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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
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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
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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
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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: Peter.Mayser@derma.med.uni-giessen.de
220 Mayser et a
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