J Oral MaxillOfac Surg

49:996-1002. 1991

Diagnosis and Treatment of

Oral Candidosis
M.A.O. LEWIS, PHD, BDS, FDS,*
L.P. SAMARANYAKE, BDS, DDS, MIBIoL, MRCPATH,t
AND P.-J. LAMEY, DDS, MB, CHB, BDS, BSc, FDS, FFDS

Oral candidosis is a common opportunistic infection that manifests in a

variety of forms. It is also recognized as one of the earliest manifestations
of human immunodeficiency virus (HIV) infection. Although a number of
antifungal agents are available for the treatment of this condition, a newly
introduced triazole group of drugs appears to be highly effective in treat-
ing oral candidosis. This article reviews the clinical presentation and man-
agement of oral candidosis, particularly with reference to the latter group
of drugs and HIV-induced disease.

Intraoral candidosis is a relatively common con-
dition that encompasses a range of clinical entities
that can be either asymptomatic or cause severe
persistent symptoms. Candidal infection has as-
sumed a renewed importance with the advent of the
acquired immunodeficiency syndrome (AIDS) epi-
demic since at least half the individuals infected
with human immunodeficiency virus (HIV) develop
oral candidosis.’
Traditionally the treatment of oral candidosis was
based on the use of topical therapy because sys-
temic administration of some antifungal agents has
been associated with serious site effects, particu-
larly hepatotoxicity. However, recent clinical trials
have shown that systemic administration of the new
triazole agents, fluconazole and itraconazole, pro-
duces minimal, if any, side effects.‘.3 In addition the
triazoles appear to be highly effective in the man-
agement of candidoses in patients who are immu-
nocompromised, including those with AIDS.4,5
Therefore, in the future, the triazoles are likely to
* Lecturer, Department of Oral Medicine and Pathology,
Glasgow Dental Hospital and School, Glasgow, Scotland.
t Associate Professor, Department of Oral Biology, Faculty of
Dentistry. University of Alberta, Edmonton, Alberta. Canada.
$ Senior Lecturer, Department of Oral Medicine and Pathol-
ogy, Glasgow Dental Hospital and School, Glasgow. Scotland.
Address correspondence and reprint requests to Dr Lewis:
Department of Oral Medicine and Pathology, Glasgow Dental
Hospital and School, 378 Sauchiehall Street, Glasgow G2 332,
Scotland.
0 1991 American Association of Oral and Maxillofacial
geons
027%2391/91/4909-0012$3.00/0
play an increasingly important role in the manage-
ment of oral candidal infection.
The aim of this article is to review the clinical
presentation and management of oral candidosis,
with particular reference to the use of fluconazole
and itraconazole.
Candidal Infection in Dental Practice
Oral candidosis is a common condition, espe-
cially in denture wearers.6 It has been estimated
that approximately 4 per 1,000 patients in general
dental practices in the United Kingdom present
with symptoms of candidal infection,’ but this fig-
ure is likely to be a gross underestimate of preva-
lence since oral candidosis is often asymptomatic.
Whenever oral candidosis is diagnosed, the pres-
ence of any local and systemic predisposing condi-
tions should be identified. Candidosis may occur in
immunocompetent individuals in relation to the use
of antibiotic or corticosteroid therapy, but it is es-
pecially important to exclude immunocompromised
states such as immunosuppressive drug therapy,
hematological malignancy, or HIV infection.8 In-
vestigation of possible HIV infection requires liai-
son with medical specialists since counseling prior
to determination of antibody status is the recom-
mended practice.
The Spectrum of Oral Candidosis
Sur-
Candida albicans accounts for 70% of the oral
isolates of Candida and is the species most fre-

996
LEWIS ET AL 997

quently associated with clinical infection.’ How- immunosuppressive drugs, leukemia and infection
ever, a number of other species, including Candida with HIV.“.‘6-‘8 Some authors have proposed re-
glabrata, Candida tropicalis, Candida pseudotropi- classification of acute pseudomembranous candido-
calis, Candida stellatoidea, Candida guilliermon- sis as pseudomembranous candidosis, omitting the
dii, and Candida parapsilosis, also have been iso- prefix acute, as HIV infection is a chronic condition
lated from oral sites. Candida species may become in which these lesions persist for prolonged peri-
opportunistic oral pathogens for a number of rea- ods.”
sons related to host, environmental, and microbial
factors.* ACUTE ATROPHIC CANDIDOSIS
Oral candidoses have been classified clinically in
several ways, but the most common types fall into The use of systemic antibacterial agents or corti-
six main categories (Table 1). Rarer forms of can- costeroids” may predispose to an acute atrophic
didosis may also affect the oral cavity, but are not form of candidosis that presents as an uncomfort-
discussed in detail here. These include chronic mu- able erythematous mucosa (Fig 2). Although any
cocutaneous candidosis, candidosis endocrinopa- area of mucosa can be involved, the dor-
thy syndrome, familial mucocutaneous candidosis, sal surface of the tongue and palate are most fre-
Di Georges syndrome, chronic granulomatous dis- quently affected, particularly in association with
ease, and candidosis associated with immunodefi- use of steroid inhalers. I4 There have been proposals
ciency. HIV infection- or AIDS-related oral candi- to refer to atrophic candidosis as erythematous can-
doses form a group that manifests as erythematous, didosis since such nomenclature would incorporate
pseudomembranous, hyperplastic and angular situations in which the mucosa appears erythema-
cheilitis varieties. tous either due to mucosal atrophy or increased
vascularity of the underlying connective tissue.”
ACUTE PSEUDOMEMBRANOUSCANDIDOSIS
CHRONIC ATROPHICCANDIDOSIS
Acute pseudomembraneous candidosis is rela- (DENTURE STOMATITIS)
tively common in neonates,” the elderly,6 and
those infected with HIV.” It is characterized by a Chronic atrophic candidosis has been described
soft, yellowish-white membrane on the mucosa in as many as 65% of patients, particularly those
which can be easily rubbed off (Fig 1). Predisposing who wear a full upper denture continuously.20*2’ It
factors include antibiotic therapy,12 xerostomia,‘3 is the most common form of oral candidosis and
steroid inhaler therapy.14 and smoking.” usually presents as a painless erythematous, edem-
Pseudomembranous candidosis limited to the soft atous denture bearing mucosa (Fig 3).
palate and faucal region in nonimmunocompro-
mised patients is characteristically associated with CHRONIC HYPERPLASTIC CANDIDOSIS
the use of steroid inhaler therapy. An important
systemic cause of this form of oral candidosis is T Although chronic hyperplastic candidosis may af-
cell immunodeficiency such as that associated with fect any intraoral mucosal surface, it characteristi-
cally presents as bilateral lesions in the labial com-
Table 1. Types of Candidosis That Commonly missure region.“2*‘3 Clinical signs and symptoms are
Affect the Oral Cavity and Perioral Tissues variable, ranging from painless plaquelike white
Type of
patches to nodular erythroleukoplakic lesions that
Candidosis Synonym cause considerable discomfort (Fig 4). Smoking ap-
pears to be an important local factor in the initiation
Acute pseudomembranous Thrush
Acute atrophic
or perpetuation of this form of candidosis. Biopsy is
(erythematous) Antibiotic sore mouth, essential since chronic hyperplastic candidosis is
glossodynia widely regarded as a premalignant condition, with
Chronic atrophic Denture sore mouth/denture- approximately 7% of lesions undergoing carcinoma-
(erythematous) induced stomatitis
tous change over 10 years.23
Chronic hyperplastic Candidal leukoplakia
Candida-associated
Angular cheilitis Perkhe ANGULAR CHEILITIS
Candida-associated
Median rhomboid Central papillary atrophy This condition may present either unilaterally or
glossitis of the tongue bilaterally at the angles of the mouth, usually asso-
See reference 19 for a review on classification of oral candi- ciated with ulceration surrounded by erythema (Fig
dosis. 5). Since the oral cavity can act as a reservoir of
998 ORAL CANDIDOSIS

FIGURE 1. Acute pseudomembranous candidosis. FIGURE 2. Acute atrophic candidosis.

FIGURE 3. Chronic atrophic candidosis. FIGURE 4. Chronic hyperplastic candidosis.

FIGURE 5. Candida-associated angular cheilitis. FIGURE 6. Candida-associated median rhomboid glossitis.

LEWIS ET AL
candidal infection, it is not surprising that patients
with angular cheilitis often wear dentures or other
prostheses. Intraoral candidal infection is thought
to predispose to angular cheilitis due to direct
spread from the mouth via saliva. Other bacterial
species, in particular staphylococci and strepto-
cocci, may also be encountered in angular cheilitis.
either alone or in combination with Can&da spe-
cies.14
MEDIAN RHOMBOID G~ossrrrs
Classically this condition appears as a painless
area of depapillation in the midline of the dorsum of
the tongue (Fig 6). The original concept that the
condition was developmental in origin and repre-
sented a remnant of the tuberculum impar has
largely been abandoned in favor of the belief that it
is a localized candidal infection.‘5 However, Can-
&da species have not always been isolated from
cases of median rhomboid glossitis, although this
could reflect inadequate sampling or misdiagnosis
of geographic tongue. Median rhomboid glossitis
occurs in about 1% of the general population, but is
twice as common in diabetics.“’ Lesions on the pal-
ate corresponding to areas of median rhomboid
glossitis have been described and are thought to be
due to contact with irritant candidal enzymes from
the tongue (for a review see reference 25).
Oral Candidosis in HIV Infection
There are at least four distinct clinical variants of
oral candidosis in HIV infection: 1) pseudomembra-
nous (thrush); 2) erythematous (atrophic); 3) hyper-
plastic; and 4) angular cheilitis.’ Erythematous and
pseudomembranous candidosis affects about one in
two HIV-positive individuals, while hyperplastic
candidosis and angular cheilitis are seen less fre-
quently. Another noteworthy feature of oral candi-
dosis in HIV infection is the presentation of the
disease in multiple oral sites: in HIV-negative indi-
viduals this would be called chronic multifocal oral
candidosis. About 60% of patients with HIV and
erythematous candidosis have multifocal lesions.
most frequently on the palate and dorsum of the
tongue (see reference 1 and 26 for reviews).
Progress in Antifungal Chemotherapy
Topical application of gentian violet, an aniline
dye derived from coal tar, was once the mainstay of
treatment of superficial forms of candidosis. How-
ever, it was messy to use, not particularly fungi-
tidal, and was superseded in the 1950s by the poly-
ene antifungals, nystatin and amphotericin. The
mechanism of action of the polyenes involves a di-
rect effect on the cell membrane, producing in-
999
creased permeability. However, if therapy has to be
prolonged, there is a problem with patient compli-
ance, which in part may be due to the taste of the
drugs. In addition to poor compliance, the polyene
agents do not achieve significant blood levels unless
given intravenously and have been associated with
side effects. More recently, azole-derived antimi-
crobial agents, which are believed to block synthe-
sis of ergosterol component of the fungal cell wall,
have become available. These agents would appear
to be the first antifungal drugs that can be safely
given systemically.
NYSTATIN
Nystatin became prescribable in clinical practice
in the 1950s and was the first specific polyene anti-
fungal agent shown to be effective in the treatment
of candidosis. The toxicity and insolubility of nys-
tatin when given parentally have limited its use to
topical treatment only. Analysis of pharmaceutical
preparations of nystatin has revealed that they con-
tain up to nine different components” and, there-
fore, its activity is usually expressed as interna-
tional units,‘” with a standard of 3,000 IU/mg.‘*
Nystatin can be given orally for the treatment of
gastrointestinal candidosis although it is not ab-
sorbed systemically in significant amounts. An ad-
ditional problem with prescribing nystatin is the un-
pleasant flavor, which can occasionally cause nau-
sea.”
AMPHOTERICINB
Amphotericin A and B are polyene agents that
were discovered 6 years after nystatin. Amphoteri-
tin A has subsequently been found to have no clin-
ical application, but amphotericin B has become
widely used. Like nystatin, amphotericin B is not
absorbed from the gut, but it can be given intrave-
nously or intrathecally for systemic candidosis.
However, systemic administration is associated
with side effects, particularly nausea and nephro-
toxicity,30 and therefore the use of amphotericin is
usually limited to topical application.
CLOTRIMAZOLE
Clotrimazole was the first imidazole antifungal
agent proved to be effective against human my-
coses.3’ However, since clotrimazole is poorly ab-
sorbed from the gut, its use has been limited to
topical treatment only.
MICONAZOLE
Miconazole was the second imidazole-derived
antifungal agent to be used regularly in the manage-
1000 ORAL CANDIDOSIS

ment of candidosis. It has the advantage of being
bacteriostatic in addition to having a fungicidal ef-
fect. Like clotrimazole, the drug is not absorbed
from the gut, although the intravenous route of ad-
ministration has been used with variable suc-
cess. 32*33However, miconazole has a useful role as
topical therapy for oral candidosis, particularly in
the treatment of angular cheilitis when a mixed bac-
terial/fungal flora is present.33
KETOCONAZOLE
Ketoconazole was the first of the imidazole
agents that was shown to be capable of achieving
therapeutic blood levels when given orally. This ab-
sorptive property led to the drug being used in the
treatment of chronic mucocutaneous candidosis,
gastrointestinal candidosis, and candidosis in im-
munocompromised patients.34 Although reported in
only 1: 12,000 of patients treated with ketoconazole,
a number of side effects, including nausea, cutane-
ous rashes, pruritus, and hepatotoxicity, have been
described.35 In addition, transient alterations of
liver function (usually elevation of serum transam-
inases) can occur and, therefore, it is essential to
monitor liver enzymes regularly.
FLUCONAZOLEAND ITRACONAZOLE
Fluconazole and itraconazole are two recently in-
troduced triazole antifungals that act by inhibiting
fungal ergosterol production, which is essential in
cell wall formation.36.37
A number of centers have studied the efficacy of
systemically administered triazoles in treating oral
candidosis in patients with HIV infection. In one
study, the efficacy and toxicity of ketoconazole
(200 mg daily) was compared with fluconazole (50
mg daily) in randomized prospective, double-blind
evaluation of 37 patients with either AIDS or AIDS-
related complex.38 On completion of therapy, erad-
ication of infection was seen in all patients treated
with fluconazole, but in only 75% of the patients
who were given ketoconazole. Microbiologic inves-
tigations attempting to isolate Candida species were
negative in 87% of the fluconazole group compared
with 69% of the ketoconazole group. One of 18 pa-
tients given fluconazole and 4 of 19 patients given
ketoconazole had transient rises in alanine or aspar-
tate transaminase level, indicating a degree of he-
patic dysfunction. It was concluded that flucona-
zole was more effective than ketoconazole in the
treatment of oral thrush among AIDS and ARC pa-
tients, although the rate of recurrent oral candidosis
was high in both groups. Subsequent prospective,
randomized studies have confirmed the finding that
fluconazole may be superior to ketoconazole in
treating AIDS-related oral candidosis.39,40
While some studies have compared the efficacy
of the two azole derivative drugs, others have ob-
served the usefulness of fluconazole in oral candi-
dosis, both in patients with and without HIV
infection.41-47 The various authors quoted in Table 2
have used different treatment regimes for flucona-
zole ranging from 50 mg per day for a few days or
weeks to 400 mg given as a single dose.
Examination of the information presently avail-
able (Table 2), and the results of controlled, ran-
domized double-blind studies,38-40 it would seem
that the regime of 50 mg per day (single dose ther-
apy) of fluconazole for a period of 2 to 3 weeks may

Table 2. Comparison of Fluconarole Treatment Regimes and Therapeutic Efficacy in the

Management of Oral Candidotis Related to HIV Infection
Sample Lesion
Authors Country Size Dosage Duration Resolution Comments

DuPont & France 61 50 mg/d 5 to 20 d 100% on day 7 No apparent side

Drouhet (1988) + MT effects
Lim et al UK 15 50 mg/d 2 wk 100% on -
(1989) day 14
Tschechne FR Germany 20 50 to 100 3 wk 90% on day 7 60% relapse 4 wk
et al (1989) mdd after treatment
Gil et al Spain 36 200 mg 100 mg/d In most on Relapse in 2
(1989) stat for 4 wk day 7 patients after 4 wk
Gudrun et al FR Germany 104 200 mg 100 mg/d 90% after Minimal side effects
(1989) stat for 3 wk 3 wk
Swiss AIDS Switzerland 45 150 mg - 86% on day 7 Median relapse
study group single dose interval 14 d
(1989)
Chave et al Switzerland 11 4OOmg - 100% on day 4 No resolution
(1988) single dose in one patient

Abbreviation: MT, maintenance therapy.

Modified from reference 1.
LEWIS ET AL
be adequate to prevent or suppress oral candidosis
in HIV-infected patients. Indeed, 50 mg per day is
the dose recommended by drug manufacturers for
the treatment of oral candidosis. Nevertheless, ei-
ther maintenance therapy or intermittent therapy
with fluconazole is essential to prevent relapse after
cessation of treatment. However, some workers38
feel that maintenance therapy is not warranted and
intermittent therapy is adequate. Further studies
are therefore required to ascertain both the useful-
ness and optimum doses of either maintenance or
intermittent therapy.
Itraconazole also has been found to be effective
in the treatment of chronic oral candidosis and can-
didosis of HIV infection.48*49 However, it has been
recommended that the dose of itraconazole should
be increased from the standard 100 mg once daily
for nonimmunocompromised patients to 200 mg
once daily for AIDS patients due to reduced absorp-
tion of the drug in these individuals.
Introduction of new antimicrobials is almost al-
ways associated with the emergence of resistant
flora.50 As far as triazoles and Candida species are
concerned, there are disconcerting report?.” that
indicate that the yeasts may already be developing
resistance to this new group of drugs. In one report,
the susceptibilities of 62 oral isolates of C afbicans
obtained from patients infected with HIV have been
examined and only three strains were resistant to
itraconazole, one strain was resistant to ketocona-
zole, and another to 5-fluorocytosine.51 A point of
note, however, is that the patients in whom resis-
tant strains were isolated had undergone treatment
with ketoconazole only, implying that the in vivo
exposure to the latter may have induced cross-
resistance to other antifungals. The development of
cross resistance of C albicans to different imid-
azoles during treatment with a single azole deriva-
tive has been described previously.53,54 It is. there-
fore, salutary to keep this behavior of C afbicans in
mind when planning treatment protocols.
Summary
Candidosis is a common opportunistic infection
of the oral cavity that may occur as a result of a
variety of local or systemic factors. Oral candidosis
is also now recognized as one of the earliest mani-
festations of HIV infection and, therefore, all health
workers should be aware of the presenting features
of candidal infection within the mouth.
Clinical trials have shown that fluconazole and
itraconzaole are effective in controlling candidosis
in immunocompromised patients. Both of these tri-
azole drugs appear to be much less toxic than the
systemic antifungal agents that were available pre-
viously. A new era in antifungal treatment has ar-
1001
rived and the clinician is now faced with a wider
choice of effective agents.
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