ARTICLE
Diabetes mellitus affects all socioeconomic and age groups and its incidence
is gradually increasing [1]. Currently, the disease afflicts approximately
60 million people worldwide, 16 million in the USA and 1.5 million in
Canada [2]. However, between 1958 and 1993 the number of individuals diagnosed
with diabetes mellitus increased fivefold [3], and it has been estimated
by the World Health Organization (WHO) that the incidence will rise to
300 million by the year 2025. In the USA, recent estimates suggest that
the yearly incidence of new cases of type 1 and type 2 diabetes is 30,000
[4] and 625,000 [5], respectively.
Diabetic patients may present with complications involving all systems
of the body, including neuropathy and impaired circulation, renal disease,
cardiovascular disease, and retinopathy, possibly leading to blindness
[6]. The development of several skin manifestations in insulin-dependent
patients seems to be related to the duration of diabetes and the development
of diabetic microvascular complications. Foot problems are a major cause
of morbidity, disability and mortality among diabetic patients and are
usually related to peripheral vascular disease and diabetic neuropathy.
In particular, diabetes is the most frequent reason for non-traumatic
lower extremity amputations in the USA and it is usually preceded by diabetic
foot ulcer [7]. The combination of sensory neuropathy, ischaemia and direct
adverse effect on host defense mechanisms makes these patients especially
vulnerable to foot infections.
The diabetic foot is highly complex and represents one of the most serious
complications of diabetes. Fungal nail infections can also contribute
to the severity of the diabetic foot. While mild onychomycosis of the
toenails may pose little threat to diabetic subjects, more severe, neglected
onychomycosis can be a greater problem. The presence of the mycotic nail
may result in adjacent nail or skin injury and provide a reservoir of
organisms, thereby further increasing the risk of serious sequelae and
infection [8]. In one retrospective study conducted in the USA, the percentage
of patients with secondary infection was higher among diabetic patients
with onychomycosis (16%) compared to diabetic patients without onychomycosis
(6%) [9]. Diabetic patients with onychomycosis had a higher percentage
of gangrene and/or foot ulcer (12.2%) compared to diabetic patients without
onychomycosis (3.8%), a 3-fold higher risk [9].
Epidemiology of onychomycosis
In the USA, an estimated 10 million individuals suffer from onychomycosis.
Recent estimates suggest that onychomycosis accounts for approximately
33% of all fungal skin infections and 50% of all nail disorders [2, 10,
11]. The toenails, usually the hallux, tend to be affected four times
as often as fingernails [11]. Although the exact incidence of onychomycosis
is unknown, studies suggest that between 2 to 26% of the general population
worldwide are affected [12-15].
Risk factors
The prevalence of onychomycosis in different patient populations is
shown in Figure 1 [2,
12, 13, 16, 17]. In general, the prevalence of onychomycosis increases
with age. Results from epidemiological surveys suggest that overall the
incidence is 30 times higher in adults than in children [12, 13]. Listed
below are common factors, which have contributed to the recent proliferation
of fungal nail and other superficial fungal infections:
* growing elderly population;
* immunosuppressive conditions such as diabetes, HIV, acquired immunodeficiency
syndrome (AIDS), transplant recipients;
* immunosuppressive therapy and other drugs (e.g. corticosteroids,
antibiotics);
* peripheral vascular disease;
* family history of onychomycosis;
* occlusive footwear;
* vigorous physical activity;
* swimming pools;
* communal bathing facilities.
Prevalence of onychomycosis among
diabetic patients
Although initial studies were not clear whether the prevalence of onychomycosis
was higher among diabetic patients than in the non-diabetic population
[19, 20, 22], recent large epidemiological studies indicate an increased
prevalence [2, 13, 21].
A study conducted in the USA and Canada indicates a high incidence of
onychomycosis among diabetic subjects [2]. Abnormal-appearing nails and
mycological evidence of onychomycosis were present in 253/550 (46%) and
144/550 (26%) of diabetic patients, respectively. The development of onychomycosis
in diabetic individuals was significantly correlated with age (P <
0.0001) and male gender (P < 0.0001). Males were 2.99 times more likely
to have onychomycosis compared with females (95% confidence interval,
CI 1.94-4.61). After controlling for age and sex, the risk odds ratio
for diabetic subjects to have toenail onychomycosis was 2.77 times compared
with normal individuals (95% CI 2.15-3.57). A stepwise logistic regression
demonstrated that significant predictors for onychomycosis included a
family history of onychomycosis (P = 0.0001), concurrent intake of immunosuppressive
therapy (P = 0.035) and peripheral vascular disease (P = 0.023). Furthermore,
the severity of the onychomycosis was significantly associated with the
length of time the individual had diabetes (P = 0.043). Overall, the prevalence
of onychomycosis of the toes in diabetic subjects in Ontario, Canada and
Massachusetts, USA was estimated to be 32 and 35%, respectively.
Achilles prevalence study
In the recent Achilles Project, the largest prevalence study conducted
on the frequency of fungal foot infections, over 100,000 subjects from
11 European countries were screened [13]. The survey revealed that approximately
half of the total screened population had evidence of fungal foot infections,
with tinea pedis and onychomycosis affecting one quarter of these individuals.
As part of the Achilles Project, a major objective was to investigate
the effect of diabetes mellitus on the prevalence of foot diseases. Results
from 1997 and 1998, which screened a total of 19,588 patients, suggested
a significant association between diabetes mellitus and the occurrence
of fungal foot disease [21]. In total, 59.6% on non-diabetic patients
had clinical evidence of a foot disease (any type) compared to 82.5% of
diabetic subjects (Table I)
[13, 21]. Among these, 66.6% of the non-diabetic subjects had clinical
evidence of a fungal infection compared to 79.3% of the diabetic population
(Table II) [13, 21]. The
odds ratio for observing a fungal infection (clinical evidence) in patients
with foot disease was approximately 1.4 times higher for diabetic than
for non-diabetic individuals (P < 0.001). There was also a higher incidence
of fungal infection affecting both the skin and nails among the diabetic
patients, suggesting that diabetes has an unfavorable effect with respect
to the severity of fungal infection (Table
III) [13, 21]. The analysis also indicated that diabetes mellitus
had a significant adverse effect on the occurrence of tinea pedis and
onychomycosis among patients with fungal infection (Table
IV) [13, 21]. The odds ratios for finding mycological evidence
of onychomycosis and tinea pedis among diabetic patients were 1.48 (P
= 0.016) and 2.14 times higher (P < 0.001) compared to healthy controls,
respectively.
Etiology of onychomycosis
among diabetic patients
Onychomycosis and dermatomycoses have a varied epidemiology and can
be caused by dermatophytes, yeasts and non-dermatophytic moulds [2, 22,
23]. In a recent study in diabetic patients [2], the organisms implicated
in causing onychomycosis were dermatophytes (88.2%), non-dermatophyte
moulds (9.1%) and Candida spp. (2.7%). Other investigators have
reported that Candida infections of the nail and surrounding area
may be more prevalent in diabetic patients [23]. In one study, 100 diabetic
and 100 diabetes-free patients were mycologically examined for the presence
of pathogenic fungi in their toe webs and toenails [23]. Trichophyton
rubrum was found in 46% of diabetic patients, Candida albicans
in 31%, Trichophyton mentagrophytes in 21% and Epidermophyton
floccosum in 3%. In the non-diabetic invididuals the major pathogens
were: T. rubrum 57.5%, T. mentagrophytes 35%, C. albicans
5% and E. floccosum 2.5%. In addition, an interesting correlation
was observed between the level of blood sugar and the percentage of positive
fungal findings, the patients with more than 3,000 mg/ml being 100% affected.
Possible complications of onychomycosis among
diabetic patients
Although onychomycosis causes some degree of morbidity for healthy individuals,
it is especially pronounced in high-risk patients such as diabetic subjects,
patients with HIV, AIDS or other types of immunosuppression, including
transplant recipients, and patients on long-term corticosteroid therapy
[14].
Onychomycosis poses a greater risk to diabetic patients because of the
possible sequelae [6]. In particular, high-risk diabetic patients with
compromised lower extremities and severe neuropathy are at increased risk
of developing complications from onychomycosis [24]. Most notably, impaired
sensation can make many diabetics less aware of minor abrasions and ulcerations
on their feet that may be caused by trauma, from poor nail grooming or
by the sharp, brittle or infected nails characteristic of onychomycosis
[6]. These lesions, in turn, may develop into serious paronychia, cellulitis
or bacterial infections, and contribute to the severity of the diabetic
foot. Osteomyelitis can also result from neglected, infected nail bed
erosion in diabetic patients because of the close proximity of the nail
bed to the underlying bone [24]. Thus there is an important clinical rationale
for treating diabetic patients with fungal nail infections.
Other superficial fungal infections
Onychomycosis is usually associated with tinea pedis (either moccasin
type or interdigital), a condition which should also not be ignored in
diabetic patients. Tinea pedis may lead to fissures in the plantar or
interdigital skin, which can become a portal of entry for bacteria, resulting
in deep infections often with severe consequences [25]. Yosipovitch et
al. [26] report an increased incidence of tinea pedis among diabetic
subjects. In this recent, cross-sectional study, the frequency of skin
manifestations were examined in 238 type 2 diabetes patients (disease
duration > 5 years) and 122 healthy control subjects. Tinea pedis was
detected in 32% of the diabetic population compared to 7% of non-diabetic
individuals.
Paronychia may also be important among diabetic patients with paresthesia
or anaesthesia of the foot [6]. A recent study showed that 7.5% of hospital
admissions in diabetic patients was caused by paronychia [27]. Candida
spp. are frequently the primary pathogen, followed by bacterial infection
with streptococci, staphylococci, Pseudomonas spp. and coliforms
[25]. There has also been a case report of Candida spp. isolated
from multiple leg ulcers from a diabetic patient with granulomatous panniculitis
[28].
Treatment rationale
Effective treatment is particularly important for diabetic subjects,
because up to 1/3 of these individuals are likely to have onychomycosis
[2]. In addition, the consequences of not treating this condition in diabetic
individuals may be more serious than in normal subjects and include cellulitis,
paronychia and nail bed ulceration [2]. Minor abrasions in the skin often
go unnoticed by diabetic patients due to impaired sensation. In particular,
older diabetic patients may be obese or have retinopathy and therefore
have trouble bending over or noticing small fissures or ulcerations on
their feet.
Younger individuals may also have problems with self-esteem. The diabetic
patient's low level of self confidence may be further compromised by the
unsightly appearance of the nails, which may restrict social activities.
Therefore, effective treatment may improve their quality of life and enhance
well being.
As the severity of onychomycosis may be associated with the length of
time the individual has had the infection, early intervention is advisable
due to the progressive nature of the fungal infection [2]. Relapse or
re-infection is also frequently seen in the diabetic population, possibly
due to impaired lower extremity circulation, slow growth of the nails
and immunopathy [24]. The use of effective antifungal therapy to eradicate
fungal organisms in the nail may also help prevent recurrent bouts of
tinea pedis and thereby reduce the potential for subsequent bacterial
infection [6].
Therapeutic options
The treatment of onychomycosis is similar in diabetic patients as in
normal subjects, and includes mechanical/chemical measures, topical medications
and oral antifungal therapies. However, because of the implications of
infection superimposed on primary pathology, a safe and effective broad-spectrum
treatment in this population is of paramount importance. Compliance and
drug interactions are also important as diabetic patients are frequently
taking concomitant medications.
Topical therapies have limitations in reaching the site of infection
and are only suitable for certain patients with early and mild cases of
onychomycosis, although they are frequently used as supportive therapy.
Griseofulvin was traditionally the oral treatment of choice, but it has
relatively poor efficacy in onychomycosis, with a long treatment duration.
Therefore, it has been superseded by a newer generation of antifungal
agents. The availability of the azole antifungals, itraconazole and fluconazole,
and the allylamine antifungal, terbinafine provides an opportunity for
effective treatment of onychomycosis of the toes. These agents have a
higher benefit-risk ratio with a shorter treatment duration, thus resulting
in greater compliance.
Itraconazole (pulse), terbinafine (continuous) and fluconazole (once
week) regimens have a therapeutic reservoir in the nail. The dosing regimen
with itraconazole, 1 week on, 3 weeks off therapy given for 3 pulses may
be more effective than 12 weeks of continuous dosing with the triazole
[29, 30]. In addition, pulse therapy compared to continuous treatment
with the itraconazole decreases total drug exposure and improves patient
tolerability, safety [31] and in many instances, the compliance. When
treating onychomycosis of the toe nails terbinafine should be administered
as continuous therapy for 12 weeks. Fluconazole would be administered
once weekly until there is complete outgrowth of diseased nail plate.
The duration of therapy may be in the range of 9 to 15 months.
As a wider variety of organisms are being identified in onychomycosis
and other superficial fungal infections, spectrum of fungal activity is
important for optimal treatment. Terbinafine is primarily active against
dermatophytes with some activity against Candida species, particularly
Candida parapsilosis compared to Candida albicans [32-34].
Terbinafine may also be effective against some non-dermatophytes molds
[35-36]. Itraconazole has a broad spectrum of activity including dermatophytes,
Candida species and some non-dermatophyte molds [36-44]. Fluconazole
has activity against dermatophytes and Candida species with relatively
little data where the drug has been used to treat non-dermatophyte moulds
[45, 46].
Drug interactions
Drug interactions are an important concern in diabetic patients being
treated for onychomycosis. Itraconazole is known to interact with certain
other drugs via the cytochrome P450 enzymes. The most relevant
interactions occur via the CYP 3A4 subfamily. However, drug interactions
between itraconazole and antidiabetic medications are not expected since
insulin is not metabolized by the CYP enzymes. In addition, it appears
that oral hypoglycemic agents may not be metabolized by the same CYP subfamily
as itraconazole. Data from clinical trials and extensive post-marketing
surveillance have not found evidence of drug interactions in diabetic
patients (n = 189) treated with itraconazole [47]. Most patients
concomitantly receiving oral antidiabetic medications did not experience
an enhanced therapeutic effect from their antidiabetic treatment.
Terbinafine is metabolized by the CYP 2D6 pathway and does not have
an interaction with insulin or the oral hypoglycemic agents. Fluconazole
may be metabolized by the CYP 3A4 and 2C9 pathways. The drug interactions
between fluconazole and oral hypoglycemic agents include tolbutamide,
glyburide and glipizide [48].
Safety
Safety is of particular concern among diabetic patients, as many individuals
have complications involving other systems, including impaired circulation,
renal disease, cardiovascular disease and retinopathy [9, 49-53]. Although
there are limited published data, initial studies indicate that itraconazole
and terbinafine are generally well tolerated in this patient population.
A recent study has confirmed the safety of terbinafine for distal onychomycosis
in diabetic patients [9]. Reports also indicate that itraconazole is safe
in diabetic subpopulations being treated for toenail onychomycosis [49,
51].
The dosage of terbinafine and fluconazole may need to be modified in
patients with progressively worsening renal function [54, 55]. Cutaneous
reactions may occur following treatment with terbinafine and occasionally
these are severe [56, 57]. Similarly, cutaneous adverse reactions have
also been recorded following treatment with itraconazole [53] and fluconazole
[58].
Clinical experience
To date, no large trials have been published which have evaluated the
newer antifungal agents in the treatment of fungal nail infections in
diabetic patients. Itraconazole has been found to be effective and safe
in the treatment of diabetic patients with onychomycosis [8, 28, 47, 59].
Similarly, terbinafine has been reported to be effective and safe in the
treatment of onychomycosis in diabetics [9, 32-35, 50]. To our knowledge,
there is no study where fluconazole has been used to manage diabetic patients.
Management
Proper foot care is critical in high-risk diabetic patients (sensory
neuropathy and impaired circulation of the lower extremities) to prevent
infection and diabetic foot. Programs to reduce foot disease among diabetes
patients should identify those at high risk and ensure appropriate preventive
therapy and treatment of foot problems. Improved patient education should
be implemented. For example, patients should be encouraged to examine
their feet daily for small cuts and abrasions, which can lead to serious
complications. 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 [7].
CONCLUSION
Results of two recent studies clearly indicate that diabetic patients
are at increased risk of developing onychomycosis. As the population of
diabetic subjects continues to grow, it is likely that the clinical and
economical impact of onychomycosis in these individuals will increase.
The increasing incidence, varied epidemiology and the physical and psychological
ramifications of the disease emphasize the need for effective broad-spectrum
treatment in susceptible patient populations.
The introduction of terbinafine and itraconazole has significantly improved
the outlook for diabetic patients with onychomycosis. Both agents have
a favorable safety profile which is an important consideration when treating
diabetic subjects. There are no reported trials where fluconazole has
been used to treat diabetic patients. Data from clinical trials and post-marketing
surveillance suggest that drug interactions with hypoglycemia may not
be an important issue when itraconazole and terbinafine are used to treat
diabetic patients receiving concomitant hypoglycemic medications. In contrast,
fluconazole has an interaction with some oral hypoglycemic agents.
Article accepted on 27/4/00
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