Download Update on the Management of Onychomycosis: Highlights of the

305
Update on the Management of Onychomycosis: Highlights of the Third Annual
International Summit on Cutaneous Antifungal Therapy
Boni E. Elewski and Roderick J. Hay
From the University Hospitals of Cleveland, Cleveland. Ohio. USA;
and St. John's Institute of Dermatology. Guy's Hospital,
London. United Kingdom
Onychomycosis is an increasingly common fungal infection of the nail, which has traditionally
been difficult to diagnose and treat and has physical and psychological consequences for the patient.
Onychomycosis can be caused by dermatophytes, nondermatophytic filamentous fungi, and yeasts.
The relative percentages of cases due to these etiologic agents vary with geographic location; however,
in the United States, dermatophytes are the most common pathogens. Toenails are affected four
times as often as fingernails. Microscopy and culture are the diagnostic "gold standards" for onychomycosis, although biopsy of the nail may be required to obtain a definitive diagnosis when conditions
that mimic onychomycosis, such as psoriasis, are suspected. The treatment of onychomycosis includes a combination of topical therapy, surgical or chemical nail avulsion, and systemic therapy.
The new generation of systemic agents (itraconazole, fluconazole, and terbinafine) is associated with
a higher cure rate and shorter courses of treatment than are the older systemic antifungal drugs (i.e.,
griseofulvin and ketoconazole); these characteristics have sparked new interest in onychomycosis. Of
these newer antifungals, itraconazole and terbinafine are the only agents currently approved by the
U.S. Food and Drug Administration for the treatment of onychomycosis.
Onychomycosis is a fungal infection of the nail unit. Although the exact incidence of onychomycosis is unknown, studies estimate that between 2% and 18% of the population worldwide is affected [1]. The results of a recent survey of persons
with nail dermatophytosis in the United Kingdom suggested a
prevalence of 2.7% in the general population [2]. In the previous century, onychomycosis was rare and generally occurred
in the fingernails of persons with tinea capitis and in their care
givers. Both onychomycosis and tinea pedis are now common
and have been estimated to occur in 15%-20% of persons
aged 40-60 years [3].
The rise in the incidence in onychomycosis is caused by a
variety of factors including the aging of the population, an
increase in the use of immunosuppressive therapies, an increase
in exposure to organisms through communal bathing and health
spas, and the use of tight-fitting occlusive footgear for many
athletic activities [4]. The increasing incidence of infection
due to HIV also contributes to the rise in the incidence of
onychomycosis [5] because nails are commonly infected and
are one of the important dermatologic signs of the progression
ofHIV disease. Toenail infections are four times more common
than fingernail infections [6].
Received 27 December 1995; revised 15 March 1996.
This work was presented in part at the Third Annual International Summit
on Cutaneous Antifungal Therapy held 24-27 August 1995 in New York.
Grant support: Janssen Pharmaceutica.
Reprints or correspondence: Dr. Boni E. Elewski, Associate Professor of
Dermatology, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio 44106.
Clinical Infectious Diseases 1996;23:305-13
© 1996 by The University of Chicago. All rights reserved.
1058--4838/96/2302-0015$02.00
An accurate diagnosis of onychomycosis depends on proper
collection of the specimen, suitable transport of the specimen
to the laboratory, correct interpretation of the findings on direct
microscopic examination, use of appropriate culture media, and
correct identification of the causative organism. Treatment of
the infection includes a combination of topical therapy, surgical
or chemical nail avulsion, and systemic therapy. The new generation of systemic antifungal agents is associated with a higher
cure rate and shorter courses of treatment than are griseofulvin
and ketoconazole. Of these newer agents, itraconazole and terbinafine are approved by the U.S. Food and Drug Administration (FDA) for the treatment of onychomycosis.
The Etiology of Onychomycosis
Onychomycosis is caused by dermatophytes, yeasts, and
nondermatophytic molds. The dermatophytes Trichophyton rubrum and Trichophyton mentagrophytes cause ~ 80% of all
cases of onychomycosis in temperate zones [7]. Approximately
5%-17% of fungal nail infections are caused by yeasts, and
Candida albicans is isolated in >70% of these cases [6].
C. albicans is more frequently cultured from fingernails than
from toenails. Nondermatophytic molds such as Scopulariopsis, Scytalidium, Acremonium, and Fusarium cause approximately 3%-5% of cases of fungal nail disease, which may
develop secondary to dermatophytic infection, trauma, or direct
invasion into the nail [8]. The relative percentages of cases
due to these etiologic agents vary according to geographic
location (table 1) [7, 9-12]. For example, scytalidium infections have been reported as a major cause of nail disease in
tropical and subtropical countries and may account for 50% of
cases of onychomycosis in Southeast Asia [13]. It is important
to identify fungal nail infections due to nondermatophytic
ern 1996;23
Elewski and Hay
306
(August)
Table 1. Geographic variations in etiologic agents.
Canada
(Sumerbell; n = 3,000)
Dermatophytes
Yeasts
Nondermatophyte molds
Mixed
USA
(Greer; n = 431)
90.5
5.5
4
t
UK
(Clayton; n
23
81
63
17
2
4
8
= 699)
t
Belgium
(Willemsen; n = 700)
40
43
14
3
NOTE. All data are in percent. This table is reprinted with permission from the International Journal ofDermatology [12].
t Not specified.
molds because the nondennatophytes are not effectively eradicated by most of the available antifungal agents.
Preexisting cases of tinea pedis predispose an individual
to onychomycosis. The condition usually starts when trauma
weakens the seal between the nail plate and the nail bed,
allowing fungal organisms to penetrate the nail unit. The increased incidence of onychomycosis, which is associated with
aging, may be due to slower growth of the nail, increased
trauma to the nail plate, decreased circulation, and changes in
the size and width of the foot. Exposure to heat and moisture
worsens the condition, and immunosuppression alters the
body's ability to combat the infection. Some investigators have
suggested that estrogen exerts a protective effect against onychomycosis, as the infection is observed more frequently in
postmenopausal women [14]. On the other hand, testosterone
might aggravate the condition, since onychomycosis is seen
more frequently in boys older than 14 years and is rarely seen
in children under the age of 12 years. Indeed, increased age
itself-not hormonal factors-may be a major contributor to
the development of onychomycosis.
Genetic etiologic factors that predispose individuals to onychomycosis may include an autosomal dominant transmission
with incomplete penetrance, leading to variable clinical expression; a selective T cell nonrecognition factor, which could lead
to differences in immunologic response to infection or to atopy;
or a genetic influence on the keratin itself. The presence ofthese
genetically variant patterns alters the keratin protein within
the nail structure, making the nail more susceptible to fungal
invasion [15].
Clinical Manifestations of Onychomycosis
Four patterns of onychomycosis have been described: distal
lateral subungual onychomycosis; superficial white onychomycosis; proximal subungual onychomycosis; and onychodystrophy, which is associated with candidal infection. The latter
category is further classified as candidal paronychia, onycholysis, chronic mucocutaneous candidiasis, and distal lateral subungual onychomycosis. The clinical presentations of each form
ofthe disease are presented in figure 1. The relative percentages
of etiologic agents that cause each clinical manifestation vary
according to geographic location. Total dystrophic onycho-
mycosis is sometimes considered an additional category that
is associated with an advanced stage of any of the four patterns
of onychomycosis.
Distal lateral subungual onychomycosis. This manifestation of the disease begins with initial fungal penetration of the
stratum corneum from the hyponychial area or from the lateral
nail fold. It is characterized by yellow-brown discoloration of
the nail plate, onycholysis, and subungual hyperkeratosis. It is
the most common clinical presentation of onychomycosis and
is most often caused by T rubrum or T mentagrophytes. A
small percentage of cases are caused by Epidermophyton floccosum, Trichophyton tonsurans, Trichophyton violaceum, and
miscellaneous Microsporum species.
Superficial white onychomycosis. Fungi directly invade the
nail plate in superficial white onychomycosis, creating a white,
crumbly appearance. The most common agent is T mentagrophytes, but species of Fusarium or Acremonium may also be
the etiologic agents. Superficial white onychomycosis is almost
always found in toenails. The initial lesions may be randomly
dispersed but will eventually coalesce to include the entire
surface of the nail. This infection is capable of producing progressive dystrophy of the nails and will invade the cornified
layer of the nail bed and hyponychium.
Proximal subungual onychomycosis. Proximal subungual
onychomycosis is the least common clinical presentation of
onychomycosis in healthy individuals. The infection penetrates
the proximal portion of the nail, resulting in hyperkeratosis
and onycholysis. The characteristic clinical appearance is a
white hue that extends distally from under the proximal nail
fold. The distal portion of the nail unit remains normal until
late in the course of the disease, when the entire nail plate is
affected. This infection occurs in both fingernails and toenails
and is primarily caused by T rubrum. The proximal white
subungual pattern particularly affects immunocompromised patients. A recent study showed that 87.1% of 62 patients with
AIDS had proximal white subungual onychomycosis [16].
Candidal onychomycosis. There are three recognized
forms of nail dystrophy associated with candidal infection.
Candidal paronychia results in swelling and erythema of the
proximal and lateral nail folds, with secondary involvement of
the nail plate; this condition is common in persons whose hands
are constantly immersed in water. Onycholysis is often a result
Figure 1. Manifestations of onychomycosis. Top left : Distal lateral subungual onychomycosis. Top right: Superficial white onychornyeosis. Bottom left: Proximal subungual onychomycosis. Bottom right: Candidal infection (courtesy of Dr. GaI]' D. Palmer, Dayton, Ohio).
Figure 2.
Palmer).
Psoriasis of the nail (co urtesy of Dr. Gary D.
Figure 3. Chronic onych olysis (courtesy of Dr. C. Ralph Daniel
Ill , University of Mississippi Medical Cen ter, Jackson , Missi ssippi ).
308
em 1996;23
Elewski and Hay
of the hyperkeratosis that forms in the subungual area in patients with candidal paronychia. C. albicans is isolated in
> 70% of onychomycosis cases that are caused by yeasts; Candida parapsilosis, Candida tropicalis, and Candida krusei are
less frequently the causative agents [8]. It has also been suggested that other mechanisms, including chronic contact dermatitis, contribute to the pathogenesis of this condition.
Distal and lateral onychomycosis due to Candida species
occurs when there is separation of the nail plate from the nail
bed, with erosion of the nail plate. The infection is not common
but is seen particularly in patients with Raynaud's disease or
Cushing's syndrome.
The third form of candidal onychomycosis, which occurs in
the nail and as a cutaneous infection, is chronic mucocutaneous
candidiasis (also known as candidal granuloma). The organism
directly invades the nail plate, and the proximal and lateral nail
folds become increasingly thick, until the nail becomes totally
dystrophic. This condition is also seen in immunocompromised
individuals, including HIV -infected patients, who are deficient
in specific T cell responses to Candida antigen [5].
Diagnosis of Onychomycosis
Findings on microscopy and the results of fungal cultures
confirm the diagnosis of onychomycosis. Confirmation of fungal infection of the nail is required so that appropriate therapy
can be initiated, since other nail diseases such as psoriasis
and lichen planus can mimic onychomycosis clinically. When
culturing nails, subungual debris should be collected as proximally as possible, since the outermost debris may contain contaminants and nonviable hyphae.
Before the nail specimen is viewed, it should first be softened
and cleared in 20%-30% KOH. The detection of spores and
fungal hyphae can be enhanced by using stains such as Parker's
blue-black ink (l part KOH to 1 part ink), Polychrome Multiple
Stain, or fluorochromes [8]. Chlorazol black E may also be
added as a counterstain because it is chitin specific and, unlike
the blue-black ink, is less likely to stain other potential contaminants such as cotton or elastic fibers. Calcofluor white is a
nonspecific fluorochrome stain that binds with .a-configuration
polysaccharides. It has been used for detecting fungi in clinical
specimens and has been found to be significantly more sensitive
than the KOH wet mount in observing fungal pathogens [17].
The limitation of the KOH procedure is that it is only a screening test for the presence or absence of fungi and cannot identify
specific pathogens.
The identity of the pathogen can be confirmed only by fungal
culture. Cultures can be done using dermatophyte test media,
Mycosel (BBL Becton Dickinson Microbiology Systems,
Cockeysville, MD), or Sabouraud dextrose agar. Overgrowth
by nondennatophytes and bacteria is avoided by modifying the
chosen medium with antibacterial agents (chlortetracycline and
gentamicin) and by using media with and without cycloheximide.
(August)
Table 2. Nail diseases that may mimic onychomycosis.
•
•
•
•
•
•
Traumatic onychodystrophies
Pachyonychia congenita
Contact dermatitis
Nail bed tumors
Yellow-nail syndrome
Idiopathic onycholysis
Conditions that Mimic Onychomycosis
The differential diagnosis of onychomycosis includes several
nail diseases that may be clinically indistinguishable from onychomycosis (table 2). The most common of these diseases is
psoriasis. A nail biopsy may be required to obtain a definitive
diagnosis.
Distinguishing between onychomycosis (figure 1) and psoriasis (figure 2) can be difficult, since subungual hyperkeratosis,
onycholysis, splinter hemorrhages, and diffuse crumbling are
clinical signs of both conditions. The finding of a positive
fungal culture does not rule out psoriasis because dennatophytes or other fungi can occasionally colonize psoriatic nails,
especially when the nail plate is grossly deformed, Three clinical symptoms ofpsoriasis (the presence offine pitting, the small
salmon-colored oil-drop sign of onycholysis that is present
in psoriasis but absent in onychomycosis, and the frequent
involvement of nails in both hands in cases of psoriasis), in
addition to evidence of psoriasis at another site such as the
elbows and/or knees, are helpful in differentiating between the
two conditions.
Lichen planus, an inflammatory skin disease, may involve
the nails in --10% of affected patients [6]. It may involve the
nails on both hands and both feet. The most common manifestations are onychorrhexis (exaggerated longitudinal ridging) and
"angel wing deformity" (the central portion of the nail is
raised, and the lateral portion is depressed). A key clinical
finding that differentiates lichen planus from onychomycosis
is the presence of Wickham's striae in typical lesions of the
skin or mucous membranes. Pterygium may also be seen in
patients with lichen planus but not in those with onychomycosis.
Contact dermatitis of the hyponychium may produce hyperkeratosis similar to that seen in onychomycosis. Contact dermatitis is usually occupation-related, and a differential diagnosis
can easily be made by obtaining a careful clinical history and
performing a patch test.
Repeated trauma to the nails can be responsible for onycholysis (figure 3) that resembles onychomycosis. In traumatic
onychodystrophies, the onycholytic space can be colonized by
microorganisms that produce pigmentation of the onycholytic
area. A differential diagnosis can be made by clipping the
onycholytic nail. In cases of onychomycosis, clipping the onycholytic nail reveals a hyperkeratotic nail bed. In cases of
traumatic onychodystrophy, clipping the onycholytic nail reveals a normal nail bed unless the trauma is chronic.
cm
1996;23 (August)
Treatment of Onychomycosis
Nail bed tumors should also be considered in the differential
diagnosis of onychomycosis and can be ruled out by obtaining
a radiograph. Melanomas of the nail can be differentiated from
onychomycosis by biopsy.
An uncommon nail disease that sometimes needs differentiation from onychomycosis is yellow-nail syndrome. This condition exists in conjunction with primary lymphedema and
chronic obstructive pulmonary disease. Clinical manifestations
of yellow-nail syndrome include an absence of cuticles, yellow
pigmentation, an excessive curve in the nail, and cessation of
nail growth.
Management of Onychomycosis
Once a diagnosis of onychomycosis is established, management may include topical therapy, surgical intervention, or systemic antifungal therapy, either alone or in combination with
a topical agent. Patients should also be instructed in the proper
care of their nails (table 3).
When topical agents have been used for the treatment of
onychomycosis, either alone or in conjunction with other therapies, the outcome has been disappointing; however, limited
disease or superficial white onychomycosis may occasionally
respond to this form of treatment. Nevertheless, topical agents
may be useful for preventing relapse of chronic tinea pedis,
which often accompanies onychomycosis. Because topical
agents lack efficacy, administration of oral agents such as
griseofulvin, ketoconazole, and (more recently) itraconazole,
fluconazole, and terbinafine has been the treatment of choice.
The results of conventional therapy with griseofulvin and
ketoconazole for onychomycosis have been less than satisfactory. Prolonged therapeutic regimens, poor results, and significant adverse effects have all contributed to less than optimal
compliance of patients as well as to frustration of physicians.
The newer antifungals fluconazole, itraconazole, and terbinafine are more efficacious and can be administered for shorter
periods than the older agents.
Traditional Oral Antifungal Therapy
Griseofulvin. The limited efficacy of griseofulvin was
found to result in part from incomplete absorption from the
Table 3. Recommended nail care for patientswith onychomycosis.
•
•
•
•
•
•
•
•
•
•
Keep nails short and clean
Clip toenails straight across to prevent ingrown toenails
File hypertrophic nails
Avoid trauma and irritants, especially when onychomycosis is
present
Use cotton gloves for dry manual work
Use vinyl gloves for wet work
Change instruments between care of normal and infected nails
Discourage use of community nail instruments at beauty salons
Avoid high heels and narrow-toed shoes
Encourage daily use of antifungal foot and shoe powder
309
gastrointestinal tract [18]. Thus, improved formulations have
been devised with micronized preparations. [19] When micronized griseofulvin is administered, 27%- 72% of the drug
is absorbed, and peak serum levels are reached "-'4 hours after
administration [20].
Allergic reactions to griseofulvin occur in 5%- 7% of cases
[21]. Other common side effects include headache and nausea,
both of which decrease in severity when griseofulvin is given
with a meal. Less common side effects include vomiting, diarrhea, photosensitivity, urticaria, fatigue, fever, and menstrual
irregularities. Biochemical changes include neutropenia, monocytosis, liver function abnormalities, albuminuria, and, rarely,
granulocytopenia.
Drug interactions that occur when griseofulvin is administered include reduced efficacy of birth control pills, decreased
absorption of griseofulvin with the concomitant administration
of phenobarbital, and inhibition of warfarin's effect with the
concomitant administration of griseofulvin. In addition, the
combination of alcohol and griseofulvin may cause a disulfiram-like reaction [22].
Griseofulvin therapy for onychomycosis of the fingernails
should be continued for 4-6 months, and therapy for infected
toenails should be continued for 10-18 months or until the
nail has grown out. The mycologic cure rate with griseofulvin
varies from study to study but is usually between 40% and
80% for infected fingernails and between 3% and 38% for
infected toenails [23]. There is continued controversy regarding
laboratory monitoring while patients are receiving the drug,
some clinicians recommend that a baseline complete blood
count and liver function tests be performed and be repeated
periodically. However, other clinicians do not believe that such
testing is necessary.
Ketoconazole. This agent was the first broad-spectrum oral
antifungal developed. It is well absorbed in individuals with
normal gastric acidity. Ketoconazole is metabolized by the
liver, and the major route of excretion is through the bile into
the intestinal tract. About 13% of the drug is excreted in the
urine; of this quantity, 2%-4% is excreted as unchanged
drug [24].
Significant drug interactions during ketoconazole therapy include potentiation of warfarin's effect and decreased absorption
of rifampin. Concomitant administration of both rifampin and
isoniazid may decrease serum levels of ketoconazole. Ketoconazole may also increase levels of cyclosporine, and an interaction with terfenadine that leads to cardiac dysrhythmia has been
described. Ingestion of alcohol during therapy with ketoconazole may produce a disulfiram-like effect [22].
The side effects of ketoconazole may include nausea, vomiting, abdominal pain, diarrhea, pruritus, and headache. The
nausea and headache may be relieved if the drug is given with
a meal. Hepatic reactions characterized by transient abnormalities in liver function occur in < 10% of patients receiving ketoconazole [25]. Risk factors for the development of hepatic
reactions include age of >40 years, prolonged courses of therapy (>6 months) with the drug, female sex, prior treatment
310
Elewski and Hay
with griseofulvin, and a history of other drug allergies. The
worldwide experience has shown that hepatic injury occurs in
'"" 1 of 70,000 cases [25]. This change from the originally reported incidence (l of 10,000 cases) [26] may be due to the
fact that ketoconazole is now given in short courses rather than
long courses of therapy.
Rates of treatment success are similar to those for griseofulvin (i.e., mycologic cure rate, 15%-30% for toenails and
'"" 50%- 70% for fingernails) [21]. Ketoconazole is seldom used
for onychomycosis because of the long course of treatment
(200 mg/d for 4-6 months for fingernails and 200 mg/d for
10-18 months for toenails) required for mycologic cure, which
increases the risk of hepatic reactions.
Newer Oral Antifungals
Fluconazole. Fluconazole is a triazole with a high bioavailability; it is not currently approved by the FDA for the treatment
of onychomycosis in the United States. More than 90% of an
ingested dose of fluconazole is absorbed [22]. Peak plasma
levels are reached within 1-2 hours of oral administration, and
steady-state levels are reached in 6-10 days [22]. Fluconazole's long half-life of22-30 hours may result in accumulation
of the drug in serum with multiple dosing. Fluconazole has
been detected in skin and nails within 3 hours and 2 weeks,
respectively, after the initiation of therapy [22].
The results of in vitro studies suggest that fluconazole may be
effective in treating dermatophytic infections and C. albicans
infections of the nail [27, 28]. Clinical cure rates of 100% for
infected fingernails and 90% for toenails have been reported
when fluconazole and 40% urea ointment are used concomitantly [29, 30]. However, published clinical data on the use of
fluconazole for treatment of nail infections are limited.
Side effects associated with fluconazole were reported in a
study of 4,000 patients who received the drug [31]. The side
effects that occurred at the highest rate (8.6%) were related to
the gastrointestinal system. Others included headache and
rashes. Drug interactions may occur and are listed in table 4.
Itraconazole. This drug has recently been approved by the
FDA for the treatment of onychomycosis. It is a broad-spectrum
triazole that is effective against dermatophytes, yeasts, and
many molds. Itraconazole is well absorbed when administered
orally with food, and it is distributed extensively throughout
tissue.
The pharmacokinetic properties of itraconazole are mainly
related to its pronounced lipophilic properties. Its plasma halflife varies between 15 and 25 hours; the peak plasma concentration is reached within 2-4 hours after a single 100-mg dose
is administered [32]. Itraconazole binds strongly (99.8% of
drug) to protein and has a marked avidity for lipids [32]. The
slow elimination of itraconazole from tissue may explain its
continuing therapeutic effect after treatment is discontinued.
Itraconazole's strong affinity for keratinized tissues results in
high concentrations of the drug in the nails and explains its
effectiveness in the treatment of onychomycosis.
em
1996;23 (August)
In a study of the pharmacokinetics of itraconazole, detectable
levels of the drug were found in nail clippings after 7 days of
treatment [33]. Evidence of itraconazole's penetration into the
nails so soon after treatment has begun suggests that it acts
rapidly on the fungus in the nail plate not only by incorporating
itself into the nail matrix but also by diffusing from the nail
bed into the nail plate. Detectable levels of itraconazole in the
nail plate, with no evidence of the drug in plasma, demonstrate
its affinity for keratinous material and thus efficacy in the
treatment of onychomycosis. Results of clinical studies that
support the diffusion of itraconazole from the nail bed into the
nail plate are limited because the invasive procedures required
to measure drug levels are undesirable to patients.
A subsequent study supported the theory that itraconazole
penetrates the nail bed as well as the nail matrix [34]. Nineteen
patients with onychomycosis were treated with itraconazole (100
mg/d) for up to 7 months. After the first month, mean concentrations of the drug were about three times higher in the fingernails
(42 ng/g) than in the toenails (16 ng/g). The faster distribution
of itraconazole into fingernails than into toenails may be due to
differences in the structure and thickness of the two types of
nail and the faster outgrowth of the fingernails. The detection
of itraconazole in distal nail clippings before full outgrowth of
the fastest-growing nail shows that the nail matrix is not the
only means by which this drug penetrates the nail [34].
In a dose-response study designed to examine the kinetics
of itraconazole in the nails in relation to therapeutic outcome,
39 patients with onychomycosis received a daily dose of either
100 mg or 200 mg of the drug for 3 months [35]. Itraconazole
levels in distal nail clippings were determined during a 6month posttherapy period. The intergroup difference reached
significance at the follow-up, with a mean drug concentration
of 35 ng/g in the 100-mg group and 141 ng/g in the 200-mg
group 6 months after the completion of therapy (P < .05) [35].
These concentrations were well within the therapeutic range
for the most common fungal nail pathogens [36]. The mycologic cure rates were 79% for the 200-mg group and 26% for
the 100-mg group [35]. The early attainment ofextratherapeutic
drug levels and the persistence (:::::;6 months) of these levels
after treatment suggest the potential for shorter courses of therapy with itraconazole.
On the basis of the pharmacokinetic properties found in this
study, the use of intermittent or "pulse" dosing regimens of
itraconazole has been explored. In an investigation of the pharmacokinetics and pharmacodynamics of the drug, 50 patients
with confirmed onychomycosis of the toenails were randomly
assigned to receive three or four pulses of itraconazole therapy
for I week (200 mg twice daily each month) [36]. Clinical and
mycologic evaluation of the infected toenails and determination
of drug levels in the distal ends of the fingernails and toenails
were performed at the end of each month for :::::; 6 months, and
then every 2 months for :::::; 1 year. Endpoint analysis of the
follow-up findings showed that 80% of the patients in both
treatment groups had negative cultures. The rates of mycologic
cure, as defined by negative cultures and negative KOH prepa-
cm
311
Treatment of Onychomycosis
1996;23 (August)
Table 4.
Systemic antifungal drugs and potential drug interactions.
Griseofulvin
• Barbiturates
• Warfarin
• Coumarin
• Oral contraceptives
Ketoconazole
• Cyc1osporine
• Rifampin
• Isoniazid
• Phenytoin
• Sulfonylureas
• Coumarin
• Terfenadine
• Astemizole
Fluconazole
• Rifampin
• Coumarin
• Sulfonylureas
• Phenytoin
• Cyclosporine
• Hydrochlorothiazoles
• Oral contraceptives
• Isoniazid
• Valproic acid
Itraconazole
•
•
•
•
•
•
•
•
•
•
Terbinafine
• Cimetidine
• Rifampin
Terfenadine
Astemizole
Cyclosporine
Digoxin
Phenytoin
Rifampin
H2 antagonists
Isoniazid
Coumarin
Sulfonylureas
rations, were 64% and 72% for the three-pulse and four-pulse
regimens, respectively. There were no statistically significant
differences between the groups [36].
Therapy with itraconazole is well tolerated; side effects are
reported for ,...., 7% of patients with dermatologic conditions
who are treated with the drug [37]. The adverse reactions are
mostly minor and primarily consist of gastric upset and headache [37]. Drug interactions can occur with itraconazole, as is
shown in table 4.
Terbinafine. Terbinafine is an allylamine that is effective
against dermatophytes and some molds. It has recently been
approved by the FDA for the treatment of onychomycosis.
Unlike the azoles, oral terbinafine is not very effective against
C. albicans. It is well absorbed after oral administration and
binds strongly to plasma proteins. When patients were given
oral terbinafine at a dose of 250 mg/d, the drug was detected
in plasma as early as 24 hours after the initiation of treatment
[38]. Therapeutic levels persist in the nail for 3-6 months after
therapy is discontinued.
In a randomized study, terbinafine was administered for periods of 6 weeks, 12 weeks, and 24 weeks; complete cure of
toenail onychomycosis was achieved in 67%, 82%, and 85%
of patients, respectively. After an additional 24 weeks of follow-up, cure rates were 40% for patients in the 6-week group,
71% for those in the l2-week group, and 79% for those in the
24-week group [39].
In a randomized, double-blind study by Haneke and colleagues [40], terbinafine (250 mg/d) was compared with griseofulvin (500 mg/d in micronized form) in 180 patients with
dermatophytosis of the fingernails. The cure rates were 76%
in the terbinafine group and 39% in the griseofulvin group at
the end of the study [40]. The recommended dosage is 250
mg daily for 12 consecutive weeks for treatment of toenail
onychomycosis and 6 consecutive weeks for fingernail onychomycosis.
Terbinafine has a generally favorable safety profile; most
side effects are characterized as minor and transient (such as
taste disturbances), although there have also been reports of
patients who developed neutropenia, pancytopenia, and hepatotoxic reactions while receiving the drug [41]. Terbinafine does
not activate cytochrome p-450 enzyme; therefore, its potential
for interacting with drugs metabolized through this pathway is
minimal (table 4).
Surgical Treatment of Onychomycosis
Surgery can be a useful therapeutic adjuvant in the treatment
of onychomycosis. However, surgical avulsion is painful and
disfiguring, and it must generally be restricted to one or a
few nails in selected cases. General indications for surgical
treatment include pachyonychia associated with pain; contraindications to the administration of oral antifungals; the presence
of onychomycosis due to drug-resistant nondermatophytic
fungi; and the desire to limit the duration of drug therapy and/
or reduce costs and the incidence of side effects. For optimal
results, a combination of surgical, systemic, and/or topical
treatment may be used.
Before the newer antifungal agents had become available,
Baran and Hay [42] treated 12 patients with distal lateral subungual onychomycosis of the toenail, which was caused by a
dermatophyte. These investigators used a combination of surgical avulsion, a 3-month course of oral ketoconazole, and topical
treatment with an imidazole preparation. The mycologic cure
rate was 50% at 12 months. In another study [43], surgical nail
avulsion followed by daily application of ciclopirox olamine
for 4 months cleared fingernail onychomycosis due to Scytali-
312
Elewski and Hay
dium dimidiatum. The onychomycosis was clinically and mycologically cured 12 months after the cessation of therapy.
Surgical nail plate avulsion is an ambulatory procedure done
under local anesthesia. Since it is advisable to remove only the
diseased part of the nail plate, partial avulsions are always
preferred. Total nail plate avulsion and distal transversal nail
plate hemiavulsion should be avoided because these procedures
may result in secondary distal embedding of the nail plate.
It is mandatory to obtain a preoperative history and perform
a clinical examination in order to eliminate contraindications
to local anesthetics and/or nail surgery. Adequate anesthesia,
hemostasis, and sterile technique are prerequisites to surgery.
The nail folds are loosened from the nail plate, and nail bed
and nail plate attachments are freed with a nail elevator. The
diseased nail plate, including a margin of normal-appearing
nail, is cut with an English nail splitter or a heavy-duty nail
nipper and removed with forceps. Hemostasis is achieved by
topical application of Monsel's solution. The digit is wrapped,
and postoperative care is continued until the pain and exudation
have stopped. Analgesics are helpful for the first few days.
Simple nail trimming is useful for managing onycholysis. It
is performed with a heavy-duty nail nipper at the most proximal
part of the diseased nail plate; no anesthesia is administered.
Primary onychomycosis and secondary onychomycosis due to
Candida species are the most frequent indications, but trimming is also useful for the management of onycholysis due to
dermatophytic and nondermatophytic molds.
Conclusion
Onychomycosis is a common fungal infection that, until
recently, has been difficult to treat. If left untreated, it may
eventually lead to total destruction of the nail plate. The clinical
manifestations of the infection have both physical and psychological consequences for the patient. It is essential to make
an accurate diagnosis before instituting systemic therapy for
onychomycosis. Examination of a specimen with use of a KOH
preparation and culture constitute the diagnostic gold standards.
Treatment includes a combination of topical therapy, surgical
or chemical nail avulsion, and systemic therapy. The systemic
agents fluconazole, itraconazole, and terbinafine are now being
administered with great success. Of these newer antifungals,
itraconazole and terbinafine have been approved by the FDA
for the treatment of onychomycosis. The higher cure rates and
shorter courses oftreatment associated with this new generation
of antifungal drugs may improve patient compliance, produce
more favorable therapeutic outcomes, and reduce relapse rates.
References
1. Johnson M-LT, Burdick AE, Johnson KG, et al. Prevalence, morbidity
and cost of dermatological diseases. J Invest Dermatol 1979; 73(suppl):
395-401.
2. Roberts DT. Prevalence of dermatophyte onychomycosis in the United
Kingdom: results of an omnibus survey. Br J Dermatol 1992; 126(suppl
39):23-7.
em
1996;23 (August)
3. Zaias N. Onychomycosis. Dermatol Clin 1985;3:445-60.
4. Barranco V, ed. New approaches to the diagnosis and management of
onychomycosis. Int J Dermatol 1994;33:292-9.
5. Conant MA. The AIDS epidemic. JAm Acad Dermatol 1994;3 1(suppl):
S47-50.
6. Cohen J, Scher R, Pappert A. The nail and fungus infections. In: Elewski
B, ed. Cutaneous fungal infections. New York: Igaku-Shoin, 1992:
106-23.
7. Clayton YM. Clinical and mycological diagnostic aspects of onychomycoses and dermatomycoses. Clin Exp Dermatol 1992; 17(suppl 1):
37-40.
8. Andre J, Achten G. Onychomycosis. Int J Dermatol 1987;26:481-90.
9. Summerbell RC, Kane J, Krajden S. Onychomycosis, tinea pedis, and
tinea manuum caused by non-dermatophytic filamentous fungi. Mycoses
1989;32:609-19.
10. Greer DL. Etiology of onychomycosis: review of the literature. Presented
at: Issues in the modem management of onychomycosis: new approaches to diagnosis and therapy held on 1-2 April, 1993 in Monte
Carlo.
11. Willemsen M. Changing patterns in superficial infections: focus on onychomycosis. J Eur Acad Dermatol VenereoI1993;2:S6-11.
12. Brody N. Cutaneous fungal infections: innovative treatment schedules with
systemic agents. Int J Dermatol 1995; 34:284-9.
13. Kotrajaras R, Chongsathein S, Rojanavanich V, Buddhavudhikrai P, Viriyayadhakorn S. Hendersonula toruloidea infection in Thailand. Int J
DermatoI1988;27:391-5.
14. Daniel CR III. Tinea unguium. J Miss State Med Assoc 1986;27:295-6.
15. Zaias N, Tosti A, Rebell G, et al. Autosomal dominant pattern of distal
subungual onychomycosis caused by Trichophyton rubrum. J Am Acad
DermatoI1996;34:302-4.
16. Dompmartin D, Dompmartin A, Deluo1 AM, Grosshans E, Coulaud JP.
Onychomycosis and AIDS: clinical and laboratory findings in 62 patients. Int J Dermatol 1990;29:337-9.
17. Chander J, Chakrabarti A, Sharma A, Saini JS, Panigarhi D. Evaluation
of calcofluor staining in the diagnosis of fungal corneal ulcer. Mycoses
1993;36:243-5.
18. Crounse RG. Human pharmacology of griseofulvin: the effect of fat intake
on gastrointestinal absorption. J Invest Dermatol 1961;37:529-33.
19. Faergemann J, Maibach H. Griseofulvin and ketoconazole in dermatology.
Semin Dermatol 1983;2:262-69.
20. Lin C-C, Magat J, Chang R, McGlotten J, Symchowicz S. Absorption,
metabolism and excretion of C-griseofulvin in man. J Pharmacol Exp
Ther 1973; 187:415-22.
21. Zurcher K, Krebs A, eds. Cutaneous drug reactions. Basel, Switzerland:
Karger, 1992:54-105.
22. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an overview. Part
I. J Am Acad Dermatol 1994; 30:677 -98.
23. Korting HC, Schafer-Korting M. Is tinea unguium still widely incurable?
A review three decades after the introduction of griseofulvin. Arch
Dermatol 1992; 128:243-8.
24. Heel RC, Brogden RN, Carmine A, Morley PA, Speight TM, Avery GS.
Ketoconazole: a review of its therapeutic efficacy in superficial and
systemic fungal infections. Drugs 1982;23:1-36.
25. Clissold SP. Safety in clinical practice. In: Jones HE, ed. Ketoconazole
today. Auckland, New Zealand: ADIS Press, 1990:1673.
26. Lewis JH, Zimmerman HJ, Benson GD, Ishak KG. Hepatic injury associated with ketoconazole therapy: analysis of 33 cases. Gastroenterology
1984; 86:503-13.
27. Wingard JR, Merz WG, Rinaldi MG, Johnson TR, Karp JE. Increase in
Candida krusei infection among patients with bone marrow transplantation and neutropenia treated prophylactically with fluconazole. N Engl
J Med 1991; 325: 1274-7.
28. Goodman JR, Winston DJ, Greenfield RA, et al. A controlled trial of
fluconazole to prevent fungal infections in patients undergoing bone
marrow transplantation. N Engl J Med 1992;326:845-51.
em
1996;23 (August)
Treatment of Onychomycosis
29. Coldiron B. Recalcitrant onychomycosis of the toenails successfully
treated with fluconazole. Arch Dermatol 1992; 128:909-10.
30. Kuokkanen K, Alava S. Fluconazole in the treatment of onychomycosis
caused by dermatophytes. Journal of Dermatological Treatment 1992;
3:115-7.
31. Grant SM, Clissold SP. Fluconazole: a review of its pharmacodynamic
and pharmacokinetic properties, and therapeutic potential in superficial
and systemic mycoses. Drugs 1990;39:877-916.
32. Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, Kuhn
JG. Pharmacokinetics of itraconazole following oral administration to
normal volunteers. Antimicrob Agents Chemother 1988;32:1310-3.
33. Cauwenbergh G, DegreefH, Heykants J, Woestenborghs R, Van Rooy P,
Haeverans K. Pharmacokinetic profile of orally administered itraconazole in human skin. J Am Acad Dermatol 1988; 18:263-8.
34. Matthieu L, De Doncker P, Cauwenbergh G, et al. Itraconazole penetrates
the nail via the nail matrix and the nail bed-an investigation in onychomycosis. Clin Exp Dermatol1991; 16:374-6.
35. Willemsen M, De Doncker P, Willems J, et al. Posttreatment itraconazole
levels in the nail: new implications for treatment in onychomycosis. J
Am Acad DermatoI1992;26:731-5.
36. De Doncker P, Decroix J, Pierard GE, et al. Antifungal pulse therapy for
onychomycosis: a pharmacokinetic and pharmacodynamic investigation
37.
38.
39.
40.
41.
42.
43.
313
of monthly cycles of l-week pulse therapy with itraconazole. Arch
Dermatol 1996; 132:34-41.
Degreef HJ, De Doncker PRG. Current therapy of dermatophytosis. JAm
Acad DermatoI1994;31(suppl):S25-30.
Lever L, Dykes P, Thomas R, et al. How orally administered terbinafine
reaches the stratum corneum. Journal of Dermatological Treatment
1990; 1:23-5.
Van der Schroeff JG, Cirkel PKS, Crijns MB, et al. A randomized treatment duration-finding study of terbinafine in onychomycosis. Br J
Dermatol 1992; 126(suppl 39):36-9.
Haneke E, Tausch I, Brautigam M, Weidinger G, Welzel D, the LAGOS
III Study Group. Short-duration treatment of fingernail dermatophytosis:
a randomized, double-blind study with terbinafine and griseofulvin. J
Am Acad DermatoI1995;32:72-7.
Kovacs MJ, Alshammari S, Guenther L, Bourcier M. Neutropenia and
pancytopenia associated with oral terbinafine. J Am Acad Dermatol
1994; 31:806.
Baran JR, Hay R. Partial surgical avulsion of the nail in onychomycosis.
Clin Exp Dermatol 1985; 10:413-8.
Rollman 0, Johansson S. Hendersonula toruloidea infection: successful
response of onychomycosis to nail avulsion and topical ciclopiroxolamine. Acta Derm Venereol (Stockh) 1987;67:506-10.