Professional Documents
Culture Documents
DERMATOLOGIC THERAPY
ISSN 1396-0296
230..242
ABSTRACT: Candidiasis, an often encountered oral disease, has been increasing in frequency. Most
commonly caused by the overgrowth of Candida albicans, oral candidiasis can be divided into several
categories including acute and chronic forms, and angular cheilitis. Risk factors for the development of
oral candidiasis include immunosuppression, wearing of dentures, pharmacotherapeutics, smoking,
infancy and old age, endocrine dysfunction, and decreased salivation. Oral candidiasis may be asymptomatic. More frequently, however, it is physically uncomfortable, and the patient may complain of
burning mouth, dysgeusia, dysphagia, anorexia, and weight loss, leading to nutritional deficiency and
impaired quality of life. A plethora of antifungal treatments are available. The overall prognosis of oral
candidiasis is good, and rarely is the condition life threatening with invasive or recalcitrant disease.
KEYWORDS: angular cheilitis, angular cheilosis, candidosis, oral candidiasis, thrush
Introduction
Oral candidiasis, the most common fungal infection in humans, has resurged in frequency
throughout the United States. This has been attributed to the increasing prevalence of human
immunodeficiency virus (HIV), administration of
corticosteroids and a variety of other immunosuppressive medications, expanded use of
broad-spectrum antibiotics, an enlarging elderly
population with oral prostheses, and an increase
in obesity and resultant diabetes mellitus (1).
Although oral candidiasis poses a very low mortality risk, it can be physically uncomfortable, and the
patient may complain of burning mouth, dysgeusia, dysphagia, anorexia, and weight loss, leading to
nutritional deficiency and impaired quality of life.
In the immunocompromised host, there is a risk of
tracheal or esophageal extension, which may lead
to painful erosions. Systemic dissemination and
fungemia from oral candidiasis, although rare, can
occur in susceptible and debilitated hosts.
Address correspondence and reprint requests to: Victoria
Sharon, MD, Department of Dermatology, University of
California, Davis, 3301 C Street, Suite 1400, Sacramento, CA
95816, or email: victoria.sharon@ucdmc.ucdavis.edu.
230
Risk factors
Any circumstance predisposing an individual to
increased oral candidal carriage presents a potential risk for developing active infection, particularly
in the setting of transient immunosuppression.
Risk factors for active infection can be classified
into endogenous and exogenous components.
Endogenous factors include infancy and old age,
pregnancy, immunocompromised states, diabetes
mellitus, other endocrinopathies resulting in
chronically elevated serum glucose, Sjgren
syndrome-induced xerostomia, vitamin deficiencies, and poor overall health (7). Exogenous risk
factors encompass poor nutritional diet, the use
of specified pharmacotherapeutics, cigarette
smoking, ill-fitting oral prostheses, chronic local
irritation or trauma, local radiation, and malignancy with chemotherapy treatment (5,15). These
risk factors are summarized in Table 1, and discussed in further detail below.
Extreme ages of life confer decreased immunity,
and hence an increased risk for the growth of
opportunistic pathogens. Diminished saliva production has been hypothesized to promote the
growth of Candida by decreasing clearance of the
fungus in areas of colonization (5). Saliva not only
dilutes and clears candidal species from the oral
cavity, but via its proteins, among which are
lysozyme, lactoferrin, sialoperoxidase, and antiCandida antibodies, discourages proliferation
(5,7). Transient immunosuppression and immunodeficiency syndromes predispose to active infection secondary to an inability of the individual to
mount an innate or adaptive immune response.
Impaired phagocytosis, oxidative destruction,
cytokine production, or antibody formation can
lead to impaired clearance of Candida.
In patients with HIV, Candida is the most frequent oral opportunistic infection. Infection typically occurs at times of decreased CD4 counts,
although it has been reported to arise at all stages
of HIV infection (15,18). Although asymptomatic
candidal carriage has been shown by some to be
increased at all stages of HIV infection, symptomatic candidiasis predominantly occurs at CD4
counts below 500 cells/mm3, with a larger increase
seen below 200 cells/mm3 (19). Symptomatic candidiasis has been found in up to 90% of patients
with HIV, half of whom develop acquired immunodeficiency syndrome within 3 years (20). Although
oral candidal infections are primarily a nuisance in
immunocompetent individuals, they can lead to
more worrisome complications in patients with
HIV, such as esophageal candidiasis (1). It is there-
231
growth (7,22,23). The use of antibiotic mouthwashes may also increase the risk of active infection. Anticholinergics may cause xerostomia
leading to diminished salivary flow and impaired
clearance of candidal species. Oral or inhaled corticosteroids and other immunosuppressive medications, including chemotherapy in the setting
of malignancy, impair the ability of the immune
system to battle candidal antigens.
Smoking has been associated with increased
candidal carriage in some studies, but not in others
(3,24). Its role as an etiologic agent in predisposing
an individual to active Candida infection is controversial, with several studies clearly showing an
increased risk of active infection in particular
immunosuppressed populations (25).
Chronic local irritation, poorly fitting oral prostheses, epithelial dysplasia, prior local radiation,
and oral malignancy disrupt the intact epithelium,
resulting in a damaged epithelial barrier, facilitating candidal invasion of the stratum corneum and
stratum spinosum (26).
Classification
Candidiasis of the oral cavity can be broadly categorized as primary or secondary. The former
describes candidal infections only involving the
oral or perioral tissues, whereas the latter characterizes systemic candidiasis that secondarily
involves the oral cavity (1,7). Primary oral candidiasis has been traditionally subdivided into acute
pseudomembranous candidiasis, acute atrophic
candidiasis, chronic hyperplastic candidiasis,
chronic atrophic candidiasis, median rhomboid
glossitis, angular cheilitis, and linear gingival
erythema (FIG. 1) (5).
232
Primary oral
candidiasis
Acute
pseudomembranous
Thrush
Acute
atrophic
Antibiotic sore
mouth
Chronic
atrophic
Chronic
hyperplastic
Denture stomatitis
Candidal
leukoplakia
Candida associated
Actinic cheilitis
Median rhomboid
glossitis
Linear gingival
erythema
Acute atrophic candidiasis (erythematous candidiasis, antibiotic sore mouth) may be associated with
a burning oral sensation, and the patient may complain of a sore tongue or lip (1,5). Erythematous
candidiasis involving the palate is quite common,
particularly in HIV-positive patients, and is often
overlooked (FIG. 3) (1,7). Erythematous patches
may also be found on the buccal mucosa, and less
commonly the mid-posterior dorsal tongue
(median rhomboid glossitis), which can appear
bright red because of loss of the filiform papillae.
Erythematous candidiasis can arise after the white
pseudomembranes of thrush are shed, or may
alternatively arise de novo (1,28). It has been postulated that acute pseudomembranous candidiasis
and erythematous candidiasis represent a continuum of the same pathological process (1).
The differential diagnosis includes atrophic
lichen planus, oral mucositis, and nutritional deficiencies of vitamin B12, folate, and ferritin (5).
Chronic hyperplastic candidiasis
Chronic hyperplastic candidiasis has been referred
to as candidal leukoplakia, owing to the possibility
of progression to dysplasia or malignancy in some
233
234
Median rhomboid glossitis (glossal central papillary atrophy) appears clinically as a chronic, symmetric, red, elliptic or rhomboid-shaped patch on
the mid-posterior dorsal tongue anterior to the circumvallate papillae (5). On occasion, these lesions
appear exophytic (1). Biopsies of median rhomboid glossitis reveal Candida in over 80% of lesions,
and many cases resolve after treatment with
topical antifungal therapy (5). Smoking and the use
of inhaled corticosteroids are most often associated with median rhomboid glossitis.
Angular cheilitis
Angular cheilitis (perlche, angular stomatitis)
manifests as bilateral, bright red erythematous fissures at the angles of the mouth and can occur at
any age (FIG. 4). Angular cheilitis may be fostered
by both local as well as systemic factors. Angular
cheilitis has been associated with intraoral
Candida infection of the pseudomembranous or
erythematous types, cutaneous Staphylococcus or
Streptococcus infection, isolated nutritional deficiencies, particularly with vitamin B12 or iron, and
mouth breathing (5). In young children, angular
cheilitis is associated with habitual lip licking,
thumb sucking, or biting of the corners of the
mouth, whereas in older patients it occurs from
sagging at the commissures of the mouth (31).
Wrinkles or congenital excessive-angle skin folds
at the oral commissures impart an increased risk
for angular cheilitis by creating a chronic, moist,
intertriginous environment which fosters candidal
overgrowth. The long-term use of ill-fitting dentures accentuates this wrinkling by causing resorp-
235
Treatment
Diagnosis
Diagnosis of acute pseudomembranous candidiasis can be confirmed via positive Gram, methylene blue, or potassium hydroxide staining of
smears from affected tissue, which will demonstrate budding yeast and pseudohyphal elements
(5). Material for smears can be obtained by using
a no. 15 scalpel blade to gently scrape the surface
of the lesion (15). Budding yeast forms are ovoid
in shape and measure 36 mm in size, whereas
pseudohyphae are generally septate, measure
24 mm in size, and branch at 90-degree angles
adjacent to septae (43). A positive fungal culture
from an oral rinse, biopsy, or scraping will confirm
the diagnosis and is useful if candidal speciation is
desired. In the case of biopsies, fixed tissue can be
stained with routine hematoxylin and eosin to
demonstrate fungal elements. Adjunct stains on
fixed tissue to highlight these organisms include
methylene blue, periodic acid-Schiff stains, and
Grocott methenamine-silver as demonstrated in
FIG. 5.
Oral manifestations of candidiasis vary greatly.
The differential diagnosis for oral candidiasis is
broad and includes lichen planus, herpes infection, hairy leukoplakia, erythema multiforme,
pernicious anemia and other avitaminoses,
chemotherapy-related mucositis, zinc deficiency,
and pemphigus (27).
236
Oral hygiene
Treatment of oral candidiasis should begin with the
practice of good oral hygiene. This includes twice
daily brushing of the teeth and tongue, daily flossing of the teeth, and professional dental cleaning at
least every 6 months.
Patients with dentures should brush their entire
oral mucosa daily with a soft brush. Good denture
hygiene involves daily disinfection and overnight
soaking of dentures with an antiseptic agent such
as chlorhexidine gluconate (2% suspension). This
technique decreases candidal counts more than
brushing alone, as it is sometimes difficult for
brushing to remove adherent Candida from crevices of irregular denture surfaces (44). Chlorhexidine is fungicidal and helps to decrease adherence
of Candida to prosthetic or organic surfaces, and
may be used as an adjuvant to other antifungal
agents (45). After disinfecting with chlorhexidine,
the dentures should be rinsed and left to air dry
(46). Additionally, the patient should be encouraged to leave dentures out of the mouth overnight
for at least 6 hours (5,15). Chlorhexidine gluconate
(0.12%) mouth rinse may be used prophylactically
or as a supplement to topical or oral antifungal
therapy. In cases of poorly fitting dentures, a dentists intervention is necessary. Patients with xerostomia should be encouraged to drink water
frequently and suck on ice chips or sugarless lozenges to stimulate saliva production. Regular daily
Form
Adult dose
Pregnancy
risk
Gentian violet
Solution
1.5 mL BID
Nystatin
Suspension
Cream
Tablet
Lozenge
B/C
Amphotericin B
Cream
Suspension
Cream
Solution
Troche
Cream
Ointment
Oral gel
Cream
Tablet
100,000 U QID
TID-QID
100,000 U TID
100,000 U up to 5/day
7- to 14-day course
TID-QID 714 days
100 mg/mL
1%, BID-TID 34 weeks
1%, TID-QID 23 weeks
10 mg, 5/day 14 days
2%, BID 23 weeks
2%, BID 23 weeks
2%, TID-QID 23 weeks
2%, BID-TID 24 weeks
200 mg QD-BID 2 weeks
Fluconazole
Tablet
50200 mg QD or QW
Itraconazole
Capsule
Solution
Posaconazole
Suspension
100200 mg QD-TID
loading dose of 200 mg
TID 3 days
100 mg BID 1 day
followed by 100 mg
QD 13 days
For severe disease: 400 mg
BID 3 days followed by
400 mg
QD-BID 4 weeks
Clotrimazole
Miconazole
Ketoconazole
Adverse effects
Purple staining; mucosal ulceration; skin
irritation
Local skin irritation; adverse taste; nausea
and vomiting at high doses
B
C
use of saliva substitutes is recommended. Sialogogues can also be employed to increase salivary
flow (47).
Topical antifungal agents
In cases of mild candidiasis, topical antifungal
agents are the first line of therapy (1,48). Although
they often work quite well, treatment can be
unsuccessful for a variety of reasons. The need for
frequent dosing, unpleasant taste, and consequent
noncompliance, as well as short contact time
between the antifungal agent and the affected oral
tissue, contribute to treatment failures.
Gentian violet
Gentian violet, a traditional topical fungicidal
agent, was first used in the 1920s to treat oropha-
237
238
than nystatin, but are also formulated with a dextrose base and, like nystatin, increase the risk for
dental caries (15).
Clotrimazole cream should be applied to the
involved area of the oral mucosa or angles of the
mouth two to three times daily for 3 weeks. When
using the topical solution, the patient should be
instructed to swish and spit one teaspoonful three
to four times daily for 3 weeks. If the troche (10 mg)
is preferred, the patient should hold it in the mouth
with a 15- to 30-minute dissolution time five times
daily (2,48). However, frequent dosing, particularly
with the troche and solution, is associated with
poor adherence.
Clotrimazole troches (10 mg) three times daily
have been successful for the prophylaxis of oral
candidal infections in leukemic patients receiving
chemotherapy (53).
Adverse reactions are for the most part limited
to gastrointestinal upset and minor local skin
irritation.
Miconazole
Miconazole is an imidazole antifungal agent that
has anti-candidal and anti-staphylococcal properties. Like clotrimazole, it may be used for the treatment of angular cheilitis (1,30). For the treatment
of oral candidiasis, miconazole is available in gel
(Zeasorb-AF), cream, ointment, and lacquer formulations. The cream should be applied to the
affected area twice daily for 23 weeks, and the gel
should be applied three to four times daily for 24
weeks. The lacquer may be painted over denturefitting surfaces in patients with a history of denture
stomatitis, thus slowly delivering anti-candidal
therapy for prolonged periods of time. Decreased
numbers of Candida on these surfaces with one
application have been documented (54). Prior to
lacquer application, the patient should thoroughly
brush the occlusal denture surfaces under cold
running water. It is recommended that the patient
paint each denture with 1 g of lacquer (containing
55 mg/g of miconazole) and permit the lacquer to
dry for 1 hour prior to denture insertion. This
should be repeated two more times at Days 7 and
14 (55).
Miconazole is well tolerated. Side effects are
limited to nausea and local skin irritation when
used topically.
Ketoconazole
Ketoconazole, like clotrimazole and miconazole,
is an imidazole antifungal medication. However,
ketoconazole does not possess antibacterial activity. It is available topically as a 2% cream. The
patient should apply the cream two to three times
daily to affected areas for 1428 days. Topical ketoconazole is well tolerated, and side effects are
limited to skin irritation and headache.
Systemic oral antifungal agents
Systemic azoles are used to treat oral candidiasis
refractory to treatment with topical antimycotic
agents or in patients who are immunocompromised or at risk of disseminated disease (5).
Parenteral antimycotic agents such as flucytosine,
amphotericin B, and the echinocandins (e.g.,
caspofungin) are generally reserved for the treatment of invasive candidiasis (48).
Azoles are divided into the imidazoles (clotrimazole, miconazole, ketoconazole) and triazoles
(fluconazole, itraconazole, posaconazole, voriconazole) (30,48). Azoles are fungistatic and block
the synthesis of ergosterol in fungal cell membranes by inhibiting the 14a-demethylation of
lanosterol (56). Imidazoles also disturb fungal oxidative enzymes, resulting in a lethal accumulation
of hydrogen peroxide (30).
Systemic antifungals, such as ketoconazole and
itraconazole, are potent inhibitors of the cytochrome P-450 hepatic metabolism pathways. They
can result in harmful drugdrug interactions and
hepatitis, and may be associated with birth defects
(18). Therefore, a patients existing medication list
should be reviewed for potential adverse drug
drug interactions.
Ketoconazole
Oral ketoconazole is a weak base and is best
absorbed at normal acidic gastric pH. Absorption is
decreased with the concomitant use of antacids,
histamine-receptor blockers, or proton pump
inhibitors. In conditions with impaired gastric
secretion and in patients with achlorhydria,
absorption is decreased thus limiting effectiveness.
Ketoconazole (200 mg tablet) is administered
once or twice daily for 2 weeks (1). The most
common adverse effects are nausea and vomiting.
Ketoconazole can suppress cytochrome P-450mediated metabolism of several medications such
as cyclosporine, leading to increased active
metabolites (57). Ketoconazole can block steroid
synthesis, decrease the production of testosterone,
and cause hair loss. It may also be teratogenic and
is advisable to avoid in pregnancy. Idiosyncratic
hepatotoxicity may occur, and can be asymptom-
239
Itraconazole
Itraconazole is a lipophilic triazole and is particularly beneficial for the treatment of fluconazoleresistant candidal strains such as C. krusei or C.
glabrata, with response rates of 6480% (30,67).
The capsule form requires acidic pH for absorption
(1). The patient should be instructed to take itraconazole capsules with food, as its bioavailability
is two- to threefold increased when compared to
ingestion on an empty stomach (68). Acidic beverages (carbonated beverages, cranberry juice) can
heighten gastrointestinal absorption (69). The
solution form (10 mg/mL) has approximately 30%
greater bioavailability than the capsule, and does
not require acidic pH for absorption (68). The solution and capsule formulations may be prescribed
at doses of 100200 mg daily for 14 days. A loading
dose of 200 mg by mouth three times daily for 3
days should be administered in cases of severe
recalcitrant oropharyngeal disease (48).
Itraconazole is hepatically metabolized and
excreted via the biliary tract. It is generally well
tolerated, although adverse effects include asymptomatic hepatitis, hypokalemia, headache, dizziness, and gastrointestinal disturbance (1).
Posaconazole
Posaconazole is an extended-spectrum triazole
reserved for fluconazole-resistant candidal strains
or refractory disease. Improvement was noted in
75% of patients with refractory oropharyngeal candidiasis (70). It is formulated as a suspension
(40 mg/mL). A loading dose of 100 mg should be
given twice daily for the first day, followed by a dose
of 100 mg daily for 13 days (71). In refractory or
complicated cases, posaconazole 400 mg twice
daily for 3 days, followed by 400 mg daily or twice
daily for 2528 days may be necessary (48). Posaconazole has a greater bioavailability when administered with food.
Posaconazole is metabolized by the liver. Compared to other azole agents, it exerts a limited effect
on cytochrome P-450 isozymes. Posaconazole is
generally well-tolerated. Most common adverse
effects involve gastrointestinal upset, although
neutropenia was noted in 7% of patients (71).
Prophylaxis
Prophylactic anti-candidal treatment is indicated
for patients who have recurrent oral candidiasis,
who are receiving prolonged antibiotic treatment,
240
Conclusion
Oral candidiasis and angular cheilitis are frequently encountered in clinical practice. Although
acute pseudomembranous oral candidiasis is
readily recognized, other forms of oral candidiasis
may present a greater diagnostic challenge. Oral
candidiasis may be a clue to concurrent unidentified systemic diseases. In many patients, candidiasis can cause oral discomfort, leading to
decreased oral intake predisposing to nutritional
deficiency.
Uncomplicated oral candidiasis and angular
cheilitis generally respond to treatment, although
relapses often occur because of reduced compliance, poor oral hygiene, and failure to address predisposing factors. Treatment should be tailored to
the individual patients needs and preferences.
The prognosis of oral candidiasis in most
patients is good. In immunosuppressed or debilitated populations, however, oropharyngeal candidiasis places the host at risk for developing
invasive disease. Therefore, it is important to recognize and treat oral candidiasis.
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