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Office Practice–Based Confirmation of Onychomycosis
A US Nationwide Prospective Survey
Boni E. Elewski, MD;
James Leyden, MD;
Michael G. Rinaldi, PhD;
Ercem Atillasoy, MD
Arch Intern Med. 2002;162:2133-2138.
ABSTRACT
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Background Onychomycosis is sufficiently prevalent to be seen and treated by primary
care physicians. The diagnosis of onychomycosis is most often confirmed from
nail specimens by microscopy and fungal culture done at a central laboratory;
these are relatively expensive tests with a turnaround time of a month or
more. This study was conducted (1) to evaluate the use of in-office dermatophyte
test medium (DTM) culture, and (2) to determine the epidemiology of onychomycosis
in a large, nationwide sample of patients who were not participants in a clinical
trial.
Methods A nationwide sample of primary care physicians and podiatrists enrolled
670 patients with clinical signs of toenail onychomycosis. Dermatophyte test
medium cultures were performed in the office and the results were compared
with fungal cultures performed by a central laboratory.
Results Central laboratory fungal cultures were positive in 44% (n = 297) of
patients and DTM cultures in 51% (n = 345). Dermatophytes accounted for 93%
of the confirmed infections and nondermatophyte molds the rest. In the 617
patients with paired dermatophyte test medium and laboratory fungal culture
results, the 2 tests were in agreement (both positive or both negative) in
68% of cases ( , 0.37; asymptotic SE, 0.04; 95% confidence interval,
0.299-0.441).
Conclusions A DTM culture is a relatively rapid, easy, and inexpensive method to
confirm dermatophyte infections in patients with signs of onychomycosis in
the primary care setting. Because the available drugs for treating onychomycosis
are effective against all dermatophyte species, the confirmation of dermatophyte
infection, without further identification of genus and species, is sufficient
evidence to begin treatment.
INTRODUCTION
ONYCHOMYCOSIS, fungal infection of the nail bed, is a common condition
seen by primary care physicians. Estimates of its prevalence in adults range
from 2% to 8% in temperate developed countries1 to
as high as 14% in US patients identified in the primary medical care setting
with other complaints.2 Dermatophytic molds
are the predominant pathogens in onychomycosis, responsible for more than
90% of the infections.3-7 Candida species and nondermatophyte molds account for the
remaining proportion of isolates in epidemiological studies, though the role
of nondermatophyte organisms as sole pathogens in toenail onychomycosis has
not been fully established.8
A newer generation of safe, effective oral agents, represented at present
by itraconazole and terbinafine, makes onychomycosis treatable in the primary
care setting with no need for referral when the diagnosis is secure. In clinical
trials, these new agents have resulted in high clinical and mycological cure
rates in patients with laboratory-confirmed dermatophyte onychomycosis.9-11
Onychomycosis can frequently be diagnosed accurately on the basis of
history and clinical appearance, but objective confirmation of the diagnosis
is generally recommended, in part, because selective treatment is more cost-effective
than treating all patients with nail "problems."12 The
differential diagnosis of onychomycosis includes many conditions, including
psoriasis, nail trauma, contact irritants, lichen planus, neoplasms, and bacterial
infection with Pseudomonas aeruginosa or Proteus mirabilis.13-14 While
a definitive diagnosis of onychomycosis requires confirming the presence of
a dermatophyte, identification of genus and species is of less importance.
All dermatophyte pathogens are sensitive to the oral antifungals approved
for treatment of onychomycosis.2 Candida infections account for a very small proportion of onychomycosis
cases and are not discussed in this article.
Traditionally, in dermatologic practice, the diagnosis of onychomycosis
is confirmed by direct microscopic examination of a specimen prepared with
potassium hydroxide (KOH) to detect fungal elements and mycologic culture
in a central laboratory, and to identify the specific pathogen and confirm
that it is viable.3 The KOH test can indicate
the presence or absence of fungal elements. It does not give information as
to the viability or etiology of any fungal elements detetected. These techniques
are specific, but their sensitivity is unknown, with reported culture recovery
rates from nail specimens averaging about 50%.15 Also,
results of laboratory fungal culture are usually not available for 4 to 6
weeks. The results of KOH testing are useful to the primary care physician,
but the preparation of nail specimens is technically difficult because of
the quantity of keratin that it contains, and the interpretation of the results
requires experience to be done correctly. Consequently, it is generally better
to submit a specimen for testing rather than perform it in the office practice.
A KOH result indicating septate hyphae together with a clinical diagnosis
of onychomycosis may frequently be used to start treatment because of the
high likelihood that the infecting pathogen is a dermatophyte, but the disadvantages
of the standard diagnostic tests may be sufficient to dissuade clinicians
from obtaining them before treating.14 On the
other hand, reliance on diagnostic methods with limited sensitivity could
lead to undertreatment of onychomycosis.
A rapid, easily performed, accurate, low-cost confirmatory test is needed.
The present study was conducted to evaluate one such method—the dermatophyte
test medium (DTM) culture. The culture medium was originally described by
Taplin et al16 as a test for the presence of
dermatophytic molds. A DTM culture is less expensive than a fungal culture
at a central laboratory, and results are available much sooner, usually within
3 to 7 days. Dermatophyte growth is indicated by a change in the color of
the DTM, from yellow to red in response to alkaline metabolites that result
from growth of dermatophytes.16 The majority
of DTM cultures can be identified within 1 week, and fewer than 2% of cultures
require 2 weeks to show a change in color.16 The
DTM contains gentamicin and chlorotetracycline to inhibit bacterial growth
and cycloheximide to inhibit growth of saprophytic fungi. Although it does
not identify specific organisms, a positive DTM culture confirms the presence
of dermatophyte pathogens, which account for the vast majority of cases of
onychomycosis.3-5 Taplin
et al16 correctly identified dermatophytes
by DTM color change alone in 97% of 1400 fungal cultures evaluated.16 Dermatophyte test medium culture systems are commercially
available that appear suitable for use in the general-practice office setting.
A DTM culture together with KOH evaluation would be expected to provide accurate
and timely guidance for the treatment of onychomycosis. Given the potential
benefits of DTM culture to confirm a clinical diagnosis of onychomycosis,
the test is underused and may be viewed as inferior to more formal laboratory
fungal culture methods such as Sabouraud dextrose agar.17
The primary aim of the present study was to compare the sensitivity
of office-based DTM culture in the hands of primary care physicians and podiatrists
to that of fungal culture in a central mycology laboratory. Because this study
included a large patient population distributed throughout the United States,
a secondary aim was investigation of the frequency of different causative
pathogens and their regional distribution, and clinical patterns of infection.
To our knowledge, this is the largest prospective epidemiological survey conducted
in patients presenting with signs and symptoms of onychomycosis. The study
population may well be more representative than patients treated in clinical
trials with restrictive inclusion and exclusion criteria.
METHODS
SUBJECTS AND STUDY DESIGN
A total of 149 US office-based and clinic-based primary care physicians
and podiatrists were recruited for this study. The sample was stratified by
specialty to ensure approximately equal representation of primary care physicians
and podiatrists, and to represent proportionally the geographic regions of
the United States. Each physician was asked to enroll 5 or more patients,
aged 18 years or older, with signs and symptoms of onychomycosis. Patients
were excluded from the study if they had received oral antifungal therapy
within the previous 90 days and any topical antifungal agent within the previous
30 days. Patient enrollment began on July 1, 2000, and data collection was
completed May 5, 2001.
At the initial office visit, the primary care or podiatric physician
explained the nature of the study, obtained written informed consent, collected
demographic information and a relevant medical history, and obtained a specimen
from the toenail bed for mycologic evaluation. Specimens were divided and
DTM (ACU-DTM; Acuderm, Inc, Fort Lauderdale, Fla) cultures were performed
in the office on part of the specimen. The remaining specimen was sent to
the University of Texas Fungus Testing Laboratory at the University of Texas
Health Science Center, San Antonio, for KOH evaluation and Sabouraud dextrose
agar culture. The overall study design, disposition of specimens, and testing
procedures are shown in Figure 1.
The Western Institutional Review Board, Olympia, Wash, approved the study
protocol and all study materials.
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Infection confirmation survey design and procedures. DTM indicates
dermatophyte test medium; KOH, potassium hydroxide; plus sign, positive; and
minus sign, negative.
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Results of DTM culture were available in 2 weeks or less, and clinicians
were informed of the culture results from the central laboratory 4 to 6 weeks
after the sample was obtained. The initiation of antifungal therapy and the
selection of a treatment were at the physician's discretion. If the KOH test
at the central laboratory was positive for fungal elements, but the culture
result was negative, regardless of the DTM result, physicians were asked to
obtain a second sample for a repeat culture. The study protocol excluded patients
who were being treated from being retested. The primary analyses conducted
in this study were (1) a paired comparison of in-office DTM culture and central
laboratory fungal culture for each patient having results from both methods,
and (2) a tabulation of the culture results and the infectious organisms that
were identified.
MYCOLOGICAL EVALUATIONS
Physicians were supplied with DTM culture kits and a videotape to instruct
them on how to obtain the nail bed sample and inoculate the DTM tube. The
specimen was obtained after cleaning the surface of the nail plate with an
alcohol swab and cutting the nail plate with a sterilized curette or clipper
to expose the nail bed. To increase the likelihood of detecting any dermatophytes
that might be present, samples consisting of pieces of subungual debris from
the proximal portion of the nail bed underneath the nail plate were obtained
using a probe or curette. The specimen was divided, one piece was pressed
lightly onto the culture medium in the DTM tube, and the cap was loosely applied
to avoid sealing the tube off from the atmosphere. The specimen was incubated
at room temperature for up to 2 weeks. The physicians checked the DTM culture
daily for a change of color, which was interpreted as a positive result. False-positive
results were avoided by examining the medium for the growth of white colonies
typical of dermatophytes and by completing all readings by 14 days, after
which time overgrowth by nondermatophyte organisms may occur. Patients with
a negative laboratory culture, regardless of the DTM result, were asked to
submit a second specimen for retesting.
The Fungus Testing Laboratory performed its evaluations using well-established
methods. Fungal culture was carried out using 2 media: 1 containing cycloheximide
to inhibit nondermatophyte pathogens, and 1 cycloheximide-free medium, Sabouraud
dextrose agar, to allow the growth of yeasts and nondermatophyte fungi (other
pathogens that can cause onychomycosis). Lack of growth of reproductive colonies
within 4 to 6 weeks confirmed a negative fungal culture.
STATISTICAL ANALYSIS
The primary objective of this study was to determine the utility of
DTM culturing to confirm a clinical diagnosis of onychomycosis. For evaluation
of paired DTM and fungal culture results, positive DTM results were noted
to agree with cultures that grew a dermatophyte organism (ie, Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum). Agreement
of the DTM and culture methods was estimated using the statistic.18 The asymptotic SE and 95% confidence interval for
the coefficient were calculated using SAS software (SAS Institute
Inc, Cary, NC).19 Cultures of nondermatophyte
molds were included in the epidemiological results, but were noted as a "negative"
result for comparison to the corresponding DTM culture result because the
organism identified was not a dermatophyte.
RESULTS
One hundred forty-nine physicians enrolled at least 1 patient in the
study. Eighty of the practitioners (54%) were podiatrists and the remaining
69 (46%) were primary care physicians. A total of 670 patients with signs
and symptoms suggestive of onychomycosis were enrolled, 369 by podiatrists
and 301 by primary care physicians. The comparison of in-office DTM culture
and fungal culture is based on the 617 patients (92%) for whom complete data
consisting of paired DTM and laboratory culture results were available by
the cutoff for data collection. All 670 patients were included in the compilation
of demographic and epidemiologic results.
Men and women were about equally represented. A majority of patients
(73%) were white. Of note, 45% of the patients were 65 years or older and
17% were diabetic. A median of 4.8 toenails were affected, and 60% of patients
had involvement of both feet. A similar average number of toes were affected
on the right and left foot, 2.5 vs 2.4. Ten percent also had clinical evidence
of fingernail onychomycosis and 29% had symptoms of tinea pedis (Table 1). Fingernail involvement and the
presence of tinea pedis were clinical observations only, and were not confirmed
by DTM or fungal culture.
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Table 1. Demographic and Clinical Characteristics of 670 Patients Enrolled
in the Infection Confirmation Survey
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Central laboratory culture results were positive in 44% (n = 297) of
the patients. Three dermatophyte species (T rubrum, T mentagrophytes, and E floccosum)
accounted for 93% of the positive cultures (Table 2). Nondermatophyte molds accounted for the remainder of isolates,
and no Candida infections were identified. No regional
variations in the causative organisms of onychomycosis were found.
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Table 2. Pathogens Identified by Central Laboratory Culture in 297
Patients With Onychomycosis Symptoms and Positive Cultures
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Dermatophyte test medium and laboratory cultures were in agreement (both
positive [n = 206] or both negative [n = 214]) in 68% of the 617 patients
for whom paired results were available at the time of data analysis, with
a coefficient of 0.37 (asymptotic SE, 0.04; 95% confidence interval,
0.299-0.441) (Table 3). Overall,
the DTM cultures were positive in more cases than the laboratory cultures—51%
(n = 345) vs 44% (n = 297).
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Table 3. Comparison of In-Office DTM Culture and Central Laboratory
Mycological Culture (N = 617)*
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Men had positive results by both culture methods more often than women
(men, 64% for DTM and 59% for culture; women, 48% and 34%, respectively),
but the differences were not significant. None of the other demographic variables
were associated with the likelihood of a positive DTM or central laboratory
culture result.
Laboratory cultures were negative in 342 patients. A second specimen
was requested from these patients for retesting, and laboratory results were
available for 105 patients at the time of data analysis. According to the
study protocol, individuals receiving oral antifungal agents within the previous
90 days, or topical antifungal agents within the previous 30 days would not
be included in the retest data. The retest culture was positive in 23 patients,
22% of the total who were retested. Of these, 10 were in patients who had
a negative DTM culture, and 12 were in patients whose DTM culture was initially
positive (Table 4). One retest
culture grew a nondermatophyte mold. Retested patients were significantly
more likely to be female than male (58% vs 42%; P>.05),
but otherwise did not vary from the demographic profile of the entire population.
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Table 4. Patients With Completed DTM and Central Laboratory Culture
Results Who Were Retested (n = 105)*
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COMMENT
This large, prospective epidemiological study was based on a nationwide
sample of patients in a community practice setting with signs and symptoms
of onychomycosis. It is the largest study of this type to establish the concordance
of DTM culture with central laboratory fungal culture on selective media for
confirmation of a clinical diagnosis of onychomycosis. Central laboratory
and DTM cultures were in agreement in 68% of the patients for whom paired
results were available. Overall, the DTM cultures were positive in 51% of
patients and central laboratory cultures in 44%. The coefficient of
0.37, a measure of agreement between multiple tests, indicates a fair degree
of agreement beyond that which would occur by chance.18 The
investigation also confirmed dermatophytes as the primary pathogen in onychomycosis,
accounting for 93% of infections, with nondermatophyte molds accounting for
the rest. No cases of Candida onychomycosis were
identified in the central laboratory cultures. In both the original cultures
and the retested specimens, about 10% of the specimens that were DTM negative
were positive by fungal culture, perhaps reflecting the longer time available
for growth in cultures at the central laboratory.
Treatment for onychomycosis ideally should be based on a positive KOH
test and a DTM or fungal culture showing recovery of a dermatophyte or other
causative organism together with a clinical diagnosis including distally thickened
toenails and, possibly, tinea pedis. This practice is based on the assumption
that the mycological tests have a high positive predictive value in patients
who have clinical signs of onychomycosis. In the present study, 403 patients
(60%) with onychomycosis symptoms had positive results on either the laboratory
or DTM culture—a recovery rate consistent with an earlier epidemiological
study.20 Based on these results, fungal culture
identified a maximum of 74% of true positives (297/403), while DTM culture
identified 86% (345/403). The repeat cultures obtained in 105 patients suggest
that negative results are not completely reliable; 22% (23/105) of patients
with initially negative laboratory cultures were found to be positive for
a dermatophyte on repeat culture. One retest culture was a nondermatophyte.
If the retest results for those patients who were initially negative by both
culture methods are included in the estimate of total true positives, the
projected number of infected patients would be 423 (403 + [10/105 x
214] = 423). Following this adjustment, DTM culture identified 82% of the
infections (345/423), and laboratory culture identified 70% (297/423). If
DTM or fungal culture are negative when the clinical evidence strongly suggests
onychomycosis, repeat fungal culture may prove helpful. In their description
of the DTM culture method, Taplin et al16 reported
that in 610 paired cultures, 211 fungal cultures (35%) and 240 DTM cultures
(39%) were positive for dermatophytes. These authors concluded that the DTM
culture offers a higher recovery rate than the laboratory fungal culture,
and that an advantage of the DTM culture was its ability to inhibit growth
of bacteria and saprophytic contaminants.16
In this study, lack of agreement occurred most frequently in specimens
with a positive DTM result and a negative fungal culture even though KOH results
were positive for fungal elements (134/617 patients; 21.7%). In the patients
in this group for whom retest data are available, approximately 11% with negative
DTM results converted to a positive fungal culture result when retested (12/105).
There are a number of reasons for obtaining positive KOH tests and negative
cultures. The specimen submitted was insufficient for adequate culture, and
when divided, there may be sufficient fungal elements for detection by KOH
and perhaps DTM, but not by culture. Bacteria may also be present in the patient
specimen. Although selective media are used to reduce or eliminate bacterial
contamination, the bacteria present may overgrow and prevent the growth of
fungi. Other environmental fungi may be present that grow more rapidly than
dermatophytes and the other molds or fungi expected from this type of specimen.
Finally, there may be no viable fungal elements in the specimen. Also, genus
and species cannot be identified in culture if the organism produces sterile
hyphae and not conidia, which are required for reproduction. Regardless of
the culture method, the diagnostic yield can be improved by obtaining a culture
specimen from the subungual nail debris rather than from the nail bed or nail
plate.21-22 The specimen should
be obtained by trimming the nail back to reveal the nail bed and then scraping
away the subungual debris with a curette, proximally, as close to the nail
cuticle as the patient finds tolerable.
The observation that dermatophytes are the causative pathogen in more
than 90% of 277 patients with positive central laboratory cultures is consistent
with earlier reports. Kemna and Elewski5 identified
dermatophyte isolates in 82% of culture-positive onychomycosis specimens from
16 states, obtained from a variety of clinical and research sources. Dermatophytes
represented 91.3% of nail pathogens identified in the screening phase of the
US Multicenter Onychomycosis Study of Terbinafine.20 Ghannoum
et al2 identified dermatophytes in 60% of culture-positive
nail samples obtained from patients visiting a dermatologist for reasons other
than onychomycosis—the lowest prevalence identified in a recent large-scale
study. Because of lack of repeat follow-up cultures, however, the etiologic
status of the nondermatophytes that were isolated could not be determined,
and the authors concluded that most were likely to be contaminants.2 In another large study, Gupta et al23 found
that 1137 (45.4%) patients out of 2505 with toenail abnormalities had onychomycosis
confirmed by mycological culture. Of those with a positive culture, dermatophytes
were isolated in 90.5%. While these studies were large, they did not enroll
and evaluate nail specimens only from patients with a presumptive diagnosis
of onychomycosis as our study did.
This large-scale study of patients with clinical signs of onychomycosis
in the community practice setting confirms that dermatophytes are the primary
cause of nail symptoms in patients for whom a cause can be identified. Dermatophyte
test medium culture is an efficient, relatively rapid, inexpensive method
to establish the diagnosis of dermatophyte infection and can confirm a presumptive
diagnosis of onychomycosis in a large proportion of cases, with results available
before infection can be confirmed by laboratory mycological culture. Among
our sample of patients with symptoms of onychomycosis, fungal cultures were
positive in 44% and DTM cultures in 51%. These figure support the widely quoted
statistic that culture-confirmed onychomycosis represents approximately 50%
of all nail disease, which originated with a study published in 1968,24 but appears unchanged to the present day.5, 15, 23 Estimates of the proportion
of patients with clinical nail problems in whom a combination of the 2 standard
techniques can confirm a diagnosis of onychomycosis range from about 60% to
65%12, 25 to as high as 80%.26 In this study, 60% of patients had dermatophyte-confirmed
onychomycosis by either DTM or central laboratory culture.
Onychomycosis should be a concern of the primary care physician, and
not only because its prevalence in the community makes it likely to be encountered
in daily practice. Recent research has demonstrated the previously underestimated
morbidity associated with onychomycosis. Extensive toenail infections can
be painful, leading to difficulty standing or walking, limitations on wearing
shoes, and consequent limitation of physical activity.27 Effects
on overall function and quality of life have been documented, including reduced
mobility and social activity in the elderly, reduced participation in leisure
activities, and embarrassment or self-consciousness in social situations.27-29 In diabetic patients,
onychomycosis was associated with a 3-fold risk in secondary bacterial infections,
such as erysipelas, gangrene, and foot ulcers.30
Although the present study was not designed as an economic analysis,
DTM is a relatively low-cost method to confirm a diagnosis of onychomycosis
and is reimbursable. The cost of a DTM culture in this study was approximately
$1 per test compared with $25 for each fungal culture performed at the central
laboratory. Managed care providers often require a positive culture to reimburse
treatment of onychomycosis. Dermatophyte test medium cultures satisfy that
requirement and provide an economical way to assist in accurately confirming
dermatophyte involvement to guide an expensive therapeutic course for physicians
who would otherwise either treat empirically, or avoid treating onychomycosis
because of perceived difficulties in confirming a clinical diagnosis. If the
cost, delay, and limited accuracy associated with current diagnostic methods
are a barrier to treatment of onychomycosis, DTM cultures provide a way around
that barrier.
AUTHOR INFORMATION
Accepted for publication February 7, 2002.
This study was funded by an unrestricted grant from Novartis Pharmaceuticals
Corporation, East Hanover, NJ.
Corresponding author: Boni E. Elewski, MD, Department of Dermatology,
University of Alabama at Birmingham, EFH 414, 1530 Third Ave South, Birmingham,
AL 35294.
From the Department of Dermatology, University of Alabama, Birmingham
(Dr Elewski); the Department of Dermatology, University of Pennsylvania Hospital,
Philadelphia (Dr Leyden); the Department of Pathology, University of Texas
Health Science Center at San Antonio (Dr Rinaldi); and the Departments of
Dermatology, Thomas Jefferson University, Philadelphia, Pa, and Yale University
School of Medicine, New Haven, Conn. (Dr Atillasoy). Dr Atillasoy was formerly
a medical director of Novartis Pharmaceutical Corporation, East Hanover, NJ.
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