AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
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• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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Background

Candidosis describes a group of yeastlike fungal infections involving the skin and mucous membranes. Infection is caused by Candida species, typically, Candida albicans.

By tradition, the most commonly used classification of oral candidosis divides the infection into 4 types including (1) acute pseudomembranous candidosis (thrush), (2) acute atrophic (erythematous) candidosis, (3) chronic hyperplastic candidosis, and (4) chronic atrophic (erythematous) candidosis.

Chronic hyperplastic candidosis was further subdivided into 4 groups based on localization patterns and endocrine involvement including (1) chronic oral candidosis (candidal leukoplakia), (2) endocrine candidosis syndrome, (3) chronic localized mucocutaneous candidosis, and (4) chronic diffuse candidosis.

Thrush (acute pseudomembranous candidiasis) is the term used for the multiple white-fleck appearance of acute candidiasis, which purportedly resembles the appearance of the bird with the same name.

Erythematous candidosis is the term used for the red lesions of candidiasis.

Pathophysiology

C albicans is the predominant causal organism of most candidosis. Other species, including Candida krusei, have appeared in persons who are severely immunocompromised. Candida glabrata is an emerging cause of oropharyngeal candidosis in patients receiving radiation for head and neck cancer. In patients with HIV infection, new species, such as Candida dubliniensis and Candida inconspicua, have been recognized.

C albicans is a harmless commensal organism inhabiting the mouths of almost 50% of the population; however, under suitable circumstances, it can become an opportunistic pathogen. A suitable circumstance may be a disturbance in the oral flora or a decrease in the immune defenses.

Acute pseudomembranous candidosis (thrush)

Thrush may be observed in healthy neonates or in persons in whom antibiotics, corticosteroids, or xerostomia disturb the oral microflora. Oropharyngeal thrush occasionally complicates the use of corticosteroid inhalers. Immune defects, especially HIV infection, immunosuppressive treatment, leukemias, lymphomas, cancer, and diabetes, may predispose patients to candidal infection.

Erythematous candidosis

Erythematous candidosis may cause a sore red mouth, especially of the tongue, in patients taking broad-spectrum antimicrobials. It also may be a feature of HIV disease. Median rhomboid glossitis is a red patch occurring in the middle of the dorsum in the posterior area of the anterior two thirds of the tongue and especially is observed in smokers and in those with HIV disease.

Chronic mucocutaneous candidosis

Chronic mucocutaneous candidosis (CMC) describes a group of rare syndromes, which sometimes include a definable immune defect, in which persistent mucocutaneous candidosis responds poorly to topical treatment. Generally, the more severe the candidosis, the greater the likelihood that immunologic defects (particularly of cell-mediated immunity) can be identified. Recent studies suggest a defect in cytokine (interleukin 2 and interferon-g) production in response to candidal and some bacterial antigens, with reduced TH1 lymphocyte function and enhanced TH2 activity (and increased interleukin 6), and reduced serum levels of immunoglobulin G2 and immunoglobulin G4.

Frequency

United States

Candidosis is common in groups at risk, such as patients who are immunocompromised. Frequency of infection is rising, primarily because of HIV infection and both the increase in candidal species other than C albicans and the resistance to antifungals.

International

Candidosis is common in groups at risk, such as patients who are immunocompromised.

Mortality/Morbidity

Candidosis may predispose individuals to esophageal spread.

Sex

Candidosis is reported equally in males and females worldwide, except in areas where males with HIV infection outnumber females.

Age

Candidosis predominantly occurs in middle-aged or older persons; however, in those with HIV infection, candidal infection primarily occurs in the third and fourth decades.

CLINICAL

Section 3 of 11  

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History

• Thrush
• • White patches on the surface of the oral mucosa, tongue, or other parts of the body characterize thrush.
  • Lesions develop into confluent plaques that resemble milk curds and can be wiped off to reveal a raw erythematous and sometimes bleeding base.
• Erythematous candidosis
• Erythematous areas found generally on the dorsum of the tongue, palate, or buccal mucosa are characteristic.
• Lesions on the dorsum of the tongue present as depapillated areas.
• Red areas often are seen on the palate of individuals with HIV infection.
• An associated angular stomatitis may be present.
• Chronic hyperplastic candidosis (candidal leukoplakia)
• • A chronic, discrete, raised lesion that may vary from a small, palpable, translucent, or whitish area to a large, dense, opaque plaque that is hard and rough to the touch (plaquelike lesion) is observed.
  • Homogeneous or speckled areas, which do not rub off (nodular lesions), can be seen.
  • Speckled leukoplakia accounts for 3-50% of candidal leukoplakias.
  • Candidal leukoplakias usually occur on the inside surface of one or both cheeks; they occur less commonly on the tongue.
• Chronic multifocal oral candidosis
• • In a minority of individuals, chronic candidal infection may be seen in multiple oral sites with various combinations including (1) angular stomatitis, which is unilateral or bilateral and is encountered mostly in denture wearers; (2) retrocommissural leukoplakia, which is the most constant component of the tetrad; (3) median rhomboid glossitis; and (4) palatal lesions.
  • Additional criteria include (1) lesions of more than 1-month duration; (2) absence of predisposing medical conditions; (3) exclusion of individuals undergoing radiotherapy or administration of the following types of drugs: anti-inflammatory, immunosuppressive, cytotoxic, or psychotropic agents or antibiotics.
  • This type is most common in male tobacco smokers in their fifth or sixth decade.
  • Antifungal therapy clears the infection and produces clinical improvement; however, recurrence is common, unless smoking can be reduced.
• Denture-related stomatitis (denture-induced stomatitis, denture sore mouth, chronic atrophic candidosis)
• • Chronic erythema and edema of the mucosa that contacts the fitting surface of the denture are characteristic. The mucosa below the lower denture rarely is involved.
  • Occasional slight soreness is experienced; however, the patient typically is asymptomatic. The typical presenting complaint is angular stomatitis.
  • Denture-related stomatitis is classified into 3 clinical types as follows:
  • • Localized simple inflammation or a pinpoint hyperemia
    • Erythematous or generalized simple type presenting as more diffuse erythema involving a part of, or the entire, denture-covered mucosa
    • Granular type (inflammatory papillary hyperplasia) commonly involving the central part of the hard palate and the alveolar ridge
• Angular stomatitis (perlèche, angular cheilitis)
• • Lesions affect the angles of the mouth; soreness, erythema, and fissuring are characteristic; diagnosis commonly is associated with denture-related stomatitis.
  • Both yeasts (candidal) and bacteria (especially Staphylococcus aureus) may be involved.
  • Angular stomatitis commonly is an isolated initial sign of anemia or vitamin deficiency, such as vitamin B-12, and resolves when the underlying disease has been treated. Iron deficiency anemia and other vitamin deficiencies have been cited as other predisposing factors.
  • In uncommon conditions, such as orofacial granulomatosis, as many as 20% of individuals have angular stomatitis, although candidal species often are not isolated. Angular stomatitis also may be seen in individuals with HIV infection.
• Median rhomboid glossitis (glossal central papillary atrophy)
• • Papillary atrophy, which is symmetric and elliptic or rhomboidal in shape, is located centrally at the midline of the tongue, anterior to the circumvallate papillae.
  • Occasionally, median rhomboid glossitis presents with a hyperplastic exophytic or lobulated appearance.
  • Histopathologically, candidal hyphae infiltrate the superficial layers of the parakeratotic epithelium, and a polymorphonuclear leukocyte infiltrate occupies the epithelium, with elongated hyperplastic rete ridges and a lymphocyte infiltration in the corium. However, the condition frequently shows a mixed bacterial-fungal microflora, as has been documented.
• Exfoliative cheilitis may occasionally be associated with Candida species, especially in individuals with HIV infection.

Physical

• The diagnosis usually is made based on physical examination.
• Gram-stained smear (hyphae) or oral rinse may aid in the diagnosis.
• Differentiate pseudomembranous candidosis from lichen planus. Hairy leukoplakia, leukoplakia, or Fordyce spots occasionally cause confusion.
• Differentiate erythematous candidosis from other inflammatory stomatitides, lichen planus, and erythroplakia.

Causes

Members of the genus Candida are the causal organisms of candidosis. Secretion of antimicrobial proteins and peptides is decreased in saliva of patients with oral candidosis. The following factors affect candidal carriage and infection:

• Carriage is more frequent in females than in males; carriage is frequent during the summer months.
• Increased carriage rates are seen in immunocompromised states (eg, HIV infection), blood group O, and nonsecreting of blood group antigens in the saliva possibly mediated by an effect on C albicans adhesion to epithelia.
• Carriage of yeast is higher in acidic saliva.
• Xerostomia increases the carriage of C albicans.
• Use of psychotropic drugs that cause xerostomia increases carriage of candidal organisms and S aureus.
• Candidal counts increase during sleep but are reduced by eating a meal and by brushing the teeth.
• • Counts usually are highest first thing in the morning; the organism frequently cannot be isolated when counts are low, except in the early morning. Early morning saliva sample is the most dependable for making a comparison of the candidal population in individuals.
  • C albicans counts consistently are low in early morning saliva specimens from edentulous patients not wearing dentures. This is attributed to sleeping without dentures and the consequent alteration in the oral environment.
  • When dentures are worn at night, the early morning saliva candidal count is high; when dentures are not worn at night, the early morning count is the lowest. Increased candidal count following reinsertion of the dentures suggests that plaque on the dentures harbors C albicans.
  • Increase in both the frequency of carriage and the density of candidal colonization in denture wearers compared with dentate individuals suggests that prostheses encourage the presence and growth of candidal species.
• Smoking affects candidal infection as follows:
• • Some studies have reported that smoking significantly increased carriage from 30-70%.
  • Smoking increased the risk in persons with HIV infection.
  • Smoking commonly underlies multifocal candidosis and median rhomboid glossitis.
• Tetracycline therapy: Candida species can be isolated from the oral cavity with greater prevalence and in greater numbers during tetracycline therapy.
• Ecologic balance disruption: Under normal circumstances, it appears unlikely that candidal organisms establish in the mouths of noncarriers; however, if the ecologic balance is altered (by bacterial suppression, alteration of salivary flow, or immunologic deficit), candidal infection may occur.
• Similarities between carriers and noncarriers of C albicans with respect to age, caries experience, periodontal status, and intraoral temperature indicate that these factors do not influence candidal carriage significantly.
• Factors predisposing individuals to oral candidal infections are as follows:
• • Broad-spectrum antimicrobial therapy may predispose individuals to stomatitis or glossitis caused by C albicans.
  • Topical, systemic, and aerosolized corticosteroid use may result in oral yeast infection.
  • Smoking predisposes individuals to chronic atrophic candidosis and other forms of candidosis.
  • Drugs with xerostomic adverse effects (eg, psychopharmaceuticals) are associated with oral candidosis. Xerostomia (as in Sjögren syndrome and after radiotherapy) predisposes individuals to candidosis.
  • Immunologic disorders: Candidosis is common in patients with HIV infection and other secondary immunodeficiencies, including blood dyscrasias, diabetes, and malignant disease.
  • CMC can be a feature of primary immune defects such as severe combined immune deficiency syndrome.
  • Diabetes may predispose individuals to candidosis.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Hairy leukoplakia
Fordyce spots

WORKUP

Section 5 of 11  

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Lab Studies

• Quantitative saliva culture is useful in the diagnosis of oral candidosis. Carriers and patients with oral candidal infection can be distinguished reliably (95% confidence limits) on the basis of quantitative culture, since they harbor more than 400 colony-forming units of candidal organisms per mL of saliva.
• • Request patient to rinse mouth for 60 seconds with 10 mL of sterile phosphate-buffered saline (PBS; pH 7.2) or sterile water; then, return the oral rinse to the universal container. If the patient wears a denture, remove it prior to sampling.
  • A rapid commercial system (Microstix-Candida or Oricult-N test) for diagnosing oral candidosis is useful for screening patients in the clinical setting, particularly when microbiology laboratories are not in easy access.
• Because Candida species stain poorly by hematoxylin and eosin, staining with periodic acid-Schiff (PAS), Gridley stain, or Gomori methenamine silver (GMS) stain is used.
• • In both Gridley stain and the PAS procedure, fungi appear pinkish red. GMS technique stains yeast cell walls brown-black as a result of deposition of reduced silver.
  • Presence of blastospores and characteristic pseudohyphae or hyphae in the superficial epithelial tissues identifies the fungus as a species of Candida.
  • GMS staining alone cannot perform the speciation of the organism; therefore, cultural studies also should be used. Blastospores similar to those in Candida species may be seen in histoplasmosis or cryptococcosis, both of which are increasingly prevalent and may manifest orally with increasing frequency in the AIDS epidemic. If only blastospores of candidal organisms are seen in tissue sections of patients in whom infection is suspected, serial sections should be searched carefully for pseudohyphae or hyphae.
• Immunologic tests
• • Immunity in superficial candidosis and in oral candidosis is predominantly cell mediated. Cell-mediated immunity to C albicans antigens can be demonstrated in most human subjects both by the appearance of delayed skin hypersensitivity to antigens and by in vitro tests of cellular immunity, such as inhibition of leukocyte migration or stimulation of lymphocyte transformation to candidal antigens.
  • As tests of humoral immunity, the candida agglutinin test, candida complement-fixation test, candida precipitin test, immunofluorescence, and enzyme-linked immunoassay (ELISA) have been used.
  • In the serologic tests, 4 principal types of Candida antigens have been used, including (1) whole nonviable yeast cells, (2) candidal culture filtrates, (3) cell wall polysaccharides or glycoproteins, and (4) cytoplasmic antigens from mechanically disrupted yeast cells.
  • Serologic tests for candidal organisms are not diagnostic tools, since the diagnosis can be achieved more readily by clinical evaluation and by smear or culture.
• Hematologic investigations
• • Because oral candidosis frequently is associated with HIV disease, nutritional deficiencies, diabetes, or blood dyscrasias, estimates of corrected whole blood folate, vitamin B-12, serum ferritin, glucose, hemoglobin, lymphocyte, and WBC counts can be important.
  • Tests, such as lymphocyte function, serum immunoglobulins, calcium status, or parathyroid hormone levels, are unnecessary except in CMC.
  • Tests of thyroid or adrenocortical function are warranted in selected individuals, since endocrine disorders may be associated with oral candidosis.
  • HIV testing may be indicated.

Procedures

• Histopathology: Although swabs and smears are essential for a microbiological diagnosis of a number of types of oral candidosis, when candidal leukoplakia (chronic hyperplastic candidosis) is suspected, a biopsy specimen should be taken.

TREATMENT

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Medical Care

Attention to the underlying cause helps avoid prolonged or repeated courses of treatment. If antibiotics or corticosteroids (oral or inhaled) are the probable cause, reducing the dose or changing the treatment may help.

• Intermittent or prolonged topical antifungal treatment may be necessary when the underlying cause is unavoidable or incurable.
• In patients with severe immunosuppression, prevention of colonization and infection is the goal because the oropharyngeal region may be the primary source of initial colonization and allows subsequent spread of the infection.
• • Individuals at greatest risk of fungal infection, such as patients with HIV disease and people receiving cancer chemotherapy, immunosuppressive therapy, or prolonged antibiotic therapy, may need prophylactic antifungals.
  • In HIV infection, topical agents often initially control the infection until the increasing immune defect necessitates systemic agents.
  • Topical antifungal agents are available as rinses, tablets, vaginal tablets, and creams.
  • Oral rinses are useful for patients with dry mouth who may have difficulty dissolving tablets.
  • Some oral products are sweetened with sugar, predisposing patients to dental caries.
• Denture plaque often contains Candida species. To prevent denture-induced stomatitis, denture cleansing that includes removal of candidal organisms is a necessary and important factor.
• • Cleansers can be divided into groups according to their primary components: alkaline peroxides, alkaline hypochlorites, acids, disinfectants, and enzymes.
  • Yeast lytic enzymes and proteolytic enzymes are the most effective against the infection.
  • Denture soak solution containing benzoic acid completely eradicates C albicans from the denture surface as it is taken up into the acrylic resin and eliminates the organism from the internal surface of the prosthesis.
  • An oral rinse containing 0.12% chlorhexidine gluconate results in complete elimination of the presence of C albicans on the acrylic resin surface of the denture and in reduction of palatal inflammation.
  • A protease-containing denture soak (alkalize protease) also effectively removes denture plaque, especially when combined with brushing.
• Chlorhexidine oral rinses also may be of some benefit in the control of oral candidosis. It is important to note that clinical cure is not synonymous with mycologic cure.

Diet

High-sucrose diets should be avoided.

MEDICATION

Section 7 of 11  

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Antifungal treatment may be necessary for the treatment of candidiasis.

Fluconazole and HIV infection

Fluconazole has been active against oral candidosis in HIV disease and produces remission within approximately 1 week. Fluconazole has gained preference mainly because it is rapidly effective, has a long half-life, and lacks serious adverse effects. Fluconazole 100 mg qd is more effective against oropharyngeal candidosis in HIV infection than nystatin 500,000 U qid or clotrimazole troche 10 mg 5 times per day.

Maintenance therapy or intermittent therapy with fluconazole is essential to prevent relapse after cessation of treatment; 50 mg qd prevents recurrence of candidosis as does 150 mg/wk. It appears that a regime of 50 mg/d (single-dose therapy) of fluconazole for 2-3 wk may be adequate to prevent or suppress candidosis in patients infected with HIV.

Patients undergoing therapy for metastatic malignancy were assigned randomly to receive fluconazole or placebo as antifungal prophylaxis. Oropharyngeal candidosis developed in only 2% of patients receiving fluconazole but in 28% of patients receiving placebo. These favorable results indicate that fluconazole should be evaluated as antifungal prophylaxis in patients at greatest risk of developing serious fungal infections, such as transplant patients or those receiving chemotherapy for malignant diseases.

Fluconazole prophylaxis reduces not only the chance of candidosis in HIV disease but also mycoses such as cryptococcosis. Fluconazole also has been used successfully to treat some patients with acute cryptococcal meningitis in uncontrolled trials, although the time to elimination of the organism in cerebrospinal fluid (CSF) was slower than with amphotericin B.

Fluconazole was not as effective in treating cryptococcal meningitis as amphotericin B and flucytosine in a patient with HIV disease; however, fluconazole may be considered in patients with clinically mild disease. Initial use of amphotericin B and flucytosine followed by fluconazole to prevent relapse may be considered. Prevention of recurrent cryptococcal meningitis with daily fluconazole is effective and better tolerated than weekly amphotericin. While amphotericin has been standard therapy, fluconazole recently has been effective in treating patients infected with HIV with coccidioidomycosis.

Drug Category: Antifungals

Currently available azoles are imidazoles (eg, clotrimazole, miconazole, econazole, ketoconazole) and triazoles (eg, fluconazole, itraconazole), which are synthetic antifungals with broad-spectrum activity against a number of yeasts and fungi including candidal organisms. They are fungistatic and expensive. They inhibit fungal cytochrome P450-dependent enzymes, which are essential catalysts for the 14-demethylation of lanosterol in sterol biosynthesis and block synthesis of ergosterol, the principal sterol in fungal cell membranes. One adverse effect of azoles is accumulation of precursors of ergosterol, which may have effects on their own.

Diazoles (eg, ketoconazole, miconazole) have more effect on mammalian cytochromes than do triazoles (eg, fluconazole, itraconazole) and tend to have more severe adverse effects. None of the azoles is entirely benign. Hepatotoxicity may be common to all of them, and the potential for endocrine toxicities exists, particularly at high doses. As with any new agent, novel toxicities may be discovered.

Azoles are effective antifungals, but resistance increasingly is reported. Development of cross-resistance of C albicans to different azoles during treatment with a single azole derivative has been described.

A new triazole, D0870 (Voriconazole), has activity against fluconazole-resistant C albicans.

Drug Name	Miconazole (Absorbine, Femizole, Lotrimin, Monistat, Maximum Strength Desenex)
Description	For topical treatment of candidosis such as angular stomatitis. Miconazole lacquer is effective for treatment of chronic atrophic candidosis; chewing gum may be effective against intraoral candidosis. Available for parenteral use against systemic mycoses, but injection contains polyethoxylate castor oil, which may provoke allergic reactions.
Adult Dose	Cream and lotion: Apply to affected areas bid for 2-6 wk Powder: Spray or sprinkle liberally on affected area bid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	If sensitivity or chemical irritation occurs, discontinue use; use only externally; avoid contact with eyes; given IV may cause liver damage and pruritus, nausea, blood dyscrasias, hyponatremia, hyperlipidemia, and dysrhythmias

Drug Name	Econazole (Spectazole)
Description	Effective in cutaneous infections. Interferes with RNA and protein synthesis and metabolism. Disrupts fungal cell wall membrane permeability, causing fungal cell death.
Adult Dose	Apply sparingly on affected areas qd/bid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	If sensitivity or irritation develops, discontinue use; for external use only; avoid contact with eyes

Drug Name	Ketoconazole (Nizoral)
Description	First imidazole agent capable of achieving therapeutic blood levels when given orally. Used in treatment of CMC and candidosis in patients who are immunocompromised. Cream form can be used to treat angular stomatitis. Oral ketoconazole can be effective for treatment of severe oral and esophageal candidosis, but patient compliance often is poor because of taste of drug. Failures also may be related to drug malabsorption, ketoconazole-resistant strains of C albicans, or adverse effects. To be taken with food since gastric acid is essential for dissolution and absorption, but absorption is variable and adverse effects are common. Acidic pH is required for drug absorption, which can be enhanced by taking drug with orange juice, a carbonated beverage, or glutamic acid. Is poorly absorbed from an empty stomach or with concurrent use of medications, such as cimetidine, ranitidine, and other antacids. Poorly absorbed in patients with AIDS because of gastric atrophy and reduced acid production.
Adult Dose	200-400 mg/d PO
Pediatric Dose	<2 years: Not established >2 years: 3.3-6.6 mg/kg/d PO once
Contraindications	Documented hypersensitivity; fungal meningitis
Interactions	Isoniazid may decrease bioavailability of ketoconazole; coadministration decreases effects of either rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (cyclosporine dose can be adjusted); may decrease theophylline levels; ketoconazole may interact with terfenadine (recalled from US market), astemizole (recalled from US market), and cisapride to produce dysrhythmias and increase activity of anticoagulants, cyclosporin, midazolam, and sulfonylureas
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects may include nausea, rashes, abdominal pain, pruritus, and liver damage; transient disturbance of liver function (eg, increased serum aminotransferase concentrations) is so common that regular monitoring of LFTs is essential in patients on systemic ketoconazole for more than a few days; severe liver damage may occur; blocks hormone steroid synthesis and reduces testosterone levels; adrenocortical suppression may develop; less toxic than amphotericin B but less effective in treatment of severe candidosis and other mycosis; maintenance therapy often is ineffective and both fluconazole and itraconazole may be more effective in prophylaxis

Drug Name	Fluconazole (Diflucan)
Description	Inhibits fungal ergosterol production essential in cell wall formation by inhibiting the cytochrome c-dependent demethylation step in formation of ergosterol. Has little affinity for mammalian cytochromes, which is believed to explain its low toxicity. Adhesion of candidal organisms to epithelial cells, widely recognized as an essential step in the process of candidal colonization and subsequent infection, is inhibited significantly. Since fluconazole is secreted in saliva in high concentrations, it is tempting to speculate that it may interfere with synthesis or structure of candidal receptors on buccal epithelial cells. Active against most C albicans, although resistance may appear, but is less active against non-C albicans species. Tends to be active against Candida parapsilosis and Candida tropicalis, but less active against Candida glabrata, and is not active against C krusei. Well absorbed from gut, even in the absence of acidity of the stomach. Can penetrate into other body fluids including CSF. Oral absorption is rapid and almost complete within 2 h. Plasma half-life is approximately 30 h. IV preparations are available for patients who cannot take medication PO. Appears to undergo relatively little metabolism in the body; elimination is predominantly renal. With normal renal function, the serum half-life is approximately 30 h. Concentration of drug in CSF is estimated to be from 50-90% of plasma concentration, suggesting that fluconazole is given best qd and penetrates into CSF and urine in high concentrations. Enters saliva, although salivary levels are higher and persist longer after use of an oral suspension, compared to oral use. Is effective in patients with chronic atrophic oral candidosis, particularly when administered concurrently with oral antiseptic such as chlorhexidine. For patients with CMC in whom relapse after initial remission is expected, a dose of 50 mg produces clinical and mycologic responses in approximately 10 d. Active against oral candidosis in HIV disease and produces remission within approximately 1 wk.
Adult Dose	50-100 mg PO qd or 150 mg PO qwk
Pediatric Dose	3-6 mg/kg qd for 14-28 d or 6-12 mg/kg qd depending on severity of infection
Contraindications	Documented hypersensitivity
Interactions	Levels may increase with hydrochlorothiazide; fluconazole levels may decrease with chronic coadministration of rifampin; coadministration of fluconazole may decrease phenytoin clearance; may increase concentrations of theophylline, tolbutamide, glyburide, and glipizide; effects of anticoagulants may increase with fluconazole coadministration; increases in cyclosporine concentrations may occur when administered concurrently; elevated plasma concentrations of tolbutamide, cyclosporine, phenytoin, and warfarin have been observed after fluconazole administration
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Generally well tolerated; toxicity is mild and infrequent; with usual doses, fluconazole does not appear to suppress synthesis of corticosteroid hormones; nausea, headache, and rashes may occur; although serious cutaneous reactions and hepatitis have occurred in some patients, these reactions appear to be infrequent; may be teratogenic

Drug Name	Itraconazole (Sporanox)
Description	Orally active triazole that inhibits ergosterol biosynthesis in fungal cell. Has long half-life and fewer adverse effects than ketoconazole but is expensive and eliminated hepatically. Well absorbed and achieves good distribution in body and may be more active than ketoconazole. Absorption is impaired when gastric acid is reduced or when antacid, rifampicin, or phenytoin is given. May interact with terfenadine, astemizole, and cisapride to produce dysrhythmias and to increase the activity of anticoagulants, cyclosporin, midazolam, and sulfonylureas. Adverse effects have included altered liver function (hepatotoxicity is less than that of ketoconazole) and hypokalemia with hypertension resulting from accumulation of steroids with an aldosteronelike activity, mild leukopenia, nausea, epigastric pain, headache, and edema. Available in 50- and 100-mg cap and 10-mg/mL oral solution. Administering 100-200 mg/d for 2 wk gives good clinical and laboratory results compared to ketoconazole and clotrimazole. GI absorption is reduced in HIV disease. Availability of oral solution may offer advantages over capsules because it acts topically and is easier to swallow for patients with oral candidosis and to administer by NG tube. Active against all candidal species; therefore, may be indicated in patients who are immunocompromised and in whom other antifungals may predispose to selection and overgrowth of resistant species. Has been successful at a dose of 200 mg/d for 4 wk in treatment of candidosis. Absorption from GI tract in persons with HIV infection is approximately one half of that in healthy individuals. Dose of 100 mg PO qd or bid probably is as effective as fluconazole. Available for topical use as a solution. Dose of 200 mg qd is more effective than clotrimazole or ketoconazole.
Adult Dose	200 mg PO qd; not to exceed 400 mg/d; increase in 100-mg increments if no improvement (administer >200 mg/d in divided doses); 200 mg IV bid for 4 doses, followed by 200 mg/d
Pediatric Dose	Not established; 100 mg/d suggested for systemic fungal infections
Contraindications	Documented hypersensitivity; coadministration with cisapride may cause adverse cardiovascular effects (possibly death)
Interactions	Antacids may reduce absorption; edema may occur with coadministration of calcium channel blockers (eg, amlodipine, nifedipine); hypoglycemia may occur with sulfonylureas; may increase tacrolimus and cyclosporine plasma concentrations in high doses; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (lovastatin or simvastatin); coadministration with cisapride can cause cardiac rhythm abnormalities and death; may increase digoxin levels; coadministration may increase plasma levels of midazolam or triazolam; phenytoin and rifampin may reduce itraconazole levels (phenytoin metabolism may be altered)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic insufficiency

Drug Name	Voriconazole (Vfend)
Description	Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.
Adult Dose	Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses Maintenance: 4 mg/kg IV q12h infused over 2 h, when able to tolerate PO may switch to 200 mg PO q12h Note: For inadequate response, may increase to 300 mg PO q12h; <40 kg administer oral maintenance dose of 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; do not administer IV form with CrCl <50 mL/min (decreased excretion of IV vehicle); coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids
Interactions	CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin) have shown to decrease steady state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, of which some are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids) and others may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Decrease maintenance dose with hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (including Stevens-Johnson syndrome and phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity have been reported; administer PO 1 h ac or pc

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention:

• Patients should avoid smoking, xerostomic medication, antibiotics, corticosteroids, and immunosuppressants.

Complications:

• Antifungal azole resistance currently is well recognized and is becoming a significant clinical concern, particularly in persons with HIV infection and other immunocompromised conditions. Azole resistance appears to arise because of changes in the target enzyme 14-alpha sterol demethylase, reduced fungal membrane permeability to azoles, changes in delta-5 and delta-6 desaturase, or increased efflux of azoles from the organisms.
• Ketoconazole resistance has been reported, but is not a concern, since fluconazole is active against at least some ketoconazole-resistant Candida species.
• Emergence of resistance during fluconazole therapy currently is a true clinical concern, especially in persons who use illegal intravenous drugs. The commercially available E test is a simple reliable test useful in detecting fluconazole-resistant C albicans.
• • Fluconazole resistance appears to result from a mutation and may appear in patients who have received no fluconazole, since resistance may be transferred, possibly through sexual transmission.
  • Previous fluconazole use and severe immune defects are risk factors for fluconazole resistance.
  • Intermittent fluconazole or low-dose therapy is more likely than continuous or high-dose therapy to induce resistant species.
  • One US study found that at least 1 fungal species resistant to fluconazole was isolated from 41% of patients with AIDS; other studies found that as many as 20% of patients had fluconazole-resistant oral candidosis.
  • Some evidence exists of cross-resistance of some C albicans and non-C albicans isolates to ketoconazole, fluconazole, and itraconazole, although the clinical significance of this in HIV disease remains to be established.
  • Some studies indicate that ketoconazole and itraconazole may be clinically effective, despite some cross-resistance.
  • Itraconazole in particular may remain effective, although clinical efficacy may be impaired. Approximately 30% of fluconazole-resistant isolates may be resistant to itraconazole. Itraconazole also is effective as a cyclodextrin solution in patients with fluconazole-resistant candidosis.
  • Therapy in fluconazole-resistant cases includes topical amphotericin, higher oral doses of fluconazole (200-600 mg/d), a fluconazole suspension as an oral rinse, or the use of ketoconazole (400 mg/d) or itraconazole (200-400 mg/d).
• Oral, intravenous, or liposomal amphotericin also may be effective, and, although resistance to oral amphotericin eventually arises, intravenous amphotericin appears to remain effective.

Prognosis:

• Good for most infections in the immunocompetent host, but in patients who are immunocompromised, antifungal resistance is commonplace.

Patient Education:

• For excellent patient education resources, visit eMedicine's Yeast and Fungal Infections Center. Also, see eMedicine's patient education article Candidiasis (Yeast Infection).

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to take adequate specimens, possibly resulting in misdiagnosis. Early treatment is indicated, and complicating factors should be excluded.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Pseudomembranous candidosis.
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Media file 2:  Erythematous candidosis in HIV/AIDS.
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Media file 3:  Denture-related stomatitis; a common form of oral candidiasis. From Scully C, Flint SF, Porter SR, Moos K. Atlas of Oral and Maxillofacial Diseases. 2004. Martin & Taylor, London.
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Media file 4:  Angular stomatitis; a common form of oral candidiasis, typically seen in patients with denture-related stomatitis, especially those in whom the denture needs adjustment. In others, it may be a sign of diabetes, nutritional deficiency, or immune defect.
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Media type:  Image

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• Fanello S, Bouchara JP, Sauteron M, et al. Predictive value of oral colonization by Candida yeasts for the onset of a nosocomial infection in elderly hospitalized patients. J Med Microbiol. Feb 2006;55(Pt 2):223-8. [Medline].
• Golecka M, Oldakowska-Jedynak U, Mierzwinska-Nastalska E, Adamczyk-Sosinska E. Candida-associated denture stomatitis in patients after immunosuppression therapy. Transplant Proc. Jan-Feb 2006;38(1):155-6. [Medline].
• Lynch DP. Oral candidiasis. History, classification, and clinical presentation. Oral Surg Oral Med Oral Pathol. Aug 1994;78(2):189-93. [Medline].
• Rautemaa R, Hietanen J, Niissalo S, et al. Oral and oesophageal squamous cell carcinoma - A complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral Oncol. Sep 22 2006;[Medline].
• Redding SW, Dahiya MC, Kirkpatrick WR, et al. Candida glabrata is an emerging cause of oropharyngeal candidiasis in patients receiving radiation for head and neck cancer. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Jan 2004;97(1):47-52. [Medline].
• Scully C, el-Kabir M, Samaranayake LP. Candida and oral candidosis: a review. Crit Rev Oral Biol Med. 1994;5(2):125-57. [Medline].
• Sitheeque MA, Samaranayake LP. Chronic hyperplastic candidosis/candidiasis (candidal leukoplakia). Crit Rev Oral Biol Med. 2003;14(4):253-67. [Medline].
• Taillandier J, Esnault Y, Alemanni M. A comparison of fluconazole oral suspension and amphotericin B oral suspension in older patients with oropharyngeal candidosis. Multicentre Study Group. Aging. Mar 2000;29(2):117-23. [Medline].
• Tanida T, Okamoto T, Okamoto A, et al. Decreased excretion of antimicrobial proteins and peptides in saliva of patients with oral candidiasis. J Oral Pathol Med. Nov 2003;32(10):586-94. [Medline].

Article Last Updated: Mar 28, 2007