 42 rue des Serbes, 06400 Cannes, France Combination therapy is one way of improving the cure rate of onychomycosis. The LION Studyexamined the efficacies of terbinafine and itraconazole. The Icelandic cohort of the study reportedthat after 5 years only 46% of the terbinafine-treated patients and 13% of the itraconazole-treatedpatients were still disease-free, suggesting that relapses and reinfections were common in the longterm treatment of onychomycosis with monotherapy. Combination therapy is a well-establishedprinciple in mycology; the current strategy involves the combination of oral and topical antifungaltreatments. A number of specific drug combinations have proved to be useful in the treatment ofonychomycosis: tioconazole and griseofulvin, amorolfine and griseofulvin, amorolfine andterbinafine, and amorolfine and itraconazole. However, comparison of the combination trials canbe difficult because of the short duration of some of the studies and variation in global cure rates.
Although it is necessary to consider these factors it is clear that combination therapy offersadvantages when compared with monotherapy. Combination therapy can be administeredsequentially or in parallel. Parallel therapy is recommended for patients who are likely to failtherapy (e.g. patients with diabetes), whereas sequential therapy is recommended for patients whoshow a poor response to initial treatment.
Key words: combination, onychomycosis, trials 75–80% of terbinafine recipients and 38–49% of itrac- onazole recipients were classified as mycologically Combination therapy is one way of improving the speed cured.1,2 The long-term efficacy and treatment failure of cure and the overall cure rate of onychomycosis, a rates for the Icelandic cohort within this multinational common and persistent fungal infection of the nail unit.
study were then followed for a further 5 years. At Although monotherapy has proven effective in the short endpoint, only 46% of the terbinafine-treated patients term, a substantial proportion of patients does not and 13% of the itraconazole-treated patients were still experience a complete and lasting cure. Treatment disease-free, suggesting that relapses and re-infections strategies include topical and systemic antifungal ther- were common in patients who received monotherapy.3 apies, and surgical and chemical nail avulsion. This In fact, 23% of terbinafine-treated patients and 53% of paper summarizes the clinical studies investigating the the itraconazole-treated patients experienced a relapse efficacy of therapy combining oral and topical antifun- or re-infection after 5 years of treatment despite being gal agents, and considers situations in which combina- tion therapy may lead to better outcomes.
The use of combination strategies and the exploita- In the largest study of the treatment of toenail onyc- tion of antifungal drug synergy is a well-established homycosis, the LION Study, the efficacies of terbinafine principle in mycology. The combination of two or more and itraconazole were compared in patients with mild to drugs can result in increased efficacy and rapidity of moderate onychomycosis. After 72 weeks of follow-up, effects, a broader spectrum of activity and better patienttolerability. These benefits can often be the result ofdrug synergy, that is, the combination is more effective Correspondence: Dr J.H. Olafsson.
E-mail: jonho@hudlaeknastodin.is than the additive effects of each drug alone.
Ó 2003 British Association of Dermatologists mycological remission, compared with 41% of nails involves combining oral and topical antifungal agents.
receiving oral griseofulvin and placebo solution.5 The The different modes of drug administration allow for results of this study suggest that combination therapy complementary drug penetration into areas of infected of griseofulvin and 28% tioconazole topical therapy is tissue where each drug alone does not accumulate in more effective than oral treatment alone in managing effective concentrations; oral drugs rapidly suffuse and accumulate in the nail bed, while topical therapieseffectively penetrate the nail plate and may be effective in preventing reinfection of the nail itself.
As detailed below, a number of reports have described The efficacy and tolerability of combination therapy the successful combination of topical nail lacquers with amorolfine and griseofulvin was compared with and oral antifungals in the treatment of severe that of griseofulvin monotherapy in the treatment of onychomycosis with or without matrix involvement.6A total of 233 patients were given either oralgriseofulvin treatment for 2 months plus amorolfine nail lacquer for 12 months or the standard 12-month The benefits of combination therapy were first shown griseofulvin treatment. At 6 months, mycological with griseofulvin, the standard therapy for onyc- cure had occurred in 67% of patients in the combination group and 45Æ3% of the griseofulvin 30 years. More recently, combinations with amorol- group; positive cultures were obtained from 7Æ4% of fine have been shown to have even greater efficacy patients receiving combined therapy and 34Æ7% of 6 months of treatment, the number of toenails andfingernails cured in the combination group was Griseofulvin or itraconazole combination therapy approximately double that seen in the griseofulvin An open, randomized trial compared griseofulvin and itraconazole for the treatment of onychomycosis ofthe foot.4 Patients received griseofulvin or itraconaz- ole plus either placebo, 1% isoconazole (antimycoticcream) or 40% urea (keratolytic cream). The itrac- The efficacy of combined amorolfine and terbinafine onazole groups showed better results compared with therapy for severe dermatophyte toenail onychomy- the griseofulvin group; when itraconazole was com- cosis was investigated in an open study by Baran and bined with isoconazole cream, keratolytic cream or colleagues.7 A total of 147 patients were randomized placebo, the number of patients showing complete to three treatment arms: terbinafine was given orally clearance was 73Æ3%, 78Æ5% and 91Æ6%, respectively.
for 6 (AT-6 group) or 12 (AT-12 group) weeks and The griseofulvin group showed complete clearance in amorolfine nail lacquer was applied weekly for combination with isoconazole cream in 46Æ1% of 15 months. A control group received terbinafine patients, in combination with keratolytic cream in alone for 12 weeks (T-12). The global cure rate 26Æ6% of patients, and in combination with placebo was markedly better in the AT-12 combination group (72Æ3%) in comparison with the AT-6 combinationgroup (44%) and the T-12 group (37Æ5%; Fig. 1). Themajority of patients in all groups had visible clearing of the clinical signs of infection within 24 weeks. A Tioconazole 28% solution was compared with placebo typical example of the improvement in nail appear- in patients receiving 1 g daily oral griseofulvin over a ance during combination therapy of a patient in 1-year period.5 All the patients in the study had group AT-12 is illustrated in Fig. 2.
Seventy nails were treated in total; each patient received active treatment on the nails of one side andplacebo on the other. In total, 69% of nails treated Two alternative regimens of topical amorolfine and oral with griseofulvin and tioconazole achieved clinical and itraconazole therapy were compared with itraconazole Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 149 (Suppl. 65), 15–18 C O M B I N A T I O N T H E R A P Y F O R O N Y C H O M Y C O S I S cured of severe onychomycosis. Cure rates may also vary, reflecting the use of different definitions of cure.
While it is necessary to consider these factors, it is clear of patients
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that combination therapy offers potential advantages rcenta
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In our group in Iceland, current choices for treating onychomycosis include topical monotherapy with am- Figure 1. Investigator’s assessment of clinical response at last visit.7 orolfine, or a combination of oral and topical therapyusing amorolfine and terbinafine. In our experience, monotherapy in an open study of toenail onycho- amorolfine monotherapy is effective in mild cases of mycosis with matrix involvement.8 A total of 131 onychomycosis without matrix involvement and in patients were randomized to treatment. Patients in children, who normally have thin, quick-growing nails.
combination groups received amorolfine 5% nail Monotherapy can also be used as a prophylactic. In lacquer once weekly for 24 weeks and 200 mg patients who have been successfully treated but are at itraconazole once daily for 6 weeks (AI-6) or 12 weeks risk of recurrence, amorolfine can be used prophylac- (AI-12). A control group received itraconazole mono- tically, being applied once or twice a month.
therapy for 12 weeks (I-12). The global cure rate at Combination therapy may be of benefit in patients study endpoint was highest for the AI-12 group who are likely to fail monotherapy. For example, a (93Æ9%). Compared with itraconazole monotherapy, patient who had been treated with terbinafine in 1995 the difference was statistically significant (P < 0Æ05).
and was cured both mycologically and clinically within Furthermore, while improvement of the toenail was a year quickly relapsed. In 1998, the patient was again visible at 6 months, the result was still unclear treated with terbinafine and remained disease-free for regarding a cure.8 These results indicated that amor- 4 years. However, the same patient recently presented olfine and itraconazole combination therapy may be with another reinfection of onychomycosis with lateral an improved treatment strategy for patients with and matrix involvement. This patient represents a perfect case for the use of combination therapycomprised of oral and local agents, which might haveprevented the recurrences.
Frequent swimmers are another group that may benefit from the combination of oral and topical therapy.
Comparison of the combination trials can be difficult An Icelandic cohort study found that onychomycosis of because of the short duration of some of the studies and the toenail is at least three times more prevalent in the variation in global cure rates. Some of these studies swimmers than in the rest of the population: one-third lacked an observation period after the final treatment, of male swimmers and one-fifth of female swimmers and a study length of 6 months is not considered had onychomycosis.9 Such frequent swimmers are sufficiently long to determine whether a patient is candidates for prophylactic therapy.
Figure 2. Improvement in clinical appearanceof a single target nail infected with Trichophytonrubrum. Observations made at (a) baseline (b)3 months and (c) 15 months during treatmentwith once-weekly topical amorolfine nail lacquerin combination with 3 months once-daily oralterbinafine 250 mg (Group AT-12).7 Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 149 (Suppl. 65), 15–18 sequence, it can benefit patients who show a poorresponse to treatment.
sequentially or in parallel. When therapy is sequential,the oral agent alone is administered for a period of time that is then followed by a further period of treatment 1 Evans EG, Sigurgeirsson B. Double blind, randomised study of with the topical agent alone. When treatment is used in continuous terbinafine compared with intermittent itraconazole in parallel, the topical and oral antifungal agents are used treatment of toenail onychomycosis. The LIOn Study Group. BMJ simultaneously. Parallel treatment is recommended 2 Sigurgeirsson B, Billstein S, Rantanen T, Ruzicka T, di Fonzo E, when patients are likely to fail therapy, for example, Vermeer BJ et al. LIOn Study. Efficacy and tolerability of continuous patients with diabetes or patients with yellow spikes in terbinafine (Lamisil) compared to intermittent itraconazole in the the nail. Sequential treatment is recommended when treatment of toenail onychomycosis. Lamisil vs. itraconazole in patients show a poor response to treatment. A response onychomycosis. Br J Dermatol 1999; 141 (Suppl. 56): 5–14.
3 Sigurgeirsson B, Olafsson JH, Steinsson JB, Paul C, Billstein S, is considered poor when the microscopy is still positive Evans EG. Long-term effectiveness of treatment with terbinafine vs after 3–6 months of treatment. A patient who shows a itraconazole in onychomycosis: a 5-year blinded prospective positive culture at these times is unlikely to be cured.
follow-up study. Arch Dermatol 2002; 138: 353–7.
For example, in Iceland, terbinafine is first administered 4 Arenas R, Fernandez G, Dominguez L. Onychomycosis treated with itraconazole or griseofulvin alone with and without a topical for 3 months, after which the mycology is tested. If the antimycotic or keratolytic agent. Int J Dermatol 1991; 30: 586–9.
mycology is negative, the treatment can be stopped.
5 Hay RJ, Clayton YM, Moore MK. A comparison of tioconazole 28% However, if the mycology is positive, the patient can be nail solution versus base as an adjunct to oral griseofulvin in treated with amorolfine once weekly until they are patients with onychomycosis. Clin Exp Dermatol 1987; 12: 175–7.
6 Lauharanta J, Zaug M, Polak A, Reinel D. Combination of amor- olfine with griseofulvin: In vitro activity and clinical results inonychomycosis. JAMA SEA 1993.
7 Baran R. Topical amorolfine for 15 months combined with 12 weeks of oral terbinafine, a cost-effective treatment for onyc-homycosis. Br J Dermatol 2001; 145 (Suppl. 60): 15–9.
Combination therapy has resulted in the marked 8 Lecha M. Amorolfine and itraconazole combination for severe improvement of mycological and clinical outcomes toenail onychomycosis; results of an open randomized trial in associated with onychomycosis. Combination therapy spain. Br J Dermatol 2001; 145 (Suppl. 60): 21–6.
is useful in selected patient populations: in parallel, it 9 Gudnadottir G, Hilmarsdottir I, Sigurgeirsson B. Onychomycosis in icelandic swimmers. Acta Derm Venereol 1999; 79: 376–7.
can be used in patients who are likely to fail therapy; in Ó 2003 British Association of Dermatologists, British Journal of Dermatology, 149 (Suppl. 65), 15–18

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