You are on page 1of 14

Dermatologic Therapy, Vol.

23, 2010, 230242


Printed in the United States All rights reserved

2010 Wiley Periodicals, Inc.

DERMATOLOGIC THERAPY
ISSN 1396-0296

Oral candidiasis and


angular cheilitis
dth_1320

230..242

Victoria Sharon & Nasim Fazel


Department of Dermatology, University of Davis, Sacramento, California

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

Candida can be a commensal organism in the


oral cavity, and its isolation in the absence of clinical correlation does not indicate active infection.
The pseudohyphal growth of Candida is fostered
by elevated intraoral temperatures. In healthy children and adults, carriage of Candida is asymptomatic. The areas of the mouth most heavily colonized
by Candida are the posterior dorsal tongue, palate,
and buccal mucosa (2). The prevalence of carriage
of Candida varies from 45 to 65% in healthy infants,
and 3055% in normal adults (3). Colonized infants
are often exposed in utero or during passage
through the vaginal canal. Candida carriage occurs
in up to 65% of denture wearers, 78% of hospitalized elderly, and greater than 90% of patients with
HIV or individuals receiving chemotherapy (26).
Candidal carriage occurs more frequently in
women, during the summer months, in patients
with more acidic saliva, in pregnancy, and in those
with blood group O (79). Candidal counts are
most elevated in the mornings and decrease with
meals and brushing. In denture wearers, however,
this finding is reversed. Thus, carriage is lowest in
the mornings and increases throughout the day,
corresponding to the length of time dentures have
been worn. In edentulous patients who wear their
dentures overnight, candidal counts are again

Oral candidiasis and angular cheilitis

highest in the morning. These findings support the


theory that Candida adheres to dentures, and the
organism has indeed been detected in increased
numbers on denture surfaces compared to mucosa
(10). Therefore, with the exception of edentulous
patients, early-morning candidal samples are most
accurate for comparing individual differences in
carriage (7).
Denture stomatitis, identified by erythema and
edema of the denture-fitting surfaces of the mouth,
occurs in up to 65% of patients with dentures (11).
The predominant cause of denture stomatitis is
candidal colonization of the denture-covered
areas, although mechanical irritation, allergy to
denture material, and non-candidal infections
have been identified as alternate causes. The main
reservoir for candidal colonization in these
patients is the fitting denture surface as Candida
often attaches to plastic or orthodontic surfaces,
either directly or by a layer of plaque that adheres
to the polymethylmethacrylate base (12).
Although candidal carriage in the oral cavity
may be a normal phenomenon, candidiasis is a
result of Candida overgrowth (5). The most
common pathogenic species of candidiasis is
Candida albicans, occurring in 5060% of cases.
Other important pathogens include Candida glabrata (1520%), Candida parapsilosis (1020%),
Candida tropicalis (612%), Candida pseudotropicalis (<5%), Candida guilliermondii (<5%),
Candida krusei (<5%), Candida lusitaniae (<5%),
Candida dubliniensis (<5%), and Candida stellatoidea (<5%) (5,13). Less commonly identified
strains are more frequently found in immunosuppressed populations. Greater than 15% of oral candidiasis is caused by non-albicans species in those
with HIV, most often C. dubliniensis. Similarly,
46% of cases of oral candidiasis in patients with
malignancy are caused by non-albicans species
(1417).
Options for treating oral candidiasis are available in a variety of forms including rinses, suspensions, creams, ointments, lozenges, capsules, and
tablets. Topical treatment in healthy patients or in
the immunocompromised host with mild disease
is preferable to systemic therapy. However, the
unique environment of salivary flushing and the
action of oral musculature result in decreased
therapeutic drug concentration, mandating a need
for frequent dosing. Inconvenient dosing schedules combined with the occasional unpalatable
taste lead to noncompliance and frequent treatment failure. A variety of systemic therapies are
generally reserved to treat refractory or high-risk
disease.

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

Sharon & Fazel

Table 1. Risk factors for oral candidiasis and


angular cheilitisa
Endogenous risk
factors
Extremes of age (infants,
elderly)
Immunodeficiency
HIV or AIDS
Severe combined
immunodeficiency
Myeloperoxidase
deficiency
Hyper IgE syndrome
Chronic granulomatous
disease
ChediakHigashi
syndrome
DiGeorge syndrome
Nezelof syndrome
Endocrine abnormalities
Diabetes mellitus
Hyperadrenalism
(Cushing syndrome)
Hypothyroidism
Pregnancy
Systemic illnesses
Malignancy
Blood dyscrasias
Uremia
Xerostomia (Sjgren
syndrome)

Exogenous risk factors


Poor oral hygiene
Overclosure
(occlusion)
Oral prostheses
Poorly fitting
dentures
Mouth guards
Dental trays
Disrupted mucosal
barrier
Trauma
Burn
Chronic local irritation
Surgery
Radiation
Medications
Antibiotics
Anticholinergics
Antihistamines
Chemotherapeutics
Immunosuppressive
agents
Xerostomic
psychotropic
medications
Systemic or inhaled
corticosteroids
Oral contraceptives
Smoking
Prolonged
hospitalization
Poor diet
Vitamin deficiencies
(iron, folate, B12)
High carbohydrate
content

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).

Adapted from Scully et al. (7).

Acute pseudomembranous candidiasis


fore important for the clinician to perform a thorough oral examination in the patient with HIV, as
oral candidiasis can be a harbinger of worsening
immunosuppression. Highly active antiretroviral
therapy in patients with HIV correlates with
decreased recovery of Candida from the oropharyngeal tract and decreased symptomatic oral candidiasis (21).
Many pharmacotherapeutics confer an increased risk of active candidal infection. Antibiotics, such as tetracycline and minocycline, alter the
normal flora of the oral cavity, promoting candidal

232

Acute pseudomembranous candidiasis (exudative


candidiasis, thrush) is responsible for at least onethird of cases of oral candidiasis (5). In particular
populations, it has been reported to represent up
to two-thirds of symptomatic candidiasis (19).
When clinically symptomatic, the patient may
notice a burning sensation in the mouth, a sour
taste or difficulty tasting food, or discomfort and
easy bleeding in the affected areas. Thrush often
appears as confluent, loosely attached, white
pseudomembranous plaques resembling milk
curd, which frequently involve the buccal mucosa,

Oral candidiasis and angular cheilitis

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

FIG. 1. Traditional classification of primary oral candidiasis.

malignancy (27). Although thrush may occur


acutely, its presence can persist for months in
patients with HIV or in those using corticosteroid
inhalers. The differential diagnosis includes leukoplakia, lichen planus, other lichenoid eruptions,
pemphigus, mucous membrane pemphigoid, persistent food debris, and squamous cell carcinoma.
Acute atrophic candidiasis

FIG. 2. Acute pseudomembranous candidiasis. Courtesy of


Errol Craig, MD, PhD, Walnut Creek, CA.

tongue, oropharynx, hard palate, and soft palate


(FIG. 2) (5). Scraping of these pseudomembranes
with a tongue depressor, blade, or gauze reveals an
underlying erythematous base. Microscopic evaluation demonstrates hyphal forms, bacteria, inflammatory cells, and sloughed epithelial cells (27).
Conditions that predispose to thrush include,
but are not limited to, immune defects, HIV, corticosteroid inhalers, endocrine abnormalities, and

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

Sharon & Fazel

wearers are affected (5,27). Symptoms include


burning or a sore mouth. Patients with angular
cheilitis may have unrecognized chronic atrophic
candidiasis (7).
Three clinical presentations have been
described in chronic atrophic candidiasis. In type I,
local inflammation manifests as pinpoint hyperemic macules. Type II appears as diffuse erythema
of part or the entirety of the denture-occluded area.
Type III, or the granular type, most often involves
the central hard palate or alveolar ridge forming
papillary hyperplasia (1,29). Confirmatory diagnosis can be obtained by swabbing and staining
involved tissue.
The differential diagnosis of chronic atrophic
candidiasis includes mechanical irritation, allergy
to denture material, and bacterial infection (30).
Median rhomboid glossitis

FIG. 3. Acute atrophic candidiasis. Note minor component


of pseudomembranes at the periphery. Courtesy of Errol
Craig, MD, PhD, Walnut Creek, CA.

cases, if left untreated (1,5,7). Chronic hyperplastic


candidiasis is one of the least common forms of
oral candidiasis. Lesions generally occur on the
buccal mucosa, and less commonly on the lateral
sides of the tongue, as small or large wellcircumscribed translucent-to-white homogeneous
or speckled firm plaques or nodules (5). Unlike
thrush, these plaques are resistant to removal by
gentle scraping. Chronic hyperplastic candidiasis
may resolve with smoking cessation (5). Histologically, these lesions reveal candidal hyphae within
a hyperplastic epithelium. Epithelial dysplasia is
not present. However, in cases of oral malignancy,
Candida invasion may occur secondary to a disrupted or altered epithelium.
The differential diagnosis of chronic hyperplastic candidiasis is similar to that of acute
pseudomembranous candidiasis.
Chronic atrophic candidiasis
Chronic atrophic candidiasis (denture stomatitis),
as distinguished from acute atrophic candidiasis,
occurs in areas occluded by dentures, such as the
hard palate, and presents as erythema and edema
between the dentures and oral mucosa (2).
Restricted salivary flow may predispose to this distribution. Twenty to sixty percent of denture

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-

Oral candidiasis and angular cheilitis

can be helpful (36). Angular cheilitis resulting from


deep orofacial grooves may be amenable to soft
tissue augmentation with fillers at the oral commissures to correct the anatomic defect (37).
Linear gingival erythema

FIG. 4. Angular cheilitis. Courtesy of Errol Craig, MD, PhD,


Walnut Creek, CA.

tion of the bone on which the dentures lay,


reducing the vertical height of the lower face (5).
These conditions result in saliva trapping or excessive saliva at the angles of the mouth. Incorrect use
of dental floss can lead to local mechanical trauma,
predisposing to angular cheilitis (32).
Angular cheilitis has also been associated with
diseases that cause enlarged lips, such as orofacial
granulomatosis. Cases of angular stomatitis related
to staphylococcal infection have been in some
cases shown to result from nasal carriage with
spread to the angles of the mouth (33). Exfoliative
cheilitis, presenting predominantly with cracking
of the lower lip, has been associated with Candida,
particularly in HIV-positive patients (34). Angular
stomatitis refractory to treatment or chronically
recurring in a non-denture wearer should prompt
evaluation for HIV or another underlying immune
defect (7).
The treatment of angular cheilitis is most appropriately tailored to its cause. Angular cheilitis secondary to Candida infection should be treated with
topical antifungal creams (5). In patients with HIV
given topical therapy for angular cheilitis, relapses
occur more frequently than in those treated with
systemic antifungal therapy (35). To treat angular
cheilitis caused by overclosure, petrolatum or lip
balm can be used as a mechanical barrier. In cases
associated with bacteria, topical mupirocin 2%
ointment three to four times daily until resolution

Linear gingival erythema manifests as a beefy red


discrete line or punctate erythema of at least 2 mm
width along the gingival margin (38). It may
encompass many teeth, or as little as one tooth,
and can be accompanied by pain and bleeding (1).
Although first described in patients with HIV, it has
also been reported in healthy children (1). This
condition may be misdiagnosed as gingivitis. Some
reports in the literature indicate that linear gingival
erythema may signify disease progression in HIVpositive individuals (39). To prevent progression to
necrotizing periodontitis, it is important to aggressively treat linear gingival erythema (40). Cases in
which Candida is isolated should receive antifungal therapy. Patients should be instructed to
perform proper hygiene techniques and rinse
twice daily with chlorhexidine gluconate 0.12%
mouthwash. Concomitant dental referral is highly
recommended for periodontal scaling and debridement (41).
Cheilo-candidiasis, chronic multifocal
candidiasis, and chronic mucocutaneous
candidiasis
Two additional variants, cheilo-candidiasis and
chronic multifocal candidiasis, do not fit into the
traditional categories of oral candidiasis. Cheilocandidiasis is an ulcerating lesion of the lower
vermilion border of the lip. Chronic multifocal candidiasis is characterized by erythematous plaques
in two or more areas of the mouth, most commonly
identified in older male tobacco smokers. By definition, lesions must be present for greater than 4
weeks in the absence of known risk factors (1,30).
Antifungal therapy is usually successful in treating
chronic multifocal candidiasis, although recurrences are common without smoking cessation
(30).
Chronic mucocutaneous candidiasis refers to a
set of rare syndromes, at times with an identifiable
immune defect, in which the patient has persistent
mucocutaneous findings including thrush and/
or angular cheilitis, hyperkeratotic dystrophic
nails, as well as acral and scalp involvement
with erythematous, hyperkeratotic, serpiginous
plaques. These are syndromes that include autoimmune polyendocrine syndrome type 1, in which

235

Sharon & Fazel

Treatment

FIG. 5. Candida albicans (tongue biopsy, PAS stain, high


magnification). Courtesy of Maxwell A. Fung, MD, Sacramento
CA.

chronic mucocutaneous candidiasis is followed by


the appearance of hypoparathyroidism and hypoadrenalism (42). Symptoms usually begin early in
life and are often refractory to antifungal treatment
(30).

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

Initial management should begin by eliminating


predisposing factors identified during the interview and examination. Despite adequate antifungal treatment, recurrences are common in
patients in whom the underlying risk factors are
not eliminated. Selected topical and systemic
therapies for oral candidiasis and angular cheilitis
are summarized in Table 2. In cases in which the
diagnosis of candidiasis is apparent, empiric
treatment can be undertaken. In cases resistant to
initial therapy, one should consider culture and
sensitivity testing. If the diagnosis is uncertain, a
biopsy for evaluation of fixed tissue should
be obtained. Parenteral antifungal agents are
generally not used to treat isolated oral candidiasis, and should be reserved for more invasive
disease. Individuals who face an increased
risk of invasive fungal infection or suffer from
frequent recurrences may be candidates for
chemoprophylaxis.

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

Oral candidiasis and angular cheilitis

Table 2. Medical treatment of oral candidiasis and angular cheilitisa,b


Agent

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

Minimal gastrointestinal absorption

B
C

Local skin irritation; gastrointestinal upset

Skin irritation, burning, and maceration

Skin irritation and headache


Nausea and vomiting; hepatotoxicity;
drugdrug interactions
Gastrointestinal upset; hepatotoxicity;
drugdrug interactions
Gastrointestinal upset; hepatotoxicity;
drugdrug interactions

Gastrointestinal upset; hepatotoxicity;


drugdrug interactions; neutropenia

Adapted from Ellepola & Samaranayake (30).


Only selected antifungal therapy presented.
QD indicates once daily; QW, once weekly; BID, twice daily; TID, three times daily; QID, four times daily.
b

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-

ryngeal candidiasis (2). It is an antiseptic agent that


has both anti-candidal and anti-staphylococcal
properties.
Gentian violet, 1.5 mL of a 0.5% solution twice
daily, is comparable to treatment with oral ketoconazole and may be superior to nystatin mouth
rinses (49). Side effects include purple staining of
skin and clothes, skin irritation, and ulceration of
mucous membranes (50).
Nystatin
Nystatin, a polyene antifungal agent, has been one
of the most widely used topical antifungals (51). It
binds to ergosterol, a sterol specific to fungal cell
membranes, forming artificial pores to alter membrane permeability (30). This results in the seepage
of cellular components and eventual loss of cell
viability.

237

Sharon & Fazel

Nystatin is available in several forms including a


50% sucrose oral suspension, vaginal tablet, cream,
ointment, and lozenge (pastille). Shortcomings of
the oral suspension (100,000 U/mL, prescribed
four times daily for 714 days) include a short
contact time, mild gastrointestinal disturbance,
increased risk of dental caries, or worsening
glucose intolerance. Vaginal tablets (100,000 U) are
unflavored and lack a carbohydrate base, supporting their use as an alternative formulation in
patients at risk for dental caries or in those with
diabetes. One tablet three times daily for 2 weeks
should be used. The lozenge (100,000 U), one to
two taken by mouth five times daily for 714 days,
has a pleasant taste and provides a longer duration
of action, if dissolved slowly (15). However, its high
sugar content puts the patient at risk for developing secondary caries and may exacerbate underlying diabetes mellitus. In patients with xerostomia,
lozenges may be difficult to dissolve.
If the patient cannot tolerate the taste of nystatin, or if nausea and vomiting occur, alternative
agents such as clotrimazole troches may be used
instead.
Nystatin and chlorhexidine, when combined,
inactivate each other forming chlorhexidine
nystatin complexes and should not be used concomitantly (52).
Amphotericin B
Amphotericin B, like nystatin, is a polyene antifungal medication. As an oral agent, it is poorly
absorbed via the gastrointestinal tract. It is often
administered intravenously in the case of systemic
fungal infections. Although less popular than nystatin because of decreased familiarity and association with significant adverse systemic effects when
administered intravenously, amphotericin B can
be used to adequately treat Candida of the oral
cavity and is available in the United States as a
cream, lotion, and ointment (1). The patient should
be instructed to apply amphotericin B to the
affected areas three to four times daily for up to 2
weeks (1,30).
Clotrimazole
Clotrimazole is a fungistatic topical imidazole
antifungal agent that prevents the synthesis of
ergosterol in the fungal cell membrane. It is
manufactured as an oral or vaginal troche, cream,
and solution, and has the advantage of both anticandidal and anti-staphylococcal activities (1,30).
Clotrimazole troches have a more palatable taste

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,

Oral candidiasis and angular cheilitis

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-

atic, manifesting as reversible elevations of serum


aspartate and alanine aminotransferases (30). Fatal
nephrotoxicity and hepatotoxicity have been
reported. Care should be taken when prescribing
these agents to patients with liver or kidney impairment. A hepatic function panel may be monitored
periodically in anyone receiving prolonged therapy
beyond 2 weeks or in high-risk populations such as
those with known liver impairment (58). Currently,
routine hepatic monitoring is not universally recommended unless the patient develops signs of
hepatotoxicity including nausea, vomiting, anorexia, abdominal pain, fatigue, jaundice, or dark
urine.
Fluconazole
Fluconazole is a water-soluble triazole that, unlike
ketoconazole, is well absorbed from the gastrointestinal tract at any gastric pH (56). Its oral
bioavailability is approximately 90% of intravenous
administration (48). It is only weakly plasma
protein bound and therefore has good uptake into
tissue (1). Distinct from other azoles, fluconazole
is minimally metabolized and is excreted via the
kidney 80% unchanged, therefore negligibly affecting hepatic metabolism (1,30,59). It may be prescribed in doses of 50, 100, 150, or 200 mg, or
3 mg/kg daily for 714 days for oral candidiasis,
with a 200 mg loading dose (1,48). Overall, fluconazole is well tolerated and generates only mild side
effects related to gastrointestinal discomfort and
headache. In rare instances, fluconazole may be
associated with abnormal liver enzymes. Although
there is no universal consensus, some authors
suggest obtaining a baseline hepatic function
panel with periodic monthly monitoring (60).
Animal studies have suggested an association with
fetal malformation (61). Fluconazole has fewer
drugdrug interactions than does ketoconazole.
However, a complete list of potential drug interactions should be identified prior to administration.
There is an increasing trend toward fluconazoleresistant candidal species (C. krusei and C. glabrata)
(15,18). Fluconazole resistance has been detected in
excess of 20% in some studies (62,63). Higher doses
of fluconazole (up to 600 mg daily) or alternative
azoles may be necessary in such cases (30).
Fluconazole may be used for chronic suppression of oropharyngeal candidiasis in doses of 50 or
100 mg daily, 100 or 200 mg three times weekly,
150 mg weekly, or as needed (48,64,65). Continuous prophylaxis with fluconazole does not result in
higher resistance rates than as needed dosing for
oral candidiasis (66).

239

Sharon & Fazel

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

or who are immunosuppressed (transplant, chemotherapy, systemic immunosuppressives, HIV,


low CD4 counts). Continuous antifungal therapy
reduces intraoral candidal counts and resultant
infections (5). In patients receiving bone marrow
transplants, chlorhexidine has been shown to be
effective in decreasing the risk of oral candidiasis
(72).
There is no collective consensus on a standard
prophylactic regimen for oral candidiasis. The
most appropriate therapy depends on the species
of Candida isolated, as well as the underlying predisposing conditions, frequency of recurrences,
and ongoing antibiotic or immunosuppressive
therapy. Recommended regimens include, but are
not limited to, rinsing with chlorhexidine gluconate 0.12% mouthwash twice daily, using clotrimazole troches (10 mg) three times daily, or
administering fluconazole 50 or 100 mg daily, or
200 mg between one and three times weekly
(11,53,73).

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.

References
1. Samaranayake LP, Keung Leung W, Jin L. Oral mucosal
fungal infections. Periodontol 2000 2009: 49: 3959.
2. Vazquez JA, Sobel JD. Mucosal candidiasis. Infect Dis Clin
North Am 2002: 16: 793820, v.
3. Arendorf TM, Walker DM. The prevalence and intra-oral
distribution of Candida albicans in man. Arch Oral Biol
1980: 25: 110.

Oral candidiasis and angular cheilitis


4. Wilkieson C, Samaranayake LP, MacFarlane TW, Lamey PJ,
MacKenzie D. Oral candidosis in the elderly in long term
hospital care. J Oral Pathol Med 1991: 20: 1316.
5. Akpan A, Morgan R. Oral candidiasis. Postgrad Med J 2002:
78: 455459.
6. Abu-Elteen KH, Abu-Alteen RM. The prevalence of
Candida albicans populations in the mouths of complete
denture wearers. New Microbiol 1998: 21: 4148.
7. Scully C, el-Kabir M, Samaranayake LP. Candida and oral
candidosis: a review. Crit Rev Oral Biol Med 1994: 5: 125
157.
8. Barlow AJ, Chattaway FW. Observations on the carriage of
Candida albicans in man. Br J Dermatol 1969: 81: 103106.
9. Arendorf TM, Walker DM. Oral candidal populations in
health and disease. Br Dent J 1979: 147: 267272.
10. Davenport JC. The oral distribution of Candida in denture
stomatitis. Br Dent J 1970: 129: 151156.
11. Pankhurst CL. Candidiasis (oropharyngeal). Clin Evid
(Online) 2009: March 18.
12. Pereira-Cenci T, Del Bel Cury AA, Crielaard W, Ten Cate JM.
Development of Candida-associated denture stomatitis:
new insights. J Appl Oral Sci 2008: 16: 8694.
13. Vazquez JA, Sobel JD. Candidiasis. In: Dismukes WE,
Pappas PG, Sobel JD, eds. Clinical mycology. New York, NY:
Oxford University Press, 2003: 143187.
14. Wingard JR. Importance of Candida species other than C.
albicans as pathogens in oncology patients. Clin Infect Dis
1995: 20: 115125.
15. Greenspan D. Treatment of oropharyngeal candidiasis in
HIV-positive patients. J Am Acad Dermatol 1994: 31: S51
55.
16. Barchiesi F, Morbiducci V, Ancarani F, Scalise G. Emergence of oropharyngeal candidiasis caused by nonalbicans species of Candida in HIV-infected patients. Eur J
Epidemiol 1993: 9: 455456.
17. Habif TP. Superficial Fungal Infections. In: Habif TP, ed.
Clinical dermatology, 4th ed. Amsterdam: Elsevier Health
Sciences, 2004: 409456.
18. Darouiche RO. Oropharyngeal and esophageal candidiasis
in immunocompromised patients: treatment issues. Clin
Infect Dis 1998: 26: 259274.
19. Liu X, Liu H, Guo Z, Luan W. Association of asymptomatic
oral candidal carriage, oral candidiasis and CD4 lymphocyte count in HIV-positive patients in China. Oral Dis 2006:
12: 4144.
20. Samaranayake LP. Oral mycoses in HIV infection. Oral Surg
Oral Med Oral Pathol 1992: 73: 171180.
21. Martins MD, Lozano-Chiu M, Rex JH. Declining rates
of oropharyngeal candidiasis and carriage of Candida
albicans associated with trends toward reduced rates of
carriage of fluconazole-resistant C. albicans in human
immunodeficiency virus-infected patients. Clin Infect Dis
1998: 27: 12911294.
22. Ozog DM, Gogstetter DS, Scott G, Gaspari AA. Minocyclineinduced hyperpigmentation in patients with pemphigus
and pemphigoid. Arch Dermatol 2000: 136: 11331138.
23. Goulden V, Glass D, Cunliffe WJ. Safety of long-term highdose minocycline in the treatment of acne. Br J Dermatol
1996: 134: 693695.
24. Oliver DE, Shillitoe EJ. Effects of smoking on the prevalence
and intraoral distribution of Candida albicans. J Oral Pathol
1984: 13: 265270.
25. Soysa NS, Ellepola AN. The impact of cigarette/tobacco
smoking on oral candidosis: an overview. Oral Dis 2005: 11:
268273.

26. Cannon RD, Holmes AR, Mason AB, Monk BC. Oral
Candida: clearance, colonization, or candidiasis? J Dent
Res 1995: 74: 11521161.
27. Janik MP, Heffernan MP. Yeast Infections: Candidiasis and
Tinea (Pityriasis) Versicolor. In: Wolff K, Goldsmith LA, Katz
SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatricks dermatology in general medicine. New York, NY: McGraw-Hill
Medical, 2008: 18221830.
28. Samaranayake LP, Holmstrup P. Oral candidiasis and
human immunodeficiency virus infection. J Oral Pathol
Med 1989: 18: 554564.
29. Golecka M, Oldakowska-Jedynak U, MierzwinskaNastalska E, Adamczyk-Sosinska E. Candida-associated
denture stomatitis in patients after immunosuppression
therapy. Transplant Proc 2006: 38: 155156.
30. Ellepola AN, Samaranayake LP. Oral candidal infections
and antimycotics. Crit Rev Oral Biol Med 2000: 11: 172
198.
31. Appleton SS. Candidiasis: pathogenesis, clinical characteristics, and treatment. J Calif Dent Assoc 2000: 28: 942948.
32. Kahana M, Yahalom R, Schewach-Millet M. Recurrent
angular cheilitis caused by dental flossing. J Am Acad Dermatol 1986: 15: 113114.
33. MacFarlane TW, Helnarska SJ. The microbiology of angular
cheilitis. Br Dent J 1976: 140: 403406.
34. Reichart PA, Weigel D, Schmidt-Westhausen A, Pohle HD.
Exfoliative cheilitis (EC) in AIDS: association with Candida
infection. J Oral Pathol Med 1997: 26: 290293.
35. Pons V, Greenspan D, Debruin M. Therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized,
prospective multicenter study of oral fluconazole versus
clotrimazole troches. The multicenter study group. J Acquir
Immune Defic Syndr 1993: 6: 13111316.
36. de Wet PM, Rode H, van Dyk A, Millar AJ. Perianal candidosis a comparative study with mupirocin and nystatin. Int
J Dermatol 1999: 38: 618622.
37. Chernosky ME. Collagen implant in management of perleche (angular cheilosis). J Am Acad Dermatol 1985: 12:
493496.
38. Odden K, Schenck K, Koppang H, Hurlen B. Candidal infection of the gingiva in HIV-infected persons. J Oral Pathol
Med 1994: 23: 178183.
39. Velegraki A, Nicolatou O, Theodoridou M, Mostrou G,
Legakis NJ. Paediatric AIDS-related linear gingival
erythema: a form of erythematous candidiasis? J Oral
Pathol Med 1999: 28: 178182.
40. Barr CE. Periodontal problems related to HIV-1 infection.
Adv Dent Res 1995: 9: 147151.
41. Reznik DA. Oral manifestations of HIV disease. Top HIV
Med 2005: 13: 143148.
42. Shikama N, Nusspaumer G, Hollander GA. Clearing the
AIRE: on the pathophysiological basis of the autoimmune
polyendocrinopathy syndrome type-1. Endocrinol Metab
Clin North Am 2009: 38: 273288, vii.
43. Hinshaw M, Longley BJ. Fungal Diseases. In: Lever WF,
Elder DE, eds. Levers histopathology of the skin. Philadelphia, PA: Lippincott Williams & Wilkins, 2009: 597600.
44. Odman PA. The effectiveness of an enzyme-containing
denture cleanser. Quintessence Int 1992: 23: 187190.
45. Lal K, Santarpia RP 3rd, Pollock JJ, Renner RP. Assessment
of antimicrobial treatment of denture stomatitis using an in
vivo replica model system: therapeutic efficacy of an oral
rinse. J Prosthet Dent 1992: 67: 7277.
46. Douglas LJ. Surface composition and adhesion of Candida
albicans. Biochem Soc Trans 1985: 13: 982984.

241

Sharon & Fazel


47. Aframian DJ, Helcer M, Livni D, Robinson SD, Markitziu A,
Nadler C. Pilocarpine treatment in a mixed cohort of xerostomic patients. Oral Dis 2007: 13: 8892.
48. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice
guidelines for the management of candidiasis: 2009 update
by the Infectious Diseases Society of America. Clin Infect
Dis 2009: 48: 503535.
49. Nyst MJ, Perriens JH, Kimputu L, Lumbila M, Nelson AM,
Piot P. Gentian violet, ketoconazole and nystatin in
oropharyngeal and esophageal candidiasis in Zairian AIDS
patients. Ann Soc Belg Med Trop 1992: 72: 4552.
50. Balabanova M, Popova L, Tchipeva R. Dyes in dermatology.
Clin Dermatol 2003: 21: 26.
51. Epstein JB. Antifungal therapy in oropharyngeal mycotic
infections. Oral Surg Oral Med Oral Pathol 1990: 69: 3241.
52. Barkvoll P, Hurlen B. Conventional treatment of oral candidiasis new aspects. Nor Tannlaegeforen Tid 1989: 99:
116119.
53. Cuttner J, Troy KM, Funaro L, Brenden R, Bottone EJ. Clotrimazole treatment for prevention of oral candidiasis in
patients with acute leukemia undergoing chemotherapy.
Results of a double-blind study. Am J Med 1986: 81: 771
774.
54. Konsberg R, Axell T. Treatment of Candida-infected
denture stomatitis with a miconazole lacquer. Oral Surg
Oral Med Oral Pathol 1994: 78: 306311.
55. Dias AP, Samaranayake LP, Lee MT. Miconazole lacquer in
the treatment of denture stomatitis: clinical and microbiological findings in Chinese patients. Clin Oral Investig 1997:
1: 4752.
56. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994: 330: 263272.
57. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an
overview. Part I. J Am Acad Dermatol 1994: 30: 677698;
quiz 698700.
58. Hay RJ. Risk/benefit ratio of modern antifungal therapy:
focus on hepatic reactions. J Am Acad Dermatol 1993: 29:
S5054.
59. Brammer KW, Coakley AJ, Jezequel SG, Tarbit MH. The disposition and metabolism of [14C]fluconazole in humans.
Drug Metab Dispos 1991: 19: 764767.
60. Gupta AK, Sauder DN, Shear NH. Antifungal agents: an
overview. Part II. J Am Acad Dermatol 1994: 30: 911933;
quiz 916934.
61. Aleck KA, Bartley DL. Multiple malformation syndrome following fluconazole use in pregnancy: report of an additional patient. Am J Med Genet 1997: 72: 253256.
62. Maenza JR, Merz WG, Romagnoli MJ, Keruly JC, Moore RD,
Gallant JE. Infection due to fluconazole-resistant Candida

242

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

in patients with AIDS: prevalence and microbiology. Clin


Infect Dis 1997: 24: 2834.
Maninder J, Usha A. Isolation, characterization and antifungal susceptibility pattern of Candida species causing
oropharyngeal candidiasis in HIV positive patients. J
Commun Dis 2008: 40: 177181.
Leen CL, Dunbar EM, Ellis ME, Mandal BK. Once-weekly
fluconazole to prevent recurrence of oropharyngeal candidiasis in patients with AIDS and AIDS-related complex:
a double-blind placebo-controlled study. J Infect 1990:
21: 5560.
Corvo R, Amichetti M, Ascarelli A, et al. Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in
patients undergoing radiotherapy for head and neck
tumour: results from a double-blind placebo-controlled
trial. Eur J Cancer Care (Engl) 2008: 17: 270277.
Goldman M, Cloud GA, Wade KD, et al. A randomized study
of the use of fluconazole in continuous versus episodic
therapy in patients with advanced HIV infection and a
history of oropharyngeal candidiasis: AIDS Clinical Trials
Group Study 323/Mycoses Study Group Study 40. Clin
Infect Dis 2005: 41: 14731480.
Saag MS, Fessel WJ, Kaufman CA, et al. Treatment of
fluconazole-refractory oropharyngeal candidiasis with
itraconazole oral solution in HIV-positive patients. AIDS
Res Hum Retroviruses 1999: 15: 14131417.
Barone JA, Koh JG, Bierman RH, et al. Food interaction and
steady-state pharmacokinetics of itraconazole capsules in
healthy male volunteers. Antimicrob Agents Chemother
1993: 37: 778784.
Lange D, Pavao JH, Wu J, Klausner M. Effect of a cola beverage on the bioavailability of itraconazole in the presence
of H2 blockers. J Clin Pharmacol 1997: 37: 535540.
Skiest DJ, Vazquez JA, Anstead GM, et al. Posaconazole
for the treatment of azole-refractory oropharyngeal and
esophageal candidiasis in subjects with HIV infection. Clin
Infect Dis 2007: 44: 607614.
Vazquez JA. Role of posaconazole in the management of
oropharyngeal and esophageal candidiasis. Ther Clin Risk
Manag 2007: 3: 533542.
Ferretti GA, Ash RC, Brown AT, Largent BM, Kaplan A,
Lillich TT. Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving
bone marrow transplants. J Am Dent Assoc 1987: 114: 461
467.
Just-Nubling G, Gentschew G, Meissner K, et al. Fluconazole prophylaxis of recurrent oral candidiasis in HIVpositive patients. Eur J Clin Microbiol Infect Dis 1991: 10:
917921.

Copyright of Dermatologic Therapy is the property of Wiley-Blackwell and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.

You might also like