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Toenail Onychomycosis in Diabetic PatientsIssues and ManagementPeter 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2174.4 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, anddiabeticfoot. A recent large prospective study has shown that onychomycosis is among the most significant pre-

dictors 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 atrigger 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.

THERAPY IN PRACTICE Am J Clin Dermatol 2009; 10 (4): 211-221175-0561/09/0004-0211/$49.95 2009 Adis Data Information BV. All rights reserve


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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 in-

creased to 175 million in 2002.[1] By the year 2010, the totalnumber of diabetic individuals is expected to double world-

wide, 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 cir-

culation, 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 com-

plications 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 ad-

verse 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, ne-glected 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 hypo-

nychium may be noted late because of impaired sensation,

which increases the risk of subsequent bacterial infections in-

volving 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-

rene and/or foot ulcer (12.2%) compared with diabetic patient

without onychomycosis (3.8%).[5] In a prospective study, Boyk

et al.[6] investigated the ability of commonly available clinica

information to predict diabetic foot ulcer. The assessmentwere age, race, weight, current smoking, diabetes duration and

treatment, glycosylated hemoglobin (HbA1c), visual acuity

history of laser photocoagulation treatment, foot ulcer an

amputation, foot shape, claudication, foot insensitivity to th

10 g monofilament, foot callus, pedal edema, hallux limitus

tinea pedis, and onychomycosis. 1285 diabetic veterans withou

foot ulcer were followed with annual clinical evaluation

and quarterly mailed questionnaires. Mean follow-up wa

3.38 years, during which time 216 foot ulcers occurred. Amon

the most significant predictors (p 0.05) of foot ulcer, onycho

mycosis was ranked fourth place (hazard ratio 1.58; 95%CI 1.16, 2.16) after prior amputation (2.57; 1.60, 4.12), prio

foot ulcer (2.18; 1.61, 2.95), and monofilament insensitivit

(2.03; 1.50, 2.76).

3. Epidemiology of Onychomycosis

In the general population onychomycosis is a relativel

common disease, accounting for up to 50% of all nail dis

orders.[7-10] Several studies have shown a prevalence of 213%

in the general population.[11] In certain populations, such a

elderly people, the prevalence is much higher, reaching u

to 40% by the age of 60 years[2] and up to 50% by the age o

70 years.[11] Results from other epidemiological surveys sugges

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 an

a high prevalence of onychomycosis among family members.[13

Another risk factor for onychomycosis is immunosuppres

sion, for example in HIV-positive, AIDS, and transplant pa

tients. In a controlled study, more than 30% of patients infecte

with HIV were found to have onychomycosis compared with12.6% of healthy controls.[11]

Moreover, predisposing factors for toenail onychomycosi

include the presence of tinea pedis, positive family history o

onychomycosis, trauma to the nail, diabetes, poor periphera

(arterial) circulation, smoking, and possibly psoriasis, as well a

sports activities and attendance at public bathing facil

ities.[9,10,12] Onychomycosis is often associated with tinea pedis

however, in diabetic patients even widespread tinea pedis i

often mistakenly considered to be diabetes-associated dr

skin.[14] Another point demonstrated by Szepietowski et al.[1

212 Mayser et a

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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 onycho-mycosis. It was hypothesized that infected toenails may be a site

from which fungal infections could spread to other body areas.

3.1 Prevalenceof Onychomycosis among Diabetic Patients

Table I gives an overview of studies comparing the pre-

valence of onychomycosis in diabetic patients with healthy

controls.[16-21] Buxton et al.[18] showed no significant differ-

ences 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 dia-betic 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 derma-

tophyte infection and the duration or type of diabetes, or blood

sugar levels or levels of HbA1c. This is in contrast to studies by

Pie rard and Pie rard-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), absen

or feeble peripheral pulses (p < 0.15), peripheral neuropath

(p< 0.05), and retinopathy (p< 0.001). Combining histomy

cology and cultures, Pie rard and Pie rard-Franchimont[2

found the highest prevalence of onychomycosis among all o

the studies. All sampled nails showed clinical alterations re

miniscent of onychomycosis; 65.3%of the diabetic patients (19

type 2 diabetic patients, 136 men and 54 women) had onycho

mycosis compared with 48.4% of matched controls. Irrespec

tive of gender, the ratio between onychomycosis and non

infectious onychodystrophies reached 1.88 (122 : 66) in diabeti

patients, which was twice the value of 0.94 (92 : 98) found in

nondiabetic controls. The proportion in men was higher than i

women, both in the diabetic and nondiabetic groups.

Table II gives an overview of noncomparative studies investigating the prevalence of onychomycosis among only dia

betic patients.[14,22-25] In a large study, Gupta et al.[22] evaluate

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 ony

chomycosis (mostly due to dermatophytes) were present in 25

(46%) and 144 (26%) patients, respectively. After controllin

for age and sex, the risk odds ratio for diabetic patients to hav

toenail onychomycosis was 2.77 compared with data for heal

thy individuals obtained from published literature (95% C

2.15, 3.57). Toenail onychomycosis was present in 26% of th

Table I. Prevalence of onychomycosis in comparative studies of diabetic patients (pts) vs healthy controls

Reference No. of pts Prevalence of onychomycosis (%) Etiologic agent

diabetic control diabetic control diabetic control

Alteras and Saryt[16]a 100 100 73 66 69% dermatophytes

31% Candida albicans

95% dermatophytes

5% C. albicans

Lugo-Somolinos and

Sanchez[17]100 100 7 12 C. albicansin four pts C. albicansin seven pts

Buxton et al.[18] 100 100 12 11 100% dermatophytes Predominantly dermatophytes

Romano et al.[19] 171 276 1.2 1.8 100% Trichophyton

mentagrophytes

40% T. mentagrophytes

40% T. rubrum

20% Epidermophyton floccosum

Dogra et al.[20] 400 400 17b 6.8 48.1% yeasts

(C. albicanspredominant)

37% dermatophytes

(T. rubrumpredominant)

14.8% molds

62.5% dermatophytes

25% yeasts

12.% molds

Pierard and Pierard-

Franchimont[21]190 190 65.3 48.4 62.7% dermatophytes

12.7% yeasts

16.6% molds

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


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samples and was projected to affect approximately one-third of

individuals with diabetes. It was significantly correlated with

age (p


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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

Pie rard and Pie rard-Franchimont,[21] which showed that inEurope 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 sug-

gesting that these secondarily colonize nails already infected by

dermatophytes.[27] However, the role of yeasts and non-

dermatophyte 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 clearwhether 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. Fur-

thermore, the presence of onychomycosis was found to be sig-

nificantly 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 mea-

sures, 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 in-

tervention 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 areimportant considerations, as diabetic patients are frequently

taking concomitant medications.

4.1 Topical Medications

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

combination therapy over systemic therapy alone.[31] One of th

advantages of topical therapies is the avoidance of systemi

adverse effects. However, older diabetic patients may be obes

or have retinopathy and therefore may have difficulty in correctly using these agents. In addition, topical antifungals ar

indicated for the reduction of relapses and reinfection once th

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 treatmen

of onychomycosis. In clinical trials with the 5% nail lacquer ap

plied weekly for 6 months, complete cure rates ranged from 38%

to54%.[26] Higher cure rates were found with twice-weekly treat

ment, although this difference was not statistically significant

4.1.2 Ciclopirox

Two studies have been published concerning the effect o

ciclopirox 8%nail lacquer, which was approved by the US FDA

in 1999 forthe treatment of immunocompetent patients with mil

to moderate onychomycosis of fingernails and toenails withou

lunula involvement, due to T. rubrum. Seebacher et al.[30] per

formed 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. Efficac

parameters included the decrease from baseline of the affected

area of the nail. Physicians rated the level of onychomycosis a

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%. Th

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 seriou

events reported.

In an open-label, noncomparative study by Brenner et al.,[32

49 diabetic patients with distal subungual onychomycosis wer

treated once daily for 48 weeks. Clinical improvement was at

tained in 63.4% of patients. Most patients (85.7%) had a myco

logic outcome of improvement or cure, with 54.3% attainin

mycologic cure. Consideration of mycologic and clinical out

comes generated a treatment outcome of improvement, success

or cure in 84.4% of patients. However, complete cure (myco

logic and clinical cure) was achieved in only 4.4% of th

patients. No treatment-related serious adverse events wer

observed.

Toenail Onychomycosis in Diabetic Patients 21



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4.2 Experimental Therapeutic Approaches

Successful treatment of onychomycosis with photodynamic

therapy (20% methyl-aminolevulinate followed by excimerlaser; 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) regi-

mens 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 ma-

jority occurring within the first month of therapy. Most aremild and include gastrointestinal disturbance (nausea, ab-

dominal 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

(1 week on, 3 weeks off therapy given for three pulses) may b

more effective than 12 weeks of continuous administratio

with the triazole.[26]

The efficacy and safety of pulse itraconazole (200 mg twicdaily, 1 week on, 3 weeks off, for 12 weeks) versus continuou

terbinafine (250 mg once daily for 12 weeks) in diabetic patient

was recently investigated in a prospective, randomized, multi

center study in the treatment of dermatophyte toenail distal an

lateral subungual onychomycosis.[35] The fungal spectrum

consisted ofT. rubrum (80%), T. mentagrophytes (15.7%), an

Epidermophyton floccosum (4.3%). Primary efficacy measure

included mycologic cure rate (negative potassium hydroxid

and culture) and effective cure (mycologic cure plus na

plate involvement of 10% or less) at week 48. At that poin

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 wa

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 i

the form of gastrointestinal problems. No serious advers

events and no interactions with concomitant medications wer

recorded.

Itraconazole has a low incidence of adverse events, with th

most common being minor gastrointestinal upset and head

ache. Reversible elevation of liver function tests is also seen.[26

Because of reports of the spontaneous development o

congestive heart failure (CHF) in patients receiving itracona

zole therapy, some of whom required hospitalization and died

the FDA has included CHF in the black-box warning fo

itraconazole. The warning states that itraconazole should no

be administered for the treatment of onychomycosis in patient

with evidence of left ventricular dysfunction or a history o

CHF. It also recommends discontinuing itraconazole if signs o

symptoms of CHF appear during treatment of onychomycosis

For indications other than onychomycosis, benefits of treat

ment should outweigh the risks.

The black-box warning also includes the contraindication oco-administration of cisapride, pimozide, quinidine, dofetilide

or levacetylmethadol with itraconazole because of cardiac

related adverse events caused by interactions with these drugs

Itraconazole has also been associated with rare cases of live

failure, including deaths. Some of these patients had no pre

existing liver disease or other serious medical conditions. Itra

conazole should be used cautiously in patients with hepati

insufficiency. Baseline liver function tests should be considered

for all patients, and periodic liver function tests should be perfor

med in patients who receive therapy for more than 1 month. Live

216 Mayser et a



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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 ran-

domized, controlled trials has shown terbinafine to be highly

effective, with an average mycologic cure rate of 76% 3%

(meanSEM).[37] When treating onychomycosis of the toe-

nails, 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 re-

ported 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 terbi-

nafine. 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 treatmen

period in 83% of patients. No drug interactions, hypoglycemiepisodes, or reports of hypoglycemia were registered during th

treatment phase. Minor adverse effects were reported in 12 o

104 patients (12%).

The most commonly reported adverse effects for terbinafin

include gastrointestinal effects, such as nausea, diarrhea, and

mild abdominal pain. In rare cases, terbinafine has been asso

ciated with hepatotoxicity, comprising a prodrome of asthenia

anorexia, and abdominal pain about 1 week prior to the onse

of jaundice, with pale stools and dark urine that can progress t

mixed hepatocellular and cholestatic dysfunction. Althoug

terbinafine-induced hepatotoxicity is rare, it is recommendedthat 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 com

bination therapy with amorolfine nail lacquer and oral terbi

nafine compared with oral terbinafine alone for the treatmen

of onychomycosis with matrix involvement was published by

Baran et al.[43] A significantly higher rate of complete cure wa

observed for patients in the amorolfine/terbinafine group re

lative to those in the terbinafine group at 18 months (59.2% v

45.0%; p= 0.03). However, diabetes was among the exclusion

criteria.

In a study by Avner et al.[44] oral terbinafine 250 mg/da

for 16 weeks or a combination of oral terbinafine 250 mg/da

for 16 weeks and topical ciclopirox nail lacquer once daily fo

9 months were compared. After 9 months of treatment, th

Table III. Noncomparative studies of terbinafine in the treatment of onychomycosis in diabetic patients (pts)

Reference No. of

pts

Dosage

(duration; wk)

Population Follow-up

(wk)

Etiologic

agents (%

)

a

Cure (pp; %) Discontinuation for

adverse effectsmycologic clinical complete

Rich et al.[41] 32

(pp 28)

250mg/day (12) DM 72 NS 89 NS 61 NS

Bohannon and

Streja[42]81 NS DM 72 NS 64 37 NS NS

Farkas et al.[2] 104

(pp 89)

250mg/day (12) Type 2 DM

(n=52)

Type 1 DM

(n=37)

48 87.6; 4.4;

5.6; 2.2

73 57 48 1.9% (2/104)

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 terbinafine-

only 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 pa-

tients 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 itraco-nazole is a potent inhibitor of this isoenzyme. Adverse effects

due to drug-drug interactions are not expected in diabetic pa-

tients receiving oral antidiabetic agents that are not metabo-

lized 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 reac-

tions are not expected in diabetic patients who are treated

with itraconazole and concurrently take insulin or oral anti-

diabetic agents (tolbutamide, gliclazide, glyburide, glipizide,

metformin).[46]

A study by Albreski and Gross[47] on the safety of itraco-

nazole 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 re-cipients; 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

agents. Additional safety data were provided by Pollak and

Billstein,[48] who did not find any severe adverse effects due t

terbinafine in 77 patients with diabetes.

Fluconazole may be metabolized by the CYP3A4 anCYP2C9 pathways, by which sulfonylurea agents are generally

metabolized. The drug interactions between fluconazole an

oral hypoglycemic agents include tolbutamide, glyburide, and

glipizide.[45] When sulfonylureas are used concomitantly with

fluconazole, glucose levels should be closely monitored and th

dose of sulfonylurea adjusted if necessary.

5. General Management Principles

Patient counseling and education are an integral part o

onychomycosis management. For example, patients should bencouraged to examine their feet daily for small cuts an

abrasions, which can lead to serious complications. Appro

priate nail hygiene techniques, such as keeping feet cool and

dry, trimming nails, and filing down hypertrophic nails, ar

essential. Chemical nail avulsion (i.e. 2040% urea paste

should be preferred as an adjunct to topical or systemic anti

fungal therapy.[26] Surgical nail avulsion should be strictl

avoided because of increased rates of ingrown toenails an

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 in

tervention including nail drilling combined with topical anti

fungal application in 24 diabetic patients with onychomycosis

Best effects were seen in eight patients with superficial whit

onychomycosis (50% cure after 1 year), while in 16 patientswit

distal-lateral subungual onychomycosis a significant improve

ment was seen. Sumikawa et al.[50] concluded that foot-car

intervention including nail drilling increased patients aware

ness of foot care and showed educational effects.

Indeed, several large clinical centers have experienced

4485% reduction in the rate of amputations among individualwith diabetes after implementation of improved foot-car

programs.[51] As shown by Mayser et al.,[14] there is a high leve

of motivation for educational programs. Nearly all patient

included in these studies felt that they needed more informatio

about their fungal foot infections.

6. Conclusion

Toenail onychomycosis is an important issue in diabeti

disease and is among the most significant predictors of foo

218 Mayser et a



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ulcer. For diabetic patients the risk of infection is 1.9- to 2.8-

fold higher than in the healthy population. Severe onychomy-

cosis is particularly problematic in the presence of polyneuro-

pathy, as pressure erosions of the nail bed and hyponychiummay be noted latebecause of impaired sensation, which increases

the risk of subsequent bacterial infections involving bone.

The introduction of terbinafine and itraconazole has sig-

nificantly 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 ex-perience, 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.

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Correspondence: Prof. Peter Mayser, Department of Dermatology, Justu

Liebig University, Gaffkystr. 14, D-35385 Giessen, Germany.

E-mail: [email protected]

220 Mayser et a


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