THERAPY IN PRACTICE

Am J Clin Dermatol 2009; 10 (4): 211-220 1175-0561/09/0004-0211/$49.95/0

2009 Adis Data Information BV. All rights reserved.

Toenail Onychomycosis in Diabetic Patients

Issues and Management
Peter Mayser, Viviane Freund and Debby Budihardja
Center of Dermatology and Andrology, Justus Liebig University, Giessen, Germany

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 1. Complications of Diabetes Mellitus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 2. Onychomycosis as a Risk Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 3. Epidemiology of Onychomycosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 3.1 Prevalence of Onychomycosis among Diabetic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 3.2 Etiology of Onychomycosis among Diabetic Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214 4. Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 4.1 Topical Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 4.1.1 Amorolfine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 4.1.2 Ciclopirox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 4.2 Experimental Therapeutic Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 4.3 Systemic/Oral Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 4.3.1 Fluconazole. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 4.3.2 Itraconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 4.3.3 Terbinafine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 4.4 Combination Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 4.5 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 5. General Management Principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218

Abstract

Diabetes mellitus may be associated with serious sequelae, such as renal disease, retinopathy, and diabetic foot. A recent large prospective study has shown that onychomycosis is among the most significant predictors of foot ulcer. As the severity of onychomycosis may be associated with the length of time the individual has had the infection, early intervention is advisable owing to the progressive nature of the fungal infection. If left untreated, toenails can become thick, causing pressure and irritation, and thus act as a trigger for more severe complications. In the treatment of onychomycosis, compliance and drug interactions are important considerations, as diabetic patients frequently take concomitant medications. Terbinafine and itraconazole have been investigated for the treatment of onychomycosis in diabetic patients and have been shown to have efficacy and safety profiles comparable to those in the nondiabetic population. Data from clinical trials and postmarketing surveillance suggest that drug interactions resulting in hypoglycemia may not be an important issue when itraconazole and terbinafine are used to treat diabetic patients receiving concomitant hypoglycemic medications. Patient advice and education in improved foot care are an integral part of onychomycosis management, and help achieve long-term cure and reduce the complications of diabetic foot.

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Diabetes mellitus has reached epidemic proportions in many developing and newly industrialized nations. In 2000, the worldwide prevalence was already 171 million and this increased to 175 million in 2002.[1] By the year 2010, the total number of diabetic individuals is expected to double worldwide, providing an overall estimate of 240 million (24 million type 1 and 216 million type 2).[1,2] The prevalence of type 2 diabetes in Europe by 2010 is estimated to increase to 24.4 million (4.5 million in northern Europe, 8.7 million in western Europe, 6.8 million in southern Europe, and 4.4 million in eastern Europe).[2] To obtain the relevant articles for this review, we conducted a literature search in October 2008 using the MEDLINE database and the search terms onychomycosis, diabetes mellitus, therapy, review, complications, terbinafine, fluconazole, itraconazole, ciclopirox, and amorolfine. 1. Complications of Diabetes Mellitus Diabetic patients may present with complications involving all systems of the body, such as neuropathy and impaired circulation, renal and cardiovascular disease, and retinopathy. Several skin manifestations in insulin-dependent patients seem to be related to the development of diabetic microvascular complications and the duration of diabetes. The diabetic foot is highly complex and represents one of the most serious complications of diabetes.[3] Diabetes is the most frequent reason for non-traumatic lower extremity amputations in the US and the amputation is usually preceded by a diabetic foot ulcer. The combination of ischemia, sensory neuropathy, and direct adverse effects on host defense mechanisms renders these patients especially vulnerable to foot infections.[1] 2. Onychomycosis as a Risk Factor Fungal nail infections can also contribute to the severity of the diabetic foot.[4] While mild onychomycosis of the toenails may be of minor risk to diabetic patients, more severe, neglected onychomycosis can be a greater problem.[1] Severe onychomycosis is particularly problematic in the presence of polyneuropathy, as pressure erosions of the nail bed and hyponychium may be noted late because of impaired sensation, which increases the risk of subsequent bacterial infections involving bone. In a retrospective study conducted in the US, the percentage of patients with secondary infection was higher among diabetic patients with onychomycosis (16%) than among diabetic patients without onychomycosis (6%). Diabetic patients with onychomycosis had a 3-fold higher risk of gang 2009 Adis Data Information BV. All rights reserved.

rene and/or foot ulcer (12.2%) compared with diabetic patients without onychomycosis (3.8%).[5] In a prospective study, Boyko et al.[6] investigated the ability of commonly available clinical information to predict diabetic foot ulcer. The assessments were age, race, weight, current smoking, diabetes duration and treatment, glycosylated hemoglobin (HbA1c), visual acuity, history of laser photocoagulation treatment, foot ulcer and amputation, foot shape, claudication, foot insensitivity to the 10 g monofilament, foot callus, pedal edema, hallux limitus, tinea pedis, and onychomycosis. 1285 diabetic veterans without foot ulcer were followed with annual clinical evaluations and quarterly mailed questionnaires. Mean follow-up was 3.38 years, during which time 216 foot ulcers occurred. Among the most significant predictors (p 0.05) of foot ulcer, onychomycosis was ranked fourth place (hazard ratio 1.58; 95% CI 1.16, 2.16) after prior amputation (2.57; 1.60, 4.12), prior foot ulcer (2.18; 1.61, 2.95), and monofilament insensitivity (2.03; 1.50, 2.76). 3. Epidemiology of Onychomycosis In the general population onychomycosis is a relatively common disease, accounting for up to 50% of all nail disorders.[7-10] Several studies have shown a prevalence of 213% in the general population.[11] In certain populations, such as elderly people, the prevalence is much higher, reaching up to 40% by the age of 60 years[2] and up to 50% by the age of 70 years.[11] Results from other epidemiological surveys suggest that the overall incidence is 30-fold higher in adults than in children.[12] The probable reasons are slower nail growth in elderly people and common peripheral vascular diseases.[9] However, a recent study reported that onychomycosis is no longer a rare finding in children because of sports activities and a high prevalence of onychomycosis among family members.[13] Another risk factor for onychomycosis is immunosuppression, for example in HIV-positive, AIDS, and transplant patients. In a controlled study, more than 30% of patients infected with HIV were found to have onychomycosis compared with 12.6% of healthy controls.[11] Moreover, predisposing factors for toenail onychomycosis include the presence of tinea pedis, positive family history of onychomycosis, trauma to the nail, diabetes, poor peripheral (arterial) circulation, smoking, and possibly psoriasis, as well as sports activities and attendance at public bathing facilities.[9,10,12] Onychomycosis is often associated with tinea pedis; however, in diabetic patients even widespread tinea pedis is often mistakenly considered to be diabetes-associated dry skin.[14] Another point demonstrated by Szepietowski et al.[15]
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in their study of 2761 patients was that coexistence of toenail onychomycosis with other types of fungal skin infections is a frequent phenomenon. Concomitant fungal skin infections were noted in 1181 patients (42.8%) with toenail onychomycosis. It was hypothesized that infected toenails may be a site from which fungal infections could spread to other body areas.
3.1 Prevalence of Onychomycosis among Diabetic Patients

Table I gives an overview of studies comparing the prevalence of onychomycosis in diabetic patients with healthy controls.[16-21] Buxton et al.[18] showed no significant differences in skin and nail infection rates in diabetic patients (17% and 12%, respectively) compared with matched non-diabetic controls (8% and 11%, respectively). In their study of 171 diabetic patients and 276 healthy controls with suspicious lesions, Romano et al.[19] found that non-diabetic individuals had a higher prevalence of onychomycosis than diabetic patients (1.8% vs 1.2%). They observed no correlation between dermatophyte infection and the duration or type of diabetes, or blood sugar levels or levels of HbA1c. This is in contrast to studies by Pierard and Pierard-Franchimont[21] and Dogra et al.[20] In the latter, the prevalence of onychomycosis in diabetic patients was significantly higher than in controls (17% vs 6.8%).[20] Thus, diabetic patients were found to be 2.5-fold more likely to have onychomycosis. In this study, significant predictors for onycho-

mycosis included the duration of diabetes (p < 0.01), absent or feeble peripheral pulses (p < 0.15), peripheral neuropathy (p < 0.05), and retinopathy (p < 0.001). Combining histomy cology and cultures, Pierard and Pierard-Franchimont[21] found the highest prevalence of onychomycosis among all of the studies. All sampled nails showed clinical alterations reminiscent of onychomycosis; 65.3% of the diabetic patients (190 type 2 diabetic patients, 136 men and 54 women) had onychomycosis compared with 48.4% of matched controls. Irrespective of gender, the ratio between onychomycosis and noninfectious onychodystrophies reached 1.88 (122 : 66) in diabetic patients, which was twice the value of 0.94 (92 : 98) found in nondiabetic controls. The proportion in men was higher than in women, both in the diabetic and nondiabetic groups. Table II gives an overview of noncomparative studies investigating the prevalence of onychomycosis among only diabetic patients.[14,22-25] In a large study, Gupta et al.[22] evaluated a total of 550 diabetic patients (283 male, 267 female) aged 56.1 0.7 years (mean standard error of the mean [SEM]). Abnormal-appearing nails and mycologic evidence of onychomycosis (mostly due to dermatophytes) were present in 253 (46%) and 144 (26%) patients, respectively. After controlling for age and sex, the risk odds ratio for diabetic patients to have toenail onychomycosis was 2.77 compared with data for healthy individuals obtained from published literature (95% CI 2.15, 3.57). Toenail onychomycosis was present in 26% of the

Table I. Prevalence of onychomycosis in comparative studies of diabetic patients (pts) vs healthy controls Reference No. of pts diabetic Alteras and Saryt
[16]a

Prevalence of onychomycosis (%) control 100 100 100 276 diabetic 73 7 12 1.2 control 66 12 11 1.8

Etiologic agent diabetic 69% dermatophytes 31% Candida albicans C. albicans in four pts 100% dermatophytes 100% Trichophyton mentagrophytes 48.1% yeasts (C. albicans predominant) 37% dermatophytes (T. rubrum predominant) 14.8% molds 62.7% dermatophytes 12.7% yeasts 16.6% molds control 95% dermatophytes 5% C. albicans C. albicans in seven pts Predominantly dermatophytes 40% T. mentagrophytes 40% T. rubrum 20% Epidermophyton floccosum 62.5% dermatophytes 25% yeasts 12.% molds

100 100 100 171

Lugo-Somolinos and Sanchez[17] Buxton et al.[18] Romano et al.[19]

Dogra et al.[20]

400

400

17b

6.8

Pierard and PierardFranchimont[21]

190

190

65.3

48.4

64.5% dermatophytes 13.2% yeasts 14.4% molds

a No differentiation between onychomycosis and tinea pedis. b Significantly higher prevalence of onychomycosis in diabetic pts (p < 0.001).
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Table II. Noncomparative studies of the prevalence of onychomycosis in patients with diabetes mellitus Reference Gupta et al.[22] No. of patients (male/female) 550 (283/267) Diabetes type 34% type 1 66% type 2 Prevalence of onychomycosis 46% abnormal-appearing nails 26% onychomycosis Etiologic agents 88% dermatophytes (Trichophyton rubrum predominant) 3% yeasts 9% molds 70% dermatophytes 30% yeasts 93.2% dermatophytes 6.8% Candida spp. 48.6% dermatophytes (37.1% T. rubrum) 31% yeasts 10.4% non-dermatophytic molds 10% mixed infections Confirmation by positive potassium hydroxide only

Mayser et al.[14] Saunte et al.[23] Manzano-Gayosso et al.[24]

95 (52/43) 271 (194/77) 250

100% type 1 26% type 1 74% type 2 100% type 2

58% (n = 56) 22% mycologically confirmed onychomycosis 37.2% ungual dystrophy 28% onychomycosis (n = 70; 34 male, 36 female) 30.76% (n = 383; 206 male, 177 female)

Chang et al.[25]

1245 (610/635)

100% type 2

samples and was projected to affect approximately one-third of individuals with diabetes. It was significantly correlated with age (p < 0.0001) and male sex (p < 0.0001). The severity of onychomycosis was significantly associated with the length of time the individual had diabetes (p = 0.043). From their data the authors postulated that onychomycosis may be the most common disease of nails in diabetic patients and often exists with interdigital or plantar tinea pedis.[22] In 95 individuals with long-term type 1 diabetes (52 men, 43 women, mean disease duration 35.8 years), Mayser et al.[14] found skin mycoses in 9 patients, onychomycosis in 29 patients, and simultaneous infection of nails and skin in 28 patients. A significant correlation was observed between infection and sex (men more frequently affected) and the age of the patients. In addition to a 22% prevalence of onychomycosis in diabetic patients, Saunte et al.[23] reported a significant correlation between a higher prevalence of onychomycosis and increasing age (p = 0.02) and also severity of nail changes (p < 0.001). However, they found no significant correlation with sex, type of diabetes, lower extremity arterial disease, neuropathy, toe amputations, or edema. Interestingly, 15% of clinically normal toenails were mycologically positive, whereas this was only the case in 1.5% of the patients with normal toenails in the study by Gupta et al.[22] Saunte et al.[23] hypothesized that this colonization may be a risk factor for further infection. Two studies in 2008 also showed an increased prevalence of onychomycosis in diabetic patients. Manzano-Gayosso et al.[24] investigated 250 type 2 diabetes patients throughout a year. Ninety-three patients (37.2%) showed ungual dystrophy and, among these, a fungal etiology was corroborated in 75.3%.
2009 Adis Data Information BV. All rights reserved.

Furthermore, a significant correlation between type 2 diabetes evolution time and onychomycosis was found (p < 0.01), and distal-lateral subungual and total dystrophic onychomycosis were the most frequent clinical types.[24] Investigating 1245 Taiwanese diabetic patients, Chang et al.[25] found that 30.7% of them had onychomycosis (diagnosed by potassium hydroxide only). A significantly higher prevalence in men than in women was observed (p = 0.024). Furthermore, metabolic syndrome, obesity, triglyceride levels, and HbA1c were significantly associated with onychomycosis (p < 0.05).

3.2 Etiology of Onychomycosis among Diabetic Patients

Dermatophytes, yeasts, and non-dermatophytic molds can be responsible for onychomycosis. Toenails are 4- to 10-fold more frequently affected than fingernails, probably because of the slower growth and increased exposure to injury and infecting organisms.[9] Dermatophytes account for 90% of toenail infections,[26] while fingernail onychomycosis is more likely to be caused by yeasts, in up to one-third of cases, most commonly Candida albicans. As in the nondiabetic population, dermatophytes are the major pathogens of toenail onychomycosis in diabetic patients, with Trichophyton rubrum being the most prevalent species (table I, table II). In contrast, Dogra et al.[20] found that yeasts were the most common isolates causing onychomycosis in diabetic patients in India (48.1% of patients), followed by dermatophytes (37%), and molds (14.8%). This result may suggest that
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non-dermatophyte fungal pathogens are more prevalent in nail infections in hot and humid tropical and subtropical parts of the world.[20] Well in line with that finding are the results of Pierard and Pierard-Franchimont,[21] which showed that in Europe the prevalence of yeast onychomycosis was similar in diabetic patients (12.7%) and nondiabetic individuals (13.2%). Although molds (Scopulariopsis, Scytalidium) have been implicated in primary nail infections, there is evidence suggesting that these secondarily colonize nails already infected by dermatophytes.[27] However, the role of yeasts and nondermatophyte molds in causing onychomycosis is becoming increasingly appreciated. Especially in severe diabetic disease with macrovascular complications, uncommon pathogens have to be suspected.[28] In conclusion, although in initial studies it was not clear whether the prevalence of onychomycosis was higher among diabetic patients than in the nondiabetic population, recent large epidemiologic studies indicate an increased prevalence. Approximately one-third of patients with diabetes have toenail onychomycosis, the risk of infection being 1.9- to 2.8-fold higher than in the healthy population. Diabetic men experience onychomycosis more frequently than diabetic women. Furthermore, the presence of onychomycosis was found to be significantly correlated with increasing age, and the severity was significantly associated with the length of time the individual had diabetes. 4. Therapy The treatment of onychomycosis is similar in diabetic and nondiabetic patients and includes mechanical/chemical measures, topical medications, and oral antifungal therapies.[29] As the severity of onychomycosis may be associated with the length of time the individual has had the infection, early intervention is advisable owing to the progressive nature of the fungal infection. Without treatment, toenails can become thick, causing pressure and irritation and act as a trigger for more severe complications. Compliance and drug interactions are important considerations, as diabetic patients are frequently taking concomitant medications.
4.1 Topical Medications

combination therapy over systemic therapy alone.[31] One of the advantages of topical therapies is the avoidance of systemic adverse effects. However, older diabetic patients may be obese or have retinopathy and therefore may have difficulty in correctly using these agents. In addition, topical antifungals are indicated for the reduction of relapses and reinfection once the initial infection has been fully treated.
4.1.1 Amorolfine

Amorolfine has antifungal activity against dermatophytes, yeasts, and molds. It is not approved in the US for the treatment of onychomycosis. In clinical trials with the 5% nail lacquer applied weekly for 6 months, complete cure rates ranged from 38% to 54%.[26] Higher cure rates were found with twice-weekly treatment, although this difference was not statistically significant.
4.1.2 Ciclopirox

Topical therapies have limitations in reaching the site of infection and are only suitable for patients with early and mild cases of onychomycosis without lunula involvement.[30] In more severe infections they are recommended in combination with systemic antifungal therapy because of higher efficacy of
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Two studies have been published concerning the effect of ciclopirox 8% nail lacquer, which was approved by the US FDA in 1999 for the treatment of immunocompetent patients with mild to moderate onychomycosis of fingernails and toenails without lunula involvement, due to T. rubrum. Seebacher et al.[30] performed a multicenter, open-label study in 3666 patients with onychomycosis, who applied ciclopirox nail lacquer to affected toenails and fingernails once daily for 6 months. Efficacy parameters included the decrease from baseline of the affected area of the nail. Physicians rated the level of onychomycosis at 3 months and the efficacy of ciclopirox nail lacquer at 6 months. In an analysis of a subset of 215 patients (5.9%) with diabetes, ciclopirox nail lacquer reduced the mean affected nail area from 64.3% at baseline to 41.2% at 3 months and 25.7% at 6 months. At 3 months, physicians rated onychomycosis as improved in 88.7% of patients, unchanged in 9.8%, and worse in 1.5%. The efficacy of ciclopirox nail lacquer was judged to be good in 62.0% of patients, satisfactory in 23.9%, and unsatisfactory in 14.1%. Adverse events were mild to moderate, with no serious events reported. In an open-label, noncomparative study by Brenner et al.,[32] 49 diabetic patients with distal subungual onychomycosis were treated once daily for 48 weeks. Clinical improvement was attained in 63.4% of patients. Most patients (85.7%) had a mycologic outcome of improvement or cure, with 54.3% attaining mycologic cure. Consideration of mycologic and clinical outcomes generated a treatment outcome of improvement, success, or cure in 84.4% of patients. However, complete cure (mycologic and clinical cure) was achieved in only 4.4% of the patients. No treatment-related serious adverse events were observed.
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4.2 Experimental Therapeutic Approaches

Successful treatment of onychomycosis with photodynamic therapy (20% methyl-aminolevulinate followed by excimer laser; application of 20% urea ointment for 10 hours before each cycle) was recently reported.[33] Although effective, the therapy is very time consuming (67 cycles at weekly intervals) and not suitable for onychomycosis with matrix involvement.
4.3 Systemic/Oral Treatment

Since the development of new antifungal drugs in the 1990s, severe onychomycosis with matrix involvement is no longer considered incurable.[11] In several studies, itraconazole (pulse), terbinafine (continuous), and fluconazole (once weekly) regimens have shown a higher benefit-risk ratio with a shorter treatment duration than griseofulvin, thus resulting in greater compliance.[26] However, the majority of these studies involved patients with dermatophyte nail infection without risk factors such as diabetes. Diabetes is generally one of the exclusion criteria in clinical trials, which explains why there are few data available on diabetic populations.
4.3.1 Fluconazole

Fluconazole (150450 mg) is administered once weekly until there is complete outgrowth of the diseased nail plate. The duration of treatment may range between 9 and 15 months. Studies on the efficacy and safety of fluconazole in the diabetic population are not available in the literature. In nondiabetic patients, complete cure after 6 months of therapy and a further 6 months of follow-up reached 28% (150 mg), 29% (300 mg), and 36% (450 mg).[34] Fluconazole is not currently approved for the treatment of onychomycosis in the US. In the opinion of the authors, it is a very well tolerated therapy, especially if concomitant therapy or diseases are a problematic issue. Adverse events occur in about 5% of patients, with the majority occurring within the first month of therapy. Most are mild and include gastrointestinal disturbance (nausea, abdominal pain, diarrhea), headache, and insomnia. Fluconazole can also cause elevations in liver function tests.[26]
4.3.2 Itraconazole

Itraconazole is a highly lipophilic compound that rapidly penetrates the nail plate. It has a broader spectrum of antimycotic activity than terbinafine and should be considered in the management of infections caused by molds and/or Candida spp.[26] The pulsed dosage regimen with itraconazole
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(1 week on, 3 weeks off therapy given for three pulses) may be more effective than 12 weeks of continuous administration with the triazole.[26] The efficacy and safety of pulse itraconazole (200 mg twice daily, 1 week on, 3 weeks off, for 12 weeks) versus continuous terbinafine (250 mg once daily for 12 weeks) in diabetic patients was recently investigated in a prospective, randomized, multicenter study in the treatment of dermatophyte toenail distal and lateral subungual onychomycosis.[35] The fungal spectrum consisted of T. rubrum (80%), T. mentagrophytes (15.7%), and Epidermophyton floccosum (4.3%). Primary efficacy measures included mycologic cure rate (negative potassium hydroxide and culture) and effective cure (mycologic cure plus nail plate involvement of 10% or less) at week 48. At that point mycologic cure was attained by 88.2% (30 of 34) and 79.3% (23 of 29) of patients in the itraconazole and terbinafine groups, respectively (p-value not significant). Effective cure was achieved in 52.9% (18 of 34) of the itraconazole group and 51.7% (15 of 29) of the terbinafine group (not significant). Three itraconazole patients experienced adverse effects in the form of gastrointestinal problems. No serious adverse events and no interactions with concomitant medications were recorded. Itraconazole has a low incidence of adverse events, with the most common being minor gastrointestinal upset and headache. Reversible elevation of liver function tests is also seen.[26] Because of reports of the spontaneous development of congestive heart failure (CHF) in patients receiving itraconazole therapy, some of whom required hospitalization and died, the FDA has included CHF in the black-box warning for itraconazole. The warning states that itraconazole should not be administered for the treatment of onychomycosis in patients with evidence of left ventricular dysfunction or a history of CHF. It also recommends discontinuing itraconazole if signs or symptoms of CHF appear during treatment of onychomycosis. For indications other than onychomycosis, benefits of treatment should outweigh the risks. The black-box warning also includes the contraindication of co-administration of cisapride, pimozide, quinidine, dofetilide, or levacetylmethadol with itraconazole because of cardiacrelated adverse events caused by interactions with these drugs. Itraconazole has also been associated with rare cases of liver failure, including deaths. Some of these patients had no preexisting liver disease or other serious medical conditions. Itraconazole should be used cautiously in patients with hepatic insufficiency. Baseline liver function tests should be considered for all patients, and periodic liver function tests should be performed in patients who receive therapy for more than 1 month. Liver
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function tests should also be performed if a patient develops signs and symptoms of dysfunction.[36]

4.3.3 Terbinafine

Terbinafine is an allylamine with fungicidal activity against dermatophytes and some yeasts (especially C. parapsilosis). It was first approved for the treatment of onychomycosis in the UK in the early 1990s, and in the US in 1996.[37] Its efficacy and safety in dermatophyte toenail onychomycosis in adults has been established in many studies. A meta-analysis of 18 randomized, controlled trials has shown terbinafine to be highly effective, with an average mycologic cure rate of 76% 3% (mean SEM).[37] When treating onychomycosis of the toenails, terbinafine should be administered as continuous therapy for 12 weeks. In a study by Warshaw et al.[38] continuous therapy (250 mg/day for 3 months) was superior to pulse treatment (500 mg/day for 1 week per month for 3 months). Other studies demonstrated that terbinafine achieves high cure rates in the long term, which are superior to those obtained with itraconazole and other antifungals.[39,40] Three noncomparative studies have examined the use of terbinafine in the treatment of onychomycosis in patients with diabetes (table III).[2,41,42] No significant adverse effects or drug interactions were reported in an open-label study by Rich et al.[41] Bohannon and Streja[42] compared the results in diabetic patients with those of a much larger group of nondiabetic patients receiving terbinafine. There were no significant differences in mycologic cure in diabetic versus nondiabetic patients (64% and 73%, respectively). The same trend was observed with clinical cure (37% and 45%, respectively). No significant adverse effects were observed in a multicenter study by Farkas et al.[2] Two patients discontinued treatment: one patient because of amputation of

the leg with the target toenail and one patient because of a high g-glutamyl transferase level. Laboratory assessments showed that glucose levels were unchanged after the 12-week treatment period in 83% of patients. No drug interactions, hypoglycemic episodes, or reports of hypoglycemia were registered during the treatment phase. Minor adverse effects were reported in 12 of 104 patients (12%). The most commonly reported adverse effects for terbinafine include gastrointestinal effects, such as nausea, diarrhea, and mild abdominal pain. In rare cases, terbinafine has been associated with hepatotoxicity, comprising a prodrome of asthenia, anorexia, and abdominal pain about 1 week prior to the onset of jaundice, with pale stools and dark urine that can progress to mixed hepatocellular and cholestatic dysfunction. Although terbinafine-induced hepatotoxicity is rare, it is recommended that patients receiving terbinafine therapy have liver function tests performed before treatment and at 46 weeks.[26]

4.4 Combination Therapy

A large randomized, controlled, multicenter study of combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement was published by Baran et al.[43] A significantly higher rate of complete cure was observed for patients in the amorolfine/terbinafine group relative to those in the terbinafine group at 18 months (59.2% vs 45.0%; p = 0.03). However, diabetes was among the exclusion criteria. In a study by Avner et al.[44] oral terbinafine 250 mg/day for 16 weeks or a combination of oral terbinafine 250 mg/day for 16 weeks and topical ciclopirox nail lacquer once daily for 9 months were compared. After 9 months of treatment, the

Table III. Noncomparative studies of terbinafine in the treatment of onychomycosis in diabetic patients (pts) Reference No. of pts 32 (pp 28) 81 104 (pp 89) Dosage (duration; wk) 250 mg/day (12) NS 250 mg/day (12) Population Follow-up (wk) 72 72 48 Etiologic agents (%)a NS NS 87.6; 4.4; 5.6; 2.2 Cure (pp; %) mycologic 89 64 73 clinical NS 37 57 complete 61 NS 48 Discontinuation for adverse effects NS NS 1.9% (2/104)

Rich et al.

[41]

DM DM Type 2 DM (n = 52) Type 1 DM (n = 37)

Bohannon and Streja[42] Farkas et al.[2]

a Dermatophytes/yeasts/molds/mixed infections. DM = diabetes mellitus; NS = not stated; pp = per protocol population.

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mycologic cure rates were 22 of 34 (64.7%) for the terbinafineonly group and 30 of 34 (88.2%) for the combination therapy group (p < 0.05). No significant difference was noted in the complete cure rate.
4.5 Drug Interactions

Drug interactions are an important concern in diabetic patients being treated for onychomycosis.[45] Most patients who concomitantly received oral antidiabetic medications and oral antifungals did not experience an enhanced therapeutic effect from their antidiabetic treatment.[45] Itraconazole is known to interact with certain other drugs via the cytochrome P450 (CYP) isoenzymes. The most relevant interactions occur via the CYP3A4 subfamily because itraconazole is a potent inhibitor of this isoenzyme. Adverse effects due to drug-drug interactions are not expected in diabetic patients receiving oral antidiabetic agents that are not metabolized through the CYP3A4 system (e.g. tolbutamide, gliclazide, glyburide [glibenclamide], glipizide, and metformin). There is more concern about potential interactions with itraconazole when dealing with nateglinide, repaglinide, or pioglitazone, because these drugs are metabolized, at least in part, via CYP3A4.[35] Biguanide agents such as metformin undergo rapid renal excretion with very little hepatic metabolism and are thus not a concern for those taking azole antifungal agents. A postmarketing surveillance of the safety of itraconazole in diabetic patients concluded that adverse drug-drug reactions are not expected in diabetic patients who are treated with itraconazole and concurrently take insulin or oral antidiabetic agents (tolbutamide, gliclazide, glyburide, glipizide, metformin).[46] A study by Albreski and Gross[47] on the safety of itraconazole for the treatment of onychomycosis in 52 patients with diabetes revealed no significant differences in liver function test results or prestudy versus poststudy HbA1c levels between the control (palliative care) and the itraconazole groups (p > 0.05). Adverse events were observed in 4 of the 27 itraconazole recipients; no adverse events were reported in the 25 palliative treatment patients. One itraconazole recipient was withdrawn from the study because of elevated liver function tests; the other three adverse events (rash, diarrhea, and pedal edema) were considered self-limiting and did not interfere with protocol completion. Terbinafine is metabolized by the CYP2D6 pathway and does not interact with insulin or oral hypoglycemic agents. Terbinafine has no significant interaction with the CYP2C and CYP3A4 isoenzymes, which metabolize oral antidiabetic
2009 Adis Data Information BV. All rights reserved.

agents. Additional safety data were provided by Pollak and Billstein,[48] who did not find any severe adverse effects due to terbinafine in 77 patients with diabetes. Fluconazole may be metabolized by the CYP3A4 and CYP2C9 pathways, by which sulfonylurea agents are generally metabolized. The drug interactions between fluconazole and oral hypoglycemic agents include tolbutamide, glyburide, and glipizide.[45] When sulfonylureas are used concomitantly with fluconazole, glucose levels should be closely monitored and the dose of sulfonylurea adjusted if necessary. 5. General Management Principles Patient counseling and education are an integral part of onychomycosis management. For example, patients should be encouraged to examine their feet daily for small cuts and abrasions, which can lead to serious complications. Appropriate nail hygiene techniques, such as keeping feet cool and dry, trimming nails, and filing down hypertrophic nails, are essential. Chemical nail avulsion (i.e. 2040% urea paste) should be preferred as an adjunct to topical or systemic antifungal therapy.[26] Surgical nail avulsion should be strictly avoided because of increased rates of ingrown toenails and secondary infections, especially in diabetic patients. In a study in 40 nondiabetic patients with single nail onychomycosis, surgical nail avulsion followed by topical antifungal therapy was not shown to be effective.[49] Sumikawa et al.[50] investigated the effects of foot-care intervention including nail drilling combined with topical antifungal application in 24 diabetic patients with onychomycosis. Best effects were seen in eight patients with superficial white onychomycosis (50% cure after 1 year), while in 16 patients with distal-lateral subungual onychomycosis a significant improvement was seen. Sumikawa et al.[50] concluded that foot-care intervention including nail drilling increased patients awareness of foot care and showed educational effects. Indeed, several large clinical centers have experienced a 4485% reduction in the rate of amputations among individuals with diabetes after implementation of improved foot-care programs.[51] As shown by Mayser et al.,[14] there is a high level of motivation for educational programs. Nearly all patients included in these studies felt that they needed more information about their fungal foot infections. 6. Conclusion Toenail onychomycosis is an important issue in diabetic disease and is among the most significant predictors of foot
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ulcer. For diabetic patients the risk of infection is 1.9- to 2.8fold higher than in the healthy population. Severe onychomycosis is particularly problematic in the presence of polyneuropathy, as pressure erosions of the nail bed and hyponychium may be noted late because of impaired sensation, which increases the risk of subsequent bacterial infections involving bone. The introduction of terbinafine and itraconazole has significantly improved the outlook for diabetic patients with severe onychomycosis. These medications have been shown to have efficacy and safety profiles comparable to those in the nondiabetic population. Terbinafine is the most effective therapy in dermatophyte onychomycosis, possibly with concomitant topical therapy with a nail lacquer. If the causative organism is a yeast or a mold, pulse itraconazole should be used. In the authors experience, fluconazole given once weekly is a very well tolerated therapy, especially if concomitant therapies or diseases are a problematic issue. Patient advice and education in improved foot care are vital components in the management of onychomycosis to help achieve long-term cure and thus reduce complications of diabetic foot. Acknowledgments
No sources of funding were used to assist in the preparation of this review. Prof. Mayser has spoken at symposia sponsored by sanofi aventis, Novartis and Janssen-Cilag. Drs Freund and Budihardja have no conflicts of interest that are directly relevant to the content of this review.

9. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol 2005; 19: 21-9 10. Seebacher C, Brasch J, Abeck D, et al. Onychomycosis. Mycoses 2007; 50: 321-7 11. Cribier B, Bakshi R. Terbinafine in the treatment of onychomycosis: a review of its efficacy in the high-risk populations and in patients with nondermatophyte infections. Br J Dermatol 2004; 150: 414-20 12. Gupta AK, Ryder JE, Lynch LE, et al. The use of terbinafine in the treatment of onychomycosis in adults and special populations: a review of the evidence. J Drugs Dermatol 2005; 4: 302-8 13. Lange M, Roszkiewicz J, Szczerkowska-Dobosz A, et al. Onychomycosis is no longer a rare finding in children. Mycoses 2006; 49: 55-9 14. Mayser P, Hensel J, Thoma W, et al. Prevalence of fungal foot infections in patients with diabetes mellitus type 1: underestimation of moccasin-type tinea. Exp Clin Endocrinol Diabetes 2004; 112: 264-8 15. Szepietowski JC, Reich A, Garlowska E. Factors influencing coexistence of toenail onychomycosis with tinea pedis and other dermatomycoses: a survey of 2761 patients. Arch Dermatol 2006; 142: 1279-84 16. Alteras I, Saryt E. Prevalence of pathogenic fungi in the toenails of diabetic patients. Mycopathologica 1979; 67: 157-9 17. Lugo-Somolinos A, Sanchez JL. Prevalence of dermatophytosis in patients with diabetes. J Am Acad Dermatol 1992; 26: 408-10 18. Buxton PK, Milne LJ, Prescott RJ, et al. The prevalence of dermatophyte infection in well-controlled diabetics and the response to Trichophyton antigen. Br J Dermatol 1996; 134: 900-3 19. Romano C, Massai L, Asta F, et al. Prevalence of dermatophytic skin and nail infections in diabetic patients. Mycoses 2001; 44: 83-6 20. Dogra S, Kumar B, Bhansali A, et al. Epidemiology of onychomycosis in patients with diabetes mellitus in India. Int J Dermatol 2002; 41: 647-51 21. Pierard GE, Pierard-Franchimont C. The nail under fungal siege in patients with type II diabetes mellitus. Mycoses 2005; 48: 339-42 22. Gupta AK, Konnikov N, MacDonald P, et al. Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey. Br J Dermatol 1998; 139: 665-71 23. Saunte DM, Holgersen JB, Haedersdal M, et al. Prevalence of toe nail onychomycosis in diabetic patients. Acta Dermatol Venereol 2006; 86: 425-8 24. Manzano-Gayosso P, Hernandez-Hernandez F, Mendez-Tovar LJ, et al. Onychomycosis incidence in type 2 diabetes mellitus patients. Mycopathologia 2008; 166: 41-5 25. Chang SJ, Hsu SC, Tien KJ, et al. Metabolic syndrome associated with toenail onychomycosis in Taiwanese with diabetes mellitus. Int J Dermatol 2008; 47: 467-72 26. Finch J, Warshaw E. Toenail onychomycosis: current and future treatment options. Dermatol Ther 2007; 20: 31-46 27. Gupta AK, Ryder JE, Baran R, et al. Non-dermatophyte onychomycosis. Dermatol Clin 2003; 21: 257-68 28. Iorizzo M, Piraccini BM, Tosti A. New fungal nail infections. Curr Opin Infect Dis 2007; 20: 142-5 29. Winston JA, Miller JL. Treatment of onychomycosis in diabetic patients. Clin Diabetes 2006; 24: 160-6 30. Seebacher C, Nietsch KH, Ulbricht HM. A multicenter, open-label study of the efficacy and safety of ciclopirox nail lacquer solution 8% for the treatment of onychomycosis in patients with diabetes. Cutis 2001; 68 (2 Suppl.): 17-22 31. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of onychomycosis: an overview of current strategies for monotherapy and combination therapy. J Eur Acad Dermatol Venereol 2005; 19: 21-9
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Correspondence: Prof. Peter Mayser, Department of Dermatology, Justus Liebig University, Gaffkystr. 14, D-35385 Giessen, Germany. E-mail: Peter.Mayser@derma.med.uni-giessen.de

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