toenail onychomycosis in diabetic patients

Toenail Onychomycosis in Diabetic PatientsIssues 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 Diabetesmellitusmay be associatedwith serious sequelae, such as renal disease, retinopathy, and diabetic

foot. 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 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.

THERAPY IN PRACTICEAm J Clin Dermatol 2009; 10 (4): 211-220

1175-0561/09/0004-0211/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

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 total

number 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 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, 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), 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 dis-

orders.[7-10] Several studies have shown a prevalence of 2–13%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 immunosuppres-

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

tients. 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 facil-

ities.[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]

212 Mayser et al.

ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)

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 PrevalenceofOnychomycosis amongDiabetic 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

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), absentor 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 re-

miniscent of onychomycosis; 65.3% of the diabetic patients (190

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 diabetic

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

nondiabetic controls. The proportion inmenwas higher than in

women, both in the diabetic and nondiabetic groups.

Table II gives an overview of noncomparative studies in-

vestigating the prevalence of onychomycosis among only dia-

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

a total of 550 diabetic patients (283male, 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 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 heal-

thy 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 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. albicans in four pts C. albicans in 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. albicans predominant)

37% dermatophytes

(T. rubrum predominant)

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< 0.001).

Toenail Onychomycosis in Diabetic Patients 213


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 skinmycoses 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 dia-

betic 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 coloni-

zation 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%.

Furthermore, a significant correlation between type 2 diabetes

evolution time and onychomycosis was found (p < 0.01), anddistal-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 hydro-

xide only). A significantly higher prevalence in men than in

women was observed (p = 0.024). Furthermore, metabolic

syndrome, obesity, triglyceride levels, and HbA1c were sig-

nificantly 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 in-

fecting 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 dermato-

phytes (37%), and molds (14.8%). This result may suggest that

Table II. Noncomparative studies of the prevalence of onychomycosis in patients with diabetes mellitus

Reference No. of patients

(male/female)

Diabetes type Prevalence of onychomycosis Etiologic agents

Gupta et al.[22] 550 (283/267) 34% type 1

66% type 2

46% abnormal-appearing nails

26% onychomycosis

88% dermatophytes (Trichophyton rubrum

predominant)

3% yeasts

9% molds

Mayser et al.[14] 95 (52/43) 100% type 1 58% (n= 56) 70% dermatophytes

30% yeasts

Saunte et al.[23] 271 (194/77) 26% type 1

74% type 2

22% mycologically confirmed

onychomycosis

93.2% dermatophytes

6.8% Candida spp.

Manzano-Gayosso

et al.[24]250 100% type 2 37.2% ungual dystrophy

28% onychomycosis (n = 70; 34 male,

36 female)

48.6% dermatophytes (37.1% T. rubrum)

31% yeasts

10.4% non-dermatophytic molds

10% mixed infections

Chang et al.[25] 1245 (610/635) 100% type 2 30.76% (n= 383; 206male, 177 female) Confirmation by positive potassiumhydroxide

only

214 Mayser et al.


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 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 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. 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 are

important 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 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 cor-

rectly 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, andmolds. It is not approved in theUS for the treatment

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

plied weekly for 6months, complete cure rates ranged from 38%to 54%.[26] Higher cure rates were foundwith twice-weekly treat-

ment, although this difference was not statistically significant.

4.1.2 Ciclopirox

Two studies have been published concerning the effect of

ciclopirox 8% nail lacquer, whichwas approved by theUSFDA

in 1999 for the treatment of immunocompetent patients withmild

to moderate onychomycosis of fingernails and toenails without

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. Efficacy

parameters included the decrease from baseline of the affected

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

3months and the efficacy of ciclopirox nail lacquer at 6months.

In an analysis of a subset of 215 patients (5.9%) with diabetes,

ciclopirox nail lacquer reduced themean 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 at-

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

logic outcome of improvement or cure, with 54.3% attaining

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 the

patients. No treatment-related serious adverse events were

observed.



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 (6–7 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 (150–450mg) 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% (150mg), 29% (300mg),

and 36% (450mg).[34]

Fluconazole is not currently approved for the treatment of

onychomycosis in the US. In the opinion of the authors, it is a

verywell 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 are

mild 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/orCandida spp.[26] The pulsed dosage regimen with itraconazole

(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 (200mg twice

daily, 1 week on, 3 weeks off, for 12 weeks) versus continuous

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

was recently investigated in a prospective, randomized, multi-

center 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 head-

ache. 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 itracona-

zole 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 treat-

ment 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 cardiac-

related 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 pre-

existing liver disease or other serious medical conditions. Itra-

conazole 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 perfor-

med in patientswho receive therapy formore than 1month. Liver

216 Mayser et al.


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%(mean– SEM).[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 (250mg/day for 3 months) was superior to pulse

treatment (500mg/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 obtainedwith

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 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 asso-

ciated 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 4–6 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 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 re-

lative 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 250mg/dayfor 16 weeks or a combination of oral terbinafine 250mg/dayfor 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

Dosage

(duration; wk)

Population Follow-up

(wk)

Etiologic

agents (%)aCure (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.



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 excretionwith very little hepaticmetabolism 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 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. Appro-

priate nail hygiene techniques, such as keeping feet cool and

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

essential. Chemical nail avulsion (i.e. 20–40% urea paste)

should be preferred as an adjunct to topical or systemic anti-

fungal 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 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 white

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

distal-lateral subungual onychomycosis a significant improve-

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

intervention including nail drilling increased patients’ aware-

ness of foot care and showed educational effects.

Indeed, several large clinical centers have experienced a

44–85% reduction in the rate of amputations among individuals

with diabetes after implementation of improved foot-care

programs.[51] As shown byMayser et al.,[14] there is a high level

of motivation for educational programs. Nearly all patients

included in these studies felt that they neededmore 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

218 Mayser et al.


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 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 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.

References1. Gupta AK, Humke S. The prevalence and management of onychomycosis in

diabetic patients. Eur J Dermatol 2000; 10: 379-84

2. Farkas B, Paul C, Dobozy A, et al. Terbinafine (Lamisil) treatment of

toenail onychomycosis in patients with insulin-dependent and non-insulin-

dependent diabetes mellitus: a multicentre trial. Br J Dermatol 2002; 146:

254-60

3. Joshi N, Caputo GM, Weitekamp MR, et al. Infections in patients with dia-

betes mellitus. N Engl J Med 1999; 341: 1906-12

4. Rich P, Hare A. Onychomycosis in a special patient population: focus on the

diabetic. Int J Dermatol 1999; 38: 17-9

5. BoykoWL,Doyle JJ, Ryu S, et al. Onychomycosis and its impact on secondary

infection development in the diabetic population. 4th Annual International

Meeting of the International Society for Pharmacoeconomics and Outcomes

Research (ISPOR); 1999 May 23-26; Arlington (VA)

6. Boyko EJ, Ahroni JH, Cohen V, et al. Prediction of diabetic foot ulcer oc-

currence using commonly available clinical information: the Seattle Diabetic

Foot Study. Diabetes Care 2006; 6: 1202-7

7. Effendy I, LechaM, Feuilhade de ChauvinM, et al. Epidemiology and clinical

classification of onychomycosis. J Eur Acad Dermatol Venereol 2005;

19 Suppl. 1: 8-12

8. Scher RK, Tavakkol A, Sigurgeirsson B, et al. Onychomycosis: diagnosis and

definition of cure. J Am Acad Dermatol 2007; 56: 939-44

9. Baran R, Kaoukhov A. Topical antifungal drugs for the treatment of ony-

chomycosis: an overview of current strategies for monotherapy and combi-

nation 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 non-

dermatophyte 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 Der-

matol 1998; 139: 665-71

23. Saunte DM, Holgersen JB, Haedersdal M, et al. Prevalence of toe nail ony-

chomycosis 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. Mycopatho-

logia 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. IorizzoM, 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 treat-

ment 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 ony-

chomycosis: an overview of current strategies for monotherapy and combi-

nation therapy. J Eur Acad Dermatol Venereol 2005; 19: 21-9



32. Brenner MA, Harkless LB, Mendicino RW, et al. Ciclopirox 8% nail lacquer

topical solution for the treatment of onychomycosis in patients with diabetes:

a multicenter, open-label study. J Am Podiatr Med Assoc 2007; 97: 195-202

33. Watanabe D, Kawamura C, Masuda Y, et al. Successful treatment of toenail

onychomycosis with photodynamic therapy. Arch Dermatol 2008; 144: 19-21

34. Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or

450mg) in the treatment of distal subungual onychomycosis of the toenail.

J Am Acad Dermatol 1998; 38: s87-94

35. Gupta AK, Gover MD, Lynde CW. Pulse itraconazole vs. continuous terbi-

nafine for the treatment of dermatophyte toenail onychomycosis in patients

with diabetes mellitus. J Eur Acad Dermatol Venereol 2006; 20: 1188-93

36. Kill J. Treatment options for onychomycosis [online]. Available from URL:

http://www.infectiousdiseasenews.com/article/33478.aspx [Accessed 2009Apr 28]

37. 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

38. Warshaw EM, Fett DD, Bloomfield HE, et al. Pulse versus continuous terbi-

nafine for onychomycosis: a randomized, double-blind, controlled trial. J Am

Acad Dermatol 2005; 53: 578-84

39. Evans EG, Sigurgeirsson B. Double blind, randomised study of continuous

terbinafine compared with intermittent itraconazole in treatment of toenail

onychomycosis: the LION Study Group. BMJ 1999; 318: 1031-5

40. Sigurgeirsson B, Olafsson JH, Steinsson JB, et al. Long-term effectiveness of

treatment with terbinafine vs itraconazole in onychomycosis: a 5-year blinded

prospective follow-up study. Arch Dermatol 2002; 138: 353-7

41. Rich F,KarchmerA,Atillasoy ES. The safety and efficacy of oral terbinafine in

the treatment of onychomycosis in diabetic patients. J Eur Acad Dermatol

Venereol 1999; 12 Suppl. 2: 229

42. Bohannon NJ, Streja L. Effectiveness of terbinafine therapy for toenail

onychomycosis in persons with diabetes. Diabetes 2000; 49 Suppl. 1: A195

43. Baran R, Sigurgeirsson B, de Berker D, et al. A multicentre, randomized,

controlled study of the efficacy, safety and cost-effectiveness of a combination

therapy with amorolfine nail lacquer and oral terbinafine compared with oral

terbinafine alone for the treatment of onychomycosis with matrix involve-

ment. Br J Dermatol 2007; 157: 149-57

44. Avner S, Nir N, Henri T. Combination of oral terbinafine and topical

ciclopirox compared to oral terbinafine for the treatment of onychomycosis.

J Dermatol Treat 2005; 16: 327-30

45. Gupta AK, Katz I, Shear NH. Drug interactions with itraconazole, flucona-

zole, and terbinafine and their management. J Am Acad Dermatol 1999; 41:

237-49

46. Verspeelt J, Marynissen G, Gupta AK, et al. Safety of itraconazole in diabetic

patients. Dermatology 1999; 198: 382-4

47. Albreski DA, Gross EG. The safety of itraconazole in the diabetic population.

J Am Podiatr Med Assoc 1999; 89: 339-45

48. Pollak R, Billstein SA. Safety of oral terbinafine for toenail onychomycosis.

J Am Podiatr Med Assoc 1987; 87: 565-70

49. Grover C, Bansal S, Nanda S, et al. Combination of surgical avulsion and

topical therapy for single nail onychomycosis: a randomized controlled trial.

Br J Dermatol 2007; 157: 364-8

50. Sumikawa M, Egawa T, Honda I, et al. Effects of foot care intervention in-

cluding nail drilling combined with topical antifungal application in diabetic

patients with onychomycosis. J Dermatol 2007; 34: 456-64

51. Bild DE, Selby JV, Sinnock P, et al. Lower-extremity amputation in

people with diabetes: epidemiology and prevention. Diabetes Care 1989; 12:

24-31

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

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

E-mail: [email protected]

220 Mayser et al.


toenail onychomycosis in diabetic patients

Documents