Evidence based Dermatology - part 7 potx

436 Background Definition Athlete’s foot or tinea pedis is most frequently caused by dermatophyte (ringworm) invasion of the skin of the feet. It usually manifests in one of three ways: interdigital skin appears macerated (white) and soggy; patches of skin on the foot may be affected by recurrent vesicular eruptions which make the skin itchy and red; and finally the soles of the feet, including the sides and heels can appear dry and scaly. 1 Incidence/prevalence Tinea infections are common. It has been estimated that 15% of the general population have a fungal infection of the feet. 2 Gentles and Evans 3 found the prevalence of athlete’s foot to be 21⋅5% in a sample of adult male swimmers, but the prevalence amongst adult females participating in the same survey was only 3⋅3%. Aetiology The dermatophytes most frequently reported in clinical trials to be present on patients’ skin at trial entry are Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum and T. interdigitale. 4 Scaling, fissuring, pruritus and itching are some of the clinical features of fungal infections of the skin and it is these irritations that make the patient seek treatment. The natural history of the condition if untreated is a chronic, worsening infection which can lead to fissuring and breaks in the epidermis. Although the condition will not resolve spontaneously, some evidence from cure rates collected from people in the placebo arms of controlled trials suggests that improved foot hygiene alone may cure the infection in a proportion of people. 5,6 Diagnosis The use of laboratory tests to diagnose the presence of dermatophyte infection is very important because athlete’s foot can be mistaken for other skin conditions. For example, interdigital maceration can look exactly like interdigital athlete’s foot, and juvenile chronic dermatosis and bacterial infections such as erythrasma can also have a similar appearance to fungal infections on the skin of the feet. Aims of treatment Treatment aims to reduce the signs and symptoms such as itching and flaking of the skin, and ultimately to eradicate the infection. 32 Athlete’s foot Fay Crawford Figure 32.1 Athlete’s foot The many creams available for the treatment of athlete’s foot differ in cost and availability. The azoles (for example miconazole, clotrimazole) and allylamines (terbinafine, naftifine) are sold over the counter in pharmacies. Other creams (for example tolnaftate, undecenoic acid) are available in supermarkets. This last group is the cheapest of the topical preparations and the allylamine creams are the most expensive. Oral drugs are sometimes used in the management of chronic manifestations of athlete’s foot. Griseofulvin is the oldest and cheapest of the oral antifungal drugs but it must be taken for a long time. Newer azoles such as itraconazole, ketoconazole and fluconazole are effective in a much shorter time. The newest oral antifungal drugs are allylamines (terbinafine, naftifine). The allylamines (both topical and oral) are fungicidal whereas all other antifungal agents are fungistatic. Relevant outcomes The effects of treatment on these symptoms are measured in randomised controlled trials (RCTs) but microscopy and culture are usually the primary outcomes. Secondary outcomes are measured using a variety of signs and symptoms (redness, flaking, itching etc.). A reduction in symptoms may be achieved quite quickly but the tenacity of tinea infections often means that complete cure takes a long time. Methods of search Systematic reviews and RCTs were identified using a search strategy published elsewhere. 7 This was updated to September 2001 with a Medline and Embase search using the same strategy and supplemented by a search of the Cochrane Central Register of Controlled Trials (September 2001). The inclusion criterion for study selection was the mycological confirmation of the presence of fungi in the trial populations. The search found two systematic reviews, one of topical treatments for skin infections 7 and the other of oral treatments for skin infections. 4 The search also identified three RCTs not included in the reviews, which compared topical allylamines with topical azoles. Generic drug names are used in the effectiveness analyses below. Martindale 8 gives a complete list of brand names of antifungal drugs. QUESTIONS How effective are allylamine creams in the treatment of athlete’s foot? One systematic review 7 found 12 RCTs comparing allylamines (terbinafine 1% cream or naftifine 1% gel) with placebo controls, used for 4 weeks. The two active preparations were similarly effective. A pooled analysis of data from seven trials (n = 683) comparing either naftifine or terbinafine with placebo controls produced a relative risk (RR) of 3⋅69 (95% confidence intervals (CI) 2⋅41 to 5⋅66). The allylamine creams, used twice daily for 4 weeks, are highly effective in the management of athlete’s foot. How effective are azole creams in the treatment of athlete’s foot? One systematic review 7 found 14 RCTs comparing 4–6 weeks treatment with azole creams (1% clotrimazole, 1% tioconazole, 1% bifonazole, 1% econazole, 2% miconazole nitrate with placebo controls. They were similarly effective. Treatment with 6 weeks of clotrimazole or tioconazole applied twice daily was evaluated in four trials (n = 434) (RR 1⋅85, CI 1⋅27 to 2⋅69). Shorter treatment times (4 weeks) with 437 Athlete’s foot 438 Evidence-based Dermatology bifonazole, econazole nitrate or miconazole nitrate gave a RR of 2⋅25 (CI 1⋅44 to 3⋅52, n = 520). All the creams were similarly effective whether used for 4 or 6 weeks. Over-the-counter antifungal creams are very effective in the treatment of athlete’s foot when compared with placebo controls. How do allylamines creams compare with azole creams in curing athlete’s foot? One systematic review of topical treatments (search date December 1997) indicated slightly better mycological cure rates with the allylamines (terbinafine 1% and butenafine 1% creams) than with azoles (clotrimazole 1% and miconazole 1% creams) used for 4 weeks (RR 1·1⋅95% CI 0⋅99 to 1⋅23). This analysis was based on data from 11 RCTs (n = 1554). 7 The analysis showed the allylamines to cure 80% of cases of athlete’s foot, compared with a cure rate of 72% achieved with azole creams. The systematic review 7 included one RCT 9 which compared 1 week of terbinafine 1% cream with 4 weeks of clotrimazole 1% cream. There was no difference in the cure rates (n = 211) after 1 week of treatment but 6 weeks after the start of treatment the cure rate for terbinafine was significantly better than that of clotrimazole (RR 1⋅16, CI 1⋅06 to 1⋅27). Patel et al. 10 found exactly the opposite effect in a smaller but similar trial (n = 104). They compared 1 week of terbinafine cream with 4 weeks of clotrimazole cream in people with interdigital tinea pedis. Terbinafine was found to more effective after 1 week (RR 1⋅51, CI 1⋅16 to 1⋅98) but there were no differences in effectiveness for outcomes assessed at later times. In the smallest of the trials, comparing 1 week of 1% terbinafine with 4 weeks of 2% miconazole (n = 48), 11 no difference in cure rate emerged at any time during the trial (RR at 1 week 0⋅99, CI 0⋅57 to 1⋅7). At 4 weeks there were 12/22 cures (54⋅6%) in the terbinafine group and 15/23 (65⋅2%) in the miconazole group (RR 0⋅83, CI 0⋅51 to 1⋅35). Schopoff et al. 12 compared terbinafine cream used for 1 week with clotrimazole cream for 4 weeks in 429 people with interdigital tinea pedis and found no differences in the effectiveness at any time during the trial. Pooling the data from all three trials (n = 792) comparing 1 week of terbinafine cream with either 2% miconazole or 1% clotrimazole found no statistical difference between these treatments (RR 1⋅15, CI 0⋅82 to 1⋅61). How effectively do creams that can be bought in the supermarket cure athlete’s foot? A systematic review 7 found two three-arm trials comparing undecenoic acid with tolnaftate and placebo, another trial comparing undecenoic acid with placebo and no treatment, a fourth trial comparing undecenoic acid with placebo and a fifth trial comparing tolnaftate with tea-tree oil and placebo. Pooling the tolnaftate data from the arms of three trials that compared it with placebo indicates that tolnaftate is more effective than placebo against dermatophyte infections (RR 1⋅56; CI 1⋅05 to 2⋅31). Pooled data from four trials showed undecenoic acid to be more effective than placebo in the management of athlete’s foot (RR 2⋅83, CI 1⋅91 to 4⋅19). Two trials of ciclopirox olamine 1% (which is not available in the UK) found it effective in treating athlete’s foot. In one placebo-controlled trial (n = 163) the RR was 6⋅85 (CI 3⋅10 to 15⋅15). A second small trial (n = 87) comparing ciclopirox olamine with clotrimazole found no statistical difference (RR 1⋅12, CI 0⋅90 to 1⋅38). Only one small RCT (n = 137) has compared the efficacy of an oral drug with a cream in the management of interdigital athlete’s foot. 13 Cure rates were similar in those treated for 1 week with oral terbinafine 250 mg/day and those using clotrimazole 1% cream twice daily for 4 weeks. The relapse rates among those who were cured differed significantly, however: 11/39 in the terbinafine group and 5/50 in the clotrimazole group relapsed after 3 months. What are the most effective oral drugs in the treatment of athlete’s foot? One systematic review 4 found 10 RCTs that compared two antifungal drugs and two RCTs that compared oral antifungal drugs with placebos. The sample sizes in all trials were small (range 14–66). The review found four trials comparing oral terbinafine 250 mg/day with itraconazole 100 mg/day. One trial (n = 117) compared 2 weeks of terbinafine with 2 weeks of itraconazole and found a significant difference in favour of terbinafine (RR 1⋅5, CI 1⋅23 to 2⋅02). Three trials (n = 339) comparing 2 weeks of terbinafine with 4 weeks of itraconazole found no statistical differences in cure rates (RR 1⋅17, CI 0⋅94 to 1⋅46). The systematic review found two small trials that compared griseofulvin 500 mg/day with terbinafine 250 mg/day for 4 or 6 weeks. The pooled data from the two trials found terbinafine to be significantly more effective (RR 2⋅20, CI 1⋅45 to 3⋅32). The systematic review 4 found similar low cure rates for ketoconazole 200 mg (53%) and griseofulvin 1000 mg (57%). The cure rates with fluconazole 50 mg did not differ significantly from those with itraconazole 100 mg or ketoconazole 200 mg, but in both trials the cure rates were high (89–100%). Treatments were taken for 6 weeks in these trials. Drawbacks Topical antifungal compounds are well tolerated and are not associated with high rates of adverse events. One systematic review 7 found that few trial reports gave details of adverse events and the few that were reported were not severe (for example itching, redness or burning). The systematic review of oral treatments for fungal infections of the skin 4 noted that all 12 included trials reported side-effects. All drugs produced side-effects; the rate was lowest for fluconazole (11%) and highest for terbinafine (18%). Gastrointestinal effects and rashes were reported most frequently. Comment The evidence from one small trial 13 shows that oral treatments are no more effective in the management of interdigital athlete’s foot than the creams. The same study also found higher relapse rates after oral treatments. Implications for practice All antifungal creams, whether over the counter or those available in supermarkets are effective in the treatment of athlete’s foot. Prescription-only antifungal creams produce slightly higher cure rates than all other creams. The available evidence indicates that the most cost-effective management strategy for athlete’s foot is an over-the-counter cream twice daily for 4 weeks, with prescription only cream reserved for treatment failures. 14 439 Athlete’s foot Are oral drugs more effective than topical compounds in the treatment of athlete’s foot? There appears to be no therapeutic advantage in using an allylamine cream (terbinafine or naftifine) for 1 week rather than an azole cream for 4 weeks. The hypothesis that higher compliance rates are likely to be associated with shorter treatment times is often quoted but has not been tested. 15 If no advantage is gained from treating interdigital athlete’s foot with oral antifungals, physicians should be cautious in prescribing oral drugs to manage moccasin type (infection over the sole of the foot). The belief that recalcitrant cases of athlete’s foot are more effectively managed with oral drugs has not been extensively tested. Key points • Athlete’s foot is common and can be hard to cure. • Long-standing case of athlete’s foot should be confirmed using microscopy and culture laboratory tests. • All fungal creams are effective in treating athlete’s foot. There is evidence that different antifungal creams are associated with different cure rates; creams containing allylamines are the most effective in producting a cure followed by the azoles and undecenoic acid and tolnaftate. • There is some evidence to suggest that oral drugs (tablets) are no more effective than creams in producing a cure for athlete’s foot. References 1. Springett K, Merriman L. Assessment of the skin and its appendages. In: Merriman L, Tollafield D, eds. Assessment of the Lower Limb. Edinburgh: Churchill Livingstone, 1995. 2. Gupta AK, Saunder DN, Shear NH. Efficacy of antifungal agent Terbinafine in the treatment of superficial dermatophyte infections – an overview. Today Ther Trends 1995; 13 :9–20. 3. Gentles JC, Evans EGV. Foot infections in swimming baths. BMJ 1973; 3 :260–2. 4. Bell-Syer SEM, Hart R, Crawford F et al . A systematic review of oral treatments for fungal infections of the skin of the feet. J Dermatol 2001; 12 :69–74. 5. Smith EB, Graham JL, Ulrich JA. Topical clotrimazole in tinea pedis. South Med J 1977; 70 :47–8. 6. Evans EGV, James IGV, Joshipura RC. Two week treatment of tinea pedis with terbinafine a placebo controlled study. J Dermatol Treat 1991; 2 :95–7. 7. Crawford F, Bell Syer S, Hart R, Torgerson D, Young P, Russell I. Topical treatments for fungal infections of skin and nails of the foot. In: Cochrane Collaboration. Cochrane Library, Issue 1. Oxford: Update Software, 2002. 8. Martindales. The Complete Drug Reference, 32nd ed. London: Pharmaceutical Press, 1999. 9. Evans EGV, Dodman B, Williamson DM. Comparison of terbinafine and clotrimazole in treating tinea pedis. BMJ 1993; 307 :645–7. 10. Patel A, Brookman SD, Bullen MU et al. Topical treatment of interdigital tinea pedis: terbinafine compared with clotrimazole. Australas J Dermatol 1999; 40 :197–200. 11. Leenutaphong V, Tangwiwat S, Muanprasat C, Niumpradit N, Spitaveesuawan R. Double-blind study of the efficacy of one week topical terbinafine cream compared to 4 weeks miconazole cream in patients with Tinea pedis. J Med Assoc Thailand 1999; 82 :1006–9. 12. Schopof R, Hettler O, Brautigam M et al. Efficacy and tolerability of 1% topical solution used for 1 week compared with 4 weeks clotrimazole 1% topical solution in the treatment of interdigital tinea pedis: a randomised controlled clinical trial. Mycoses 1999; 42 :415–20. 13. Barnetson R St, Marley J, Bullen M et al . Comparison of one week of oral terbinafine (250 mg/per day) with four weeks of treatment with clotrimazole 1% cream in interdigital tinea pedis. Br J Dermatol 1998; 139 :675–8. 14. Hart R, Bell-Syer S, Crawford F, Torgerson D, Young P, Russell I. Systematic review of topical treatments for fungal infections of the skin and nails of the feet. BMJ 1999; 319 :79–82. 15. Williams H. Pragmatic clinical trial is now needed. [Letters] BMJ 1999; 319 :1070. 440 Evidence-based Dermatology Background Definition Onychomycosis is a fungal infection of the nail, caused predominantly by anthropophilic dermatophytes, less commonly by yeast ( Candida spp.), and by non-dermatophyte mould infections. 1–3 Onychomycosis may present with hyperkeratosis, subungual debris, thickening or discoloration of the nail plate. Total nail dystrophy may also result with advanced onychomycosis. 3 Incidence/prevalence Onychomycosis is the most common nail disorder in adults. It accounts for approximately 50% of all nail diseases 4,5 and the incidence has increased over the past 80 years. 3 In North American centres, the prevalence of onychomycosis is between approximately 6⋅5% and 13⋅8%. 4,6–8 Onychomycosis affects predominantly toenails rather than fingernails; in some reports the ratio of toenail:fingernail onychomycosis ranges from 4:1 to 19:1. 4,7,9,10 Aetiology/risk factors Predisposing factors for onychomycosis include tinea pedis, positive family history, increasing age, male sex, trauma, immunosuppression, diabetes mellitus, poor peripheral circulation and smoking. 3,4,6,7,11–17 In addition, for fingernails persistent exposure to water, the use of artificial nails and trauma induced by pushing back the cuticles and aggressive manicuring may also be predisposing factors. Prognosis Onychomycosis may be effectively treated with systemic and/or topical antifungal agents. Traditional systemic agents used to treat onychomycosis include griseofulvin and ketoconazole. The newer oral agents used to treat onychomycosis are terbinafine, itraconazole and fluconazole. 18–25 Recent available data suggests that ravuconazole, a triazole, is effective for this indication. 26 Topical treatments include ciclopirox and amorolfine nail lacquers. 27,28 Only ciclopirox 8% nail lacquer has been approved in the US for the treatment of onychomycosis. 29 Relapse of onychomycosis, especially of toenails, is not uncommon, particularly in predisposed individuals. Fingernail onychomycosis may respond better to treatment than toenail disease because perfusion of the upper extremity is generally better than of the lower extremity, which may result in improved drug delivery to the fingers compared with the toes. Also, fingernails have a faster rate of outgrowth compared with toenails (3 mm/month compared with 1 mm/month), 30 resulting in the infected fingernail growing out faster than its lower extremity counterpart. Aims of treatment Onychomycosis may be a cosmetic problem, especially when fingernails are infected. 31 The treatment objectives are to reduce the fungal burden within the nail, ultimately curing the fungal infection, and to promote healthy regrowth of 33 Onychomycosis Aditya K Gupta, Jennifer Ryder and Robyn Bluhm 441 affected nails. In instances where onychomycosis is associated with a degree of morbidity, for example, pain, discomfort and soft tissue infection, timely treatment may help to eliminate symptoms and prevent complications that could be associated with more severe consequences. 32 Relevant outcomes The most commonly reported therapeutic measure of efficacy is mycological cure, which is defined, by most, as negative light microscopic examination and negative culture. Clinical improvement has been reported in several ways. Some studies have used the parameter of clinical success, which is defined as cleared or markedly improved (90–100% clear nail). 33 Others have defined clinical success as cure or improvement sufficient to reduce the involved area of the target nail to less than 25% at the end of therapy. 34 Another term used is clinical effectiveness, which is taken to be mycological cure and at least 5 mm of new clear toenail growth. 35 Clinical cure refers to the nail after therapy appearing completely cured to the naked eye. Complete cure rate is the combined results of mycological and clinical cure. Search methods To identify studies where oral treatments – itraconazole (continuous and pulse), fluconazole, terbinafine (continuous and pulse) and griseofulvin – were used to treat adults with toenail or fingernail onychomycosis caused by dermatophytes, we searched Medline (1966–2002) for randomised controlled trials (RCTs). The reference sections of the published reports were also examined for potential studies not listed in the database. Some of the studies were completely 26,27,36–135 or partially 33,34,136–145 excluded for the following reasons. Open trials, studies conducted in a special population (for example diabetics, patients with Down’s syndrome, transplant recipients) and reports where we were unable to extract the relevant data, double publications, non-English language studies, and retrospective studies were excluded. The use of nail lacquers such as ciclopirox and amorolfine to treat onychomycosis is not considered. There are many anecdotal reports of various topical agents being effective for the management of onychomycosis; however, published reports of the efficacy of topical agents in onychomycosis in the indexed, peer- reviewed literature are far fewer. Other clinical trials have included tioconazole 28% solution, bifonazole with urea, fungoid tincture, miconazole, and tea tree oil. Also excluded were studies that used non- standard treatment dosage or duration for toenails (for example terbinafine therapy for less than 3 months or more than 4 months; continuous itraconazole therapy for less than 3 months or more than 4 months and less than 200 mg/day; itraconazole pulse therapy for fewer than three pulses or more than four pulses; fluconazole dosage other than 150 mg/week; griseofulvin therapy for less than 3 months), fingernails (terbinafine therapy for more than 6 weeks, continuous itraconazole therapy for more than 6 weeks, pulse itraconazole for more than two pulses, fluconazole dosage other than 150 mg/week), or other non-standard regimens, such as sequential or combination therapy. We have not considered trials where ketoconazole was used to treat onychomycosis, given the potential of this agent to cause hepatotoxicity and the availability of alternative agents. The use of ravuconazole for the management of onychomycosis has not been considered further 442 Evidence-based Dermatology because information currently available in a published format is restricted to abstracts. 26 This chapter discusses the distal and lateral presentation of onychomycosis, which is the most common type; treatment of the other types of onychomycosis is not considered. 3,146 Onychomycosis caused by Candida spp. and non-dermatophyte moulds is less common and is not considered in this chapter. Evidence was graded using the quality of evidence scale system employed by Cox and colleagues 147 (Box 33.1). QUESTIONS What is the role of oral antifungal therapy in the management of dermatophyte onychomycosis in adults? Griseofulvin was the first significant oral antifungal agent available for the management of dermato- mycoses. Although its use in the treatment of onychomycosis has decreased over the years, it is still widely used for the treatment of tinea capitis. 148 Ketoconazole, an oral imidazole, is no longer recommended for the treatment of onycho- mycosis, which requires a long duration of therapy, because of the potential for hepatotoxicity. 148 The introduction of the new oral antifungal agents, terbinafine, itraconazole and fluconazole has led to improved efficacy, decreased treatment duration and fewer adverse events. What are the effects of systemic treatments on fingernail and toenail onychomycosis? Griseofulvin The regimen for treating onychomycosis is continuous therapy using 500–1000 mg/day, typically administered for 6–12 months for fingernail onychomycosis and for 9–18 months for toenail disease. Fingernail onychomycosis Quality of evidence – I 443 Onychomycosis Box 33.1 The quality of evidence scale system employed by Cox and colleagues 147 I Evidence obtained from at least one properly designed randomised control trial II-i Evidence obtained from well-designed controlled trials without randomisation II-ii Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one centre or research group II-iii Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments could also be included III Options of respected authorities based on clinical experience, descriptive studies or reports of expert committees IV Evidence inadequate owing to problems of methodology (for example sample size, length of comprehensiveness of follow up or conflicts in evidence) Figure 33.1 This patient is a 47-year-old non-diabetic male exhibiting an infection of the left great toenail with no other health problems. He gave a history of approximately 15-year duration of nail abnormality that may be related to previous nail trauma. The thickened nail had large areas of yellowish–white discoloration typical of fungal nail infection. Culture revealed infection with the dermatophyte fungus, Trichophyton rubrum . One double-blind RCT compared griseofulvin, 500 mg/day for 12 weeks, with terbinafine in the treatment of onychomycosis (Table 33.1). 141 The mycological cure rate and complete cure rate were 63% and 39%, respectively. Toenail onychomycosis Quality of evidence – I Three double-blind RCTs 140,144,149 and one open RCT 142 compared griseofulvin with continuous terbinafine or itraconazole in the treatment of onychomycosis (Table 33.2). Effectiveness In the RCTs, griseofulvin, 500 mg/day or 1 g/day, was administered to treat onychomycosis. In the double-blind RCTs the mycological cure rate ranged from 46% to 69% and complete cure occurred in 2–56% of patients. In the open RCT, 6% of patients were completely cured. Drawbacks The use of griseofulvin may be associated with adverse events such as gastrointestinal upset, nausea, diarrhoea, headache, central nervous system symptoms and urticaria. 150 Few drug interactions are associated with griseofulvin therapy and no drugs are contraindicated. Comment Griseofulvin was the first systemic agent used to treat onychomycosis on a widespread basis. The newer oral agents (itraconazole, terbinafine and fluconazole) have been found to be more effective than griseofulvin and the duration of active therapy is also shorter with the more recently introduced antimycotics. 151,152 Moreover, when griseofulvin is used to treat dermatophyte toenail onychomycosis, relapse rates may be higher (40–60%) 129 than with the newer oral antifungal agents. 33,153–156 Continuous terbinafine The regimen for fingernail and toenail onychomycosis is 250 mg/day, administered for 6 and 12 weeks, respectively. Fingernail onychomycosis Quality of evidence – I Two double-blind RCTs evaluated subjects with fingernail onychomycosis only (see Table 33.1). One study administered terbinafine for 12 weeks and therefore was not included in this analysis. 141 Effectiveness The double-blind randomised placebo- controlled study used terbinafine, 250 mg/day for 6 weeks, to treat fingernail onychomycosis (Table 33.1). 156 Mycological cure was achieved in 79% of patients and complete cure in 59%. Toenail onychomycosis Quality of evidence – I The majority of studies were double-blind RCTs (Table 33.3). Terbinafine was administered at a dose of 250 mg/day for 3–4 months. Effectiveness Six double-blind RCTs compared terbinafine with placebo. 33,145,156–159 Each study reported terbinafine, 250 mg/day, to be significantly more effective than placebo in treating onychomycosis. Ten double-blind RCTs compared continuous terbinafine with other drugs. 35,149,160–167 Mycological cure rates ranged from 67% to 95% and the corresponding clinical response rates from 66% to 97% with a follow up of no more than 72 weeks. Four open RCTs reported the efficacy of continuous terbinafine for 3 or 4 months. 168–171 444 Evidence-based Dermatology Table 33.1 Treatment of dermatophyte fingernail onychomycosis Year Authors Treatment Study type No. of Regimen Treatment Follow up Efficacy measure (%) evaluable patients duration (post-treatment) MC CR CC Mycological cure (MC) is defined as negative microscopy and culture unless indicated otherwise; clinical response (CR) is defin ed as cured or markedly improved unless indicated otherwise; Complete cure (CC) is defined as mycological and clinical cure or improvement unless indicated otherwise; *not defin ed ‡ CC defined as clinical cure and negative mycological culture; ‡‡‡ CC defined as MC and continuous growth of unaffected nail; ^CR variable definitions; ⊥⊥, MC defined as negative microscopy 2001 2001 1997 1998 1995 Itraconazole package insert (US) 155 Terbinafine package insert (US) 156 Odom et al . 179 Drake et al . 137 Haneke 141 Continuous itraconazole Continuous terbinafine Pulse itraconazole Fluconazole Griseofulvin Double-blind, randomised, placebo-controlled Double-blind, randomised, placebo-controlled Double-blind, randomised, multicentre, placebo- controlled Double-blind, randomised, parallel, multicentre, placebo-controlled Double-blind, randomised, comparative (continuous terbinafine) 37 Not stated 37 78 92 200 mg/day 250 mg/day 400 mg/day 1 wk/month 150 mg/wk 500 mg/day 2 months 6 wks 2 months Up to 9 months 12 wks, followed by 12 wks placebo 24 wks Up to19 wks 6 months 6 months (61) (79) 16/22 (73) 70/78 (90)* 45/72 (63) * * 17/22 (77) 69/78 (88) (47) (59) 15/22 (68) 61/78 (78)* (39) [...]... 16 wks 72 wks 48 months 72 wks 60 wks 48 wks Up to 5 years 67/ 102 (85)^ 39/46 * 13/16 (81) 18/21 (86) ( 67) (46) 49/1 07 54/98 80/99 (81) * (38) (35) 26 /74 * * (Continued) * * * (71 )^ ( 87) (55) 67/ 95 (66)^ 81/1 07 (76 ) 41/46 (89) (70 ) 34 /74 (46) 7/ 18 (94) * (50)* 18/18 (100) Negative culture: Negative microscopy: * 20/23 ( 87) 9/18 (48)* 16 wks Negative culture: 18 comparative (pulse itraconazole) 72 wks... randomised, duration- Treatment van der Schroeff143 Regimen 1992 No of Study type Authors (Continued) Year Table 33.3 * (68) 17/ 25 * * * 27/ 34 (76 ) 13/ 17 * (79 ) 19/24 (63) 10/16 * (79 ) (71 ) * 24/34 (40) 12/30 CC * * CR Evidence- based Dermatology Mycological cure ranged between 75 % and 94% In one study, clinical response was reported to be 68%. 171 Complete cure ranged from 63% to 79 % 3 weeks with no... 19 97; 36:231–5 19 97; 59:2 17 20 4 67 Evidence- based Dermatology 192 Jones HE, Zaias N Double-blind, randomized 1 97 Marchetti A, Piech CT, McGhan WF et al comparison of itraconazole capsules and placebo Pharmacoeconomic analysis of oral therapies for in onychomycosis of toenail Int J Dermatol 1996;35: onychomycosis: a US model Clin Ther 1996;18 :75 7 77 589–90 198 Arikian SR, Einarson TR, Kobelt-Nguyen G, Schubert 193... (from 59 /70 (84) ⊥⊥ 41/62 (66) 59/109 (54) 77 /168 (46) 354/ 479 (74 ) (61) (54) MC 58 /70 (83)^ 43/62 (69) 71 /109 (65) (58) * 395/ 479 (82) (82) * CR Efficacy measure (%) (Continued) (76 ) 53 /70 * (23)* * * (14) CC Odom et al.193 Shemer et al.183 1996 1999 Minimum of 16 38 35 84 evaluable patients No of itraconazole) group patients in each Open, randomised, comparative (pulse controlled Double-blind, randomised,... Regimen 4 months 3 months 12 wks 12 wks 12 wks duration Treatment 48 wks 48 wks 52 wks baseline) period (from Follow up * * 18/38 ( 47) * 24/35 (69)* 53/84 (63) MC * * 26/38 (68) 27/ 35 (77 )* 63/84 (75 )* CR Efficacy measure (%) CC (65) (68) 14/38 ( 37) 18/35 (51)* * Evidence- based Dermatology score or conversion of KOH (potassium hydroxide) or culture from negative to positive).155 Fluconazole Fluconazole is... placebo-controlled Double-blind, randomised parallel, terbinafine) 43 Double-blind, double-placebo, randomised Havu et al.162 2000 No of 16 73 evaluable patients Study type Authors Treatment of dermatophyte toenail onychomycosis using fluconazole therapy Year Table 33 .7 150 mg/wk 150 mg/wk 150 mg/wk Regimen Treatment Follow up (77 ) (53) 3 months 6 months improved) clinically cured or (31) * 56 /73 38 /72 ... griseofulvin onychomycosis Open and double-blind studies Acta LAGOS III Study Group J Am Acad Dermatol Derm Venereol 1990 ;70 :1 37 40 1995;32 :72 7 131 Warshaw EM, Carver SM, Zielke GR, Ahmed DD 142 Korting HC, Schafer-Korting M, Zienicke H et al Intermittent terbinafine for toenail onychomycosis: is it Treatment of tinea unguium with medium and high doses 465 Evidence- based Dermatology of ultramicrosize griseofulvin... 1998;139:5 67 71 follow-up Acta Derm Venereol 19 97; 77: 66–9 159 Watson A, Marley J, Ellis D, Williams T Terbinafine in onychomycosis of the toenail: a novel treatment protocol J Am Acad Dermatol 1995;33 :77 5–9 160 Heikkila H, Stubb S Long-term results in patients with onychomycosis treated with terbinafine or itraconazole Br J Dermatol 2002;146:250–3 161 Sigurgeirsson B, Olafsson JH, Steinsson JB et al Long-term... 19 97; 37: 969 74 179 Odom RB, Aly R, Scher RK et al A multicenter, placebo- 191 Elewski BE, Scher RK, Aly R et al Double-blind, controlled, double-blind study of intermittent therapy randomized comparison of itraconazole capsules v with itraconazole for the treatment of onychomycosis of placebo in the treatment of toenail onychomycosis Cutis the fingernail J Am Acad Dermatol 19 97; 36:231–5 19 97; 59:2 17 20... Double-blind, double dummy, placebo-controlled Double-blind, randomised, (continuous terbinafine) randomised, comparative Double-blind, double dummy, 18 59 109 1 07 78 77 1 wk/month 400 mg/day 1 wk/month 400 mg/day 1 wk/month 400 mg/day 1 wk/month 400 mg/day 1 wk/month 400 mg/day 3 months 3 months 16 wks 12 wks 3 months 12 or 16 wks 6 months 12 months 72 wks 48 wks 11/18 (61) 41/59 (69) 53/108 (49) 41/107 . wks placebo 24 wks Up to19 wks 6 months 6 months (61) (79 ) 16/22 (73 ) 70 /78 (90)* 45 /72 (63) * * 17/ 22 (77 ) 69 /78 (88) ( 47) (59) 15/22 (68) 61 /78 (78 )* (39) Table 33.2 Treatment of dermatophyte toenail. months 12/29 (41) 24/34 (71 ) 28/34 (82) 37/ 45 (82) 12/16 (75 ) * (76 ) 16/ 17 (94) * * * * * * 17/ 25 (68) * 12/30 (40) 24/34 (71 ) 27/ 34 (79 ) * 10/16 (63) 19/24 (79 ) * 13/ 17 (76 ) See Table 33.1 for. (94) 34 /74 (46) (70 ) 41/46 (89) 81/1 07 (76 ) 80/99 (81) ( 67) 18/21 (86) 13/16 (81) * * * * 39/46 (85)^ 67/ 102 (66)^ 67/ 95 (71 )^ ( 87) * * 11/23 (48)* 9/18 (50)* 26 /74 (35) (38) * 49/1 07 (46) 54/98 (55) * * * Table