toenail onychomycosis in diabetic patients
Post on 15-Dec-2016
212 Views
Preview:
TRANSCRIPT
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
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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.
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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.
Toenail Onychomycosis in Diabetic Patients 215
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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.
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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.
Toenail Onychomycosis in Diabetic Patients 217
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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.
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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
Toenail Onychomycosis in Diabetic Patients 219
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
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: Peter.Mayser@derma.med.uni-giessen.de
220 Mayser et al.
ª 2009 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2009; 10 (4)
top related