Mucosal Candidiasis 

Candidiasis describes a group of fungal infections involving the skin and mucous membranes. Infection is caused by Candida species, primarily Candida albicans.[1] C albicans is a dimorphic fungus that can asymptomatically colonize the oral or genital mucosae in healthy individuals.[2] Oral colonization is estimated in 50% of healthy adults,[3] while genital colonization is seen in 21% of women.[4] When the local ecology is disturbed, or where there is an immune defect, Candida overgrowth may lead to an opportunistic infection. The mucosal surfaces primarily affected by candidiasis are the oral cavity, esophagus, angles of the mouth, and genitals (causing vulvovaginitis in females, balanitis in males).

Oral candidiasis may present as either white or erythematous lesions and either an acute or chronic infection.[5] Thus, the presentations can be divided into the following four subtypes:

• Acute pseudomembranous candidiasis (thrush): The classic multiple white-flecks on the tongue, buccal mucosa, and palate
• Chronic hyperplastic candidiasis: Thick white plaques on the buccal mucosa and labial commissures
• Acute atrophic (erythematous) candidiasis: Erythematous patches on the palate
• Chronic atrophic candidiasis (denture stomatitis): A form of erythematous candidiasis, resulting from poorly fitted dentures causing a burning, sore mouth

There are also conditions that may predispose individuals to chronic, multifocal infections from Candida. This can lead to syndromes such as chronic mucocutaneous candidiasis (CMC).

C albicans is a dimorphic fungus that asymptomatically inhabits the mouths of almost 50% of the population. Overgrowth of Candida is protected against by local T cells and interleukin (IL)–17.[6] Thus, when immunity is compromised, growth proceeds unchecked and leads to opportunistic infections.

Candidiasis is seen in people with altered ecology, which in oral cases can be attributed to dental appliances, xerostomia, antimicrobials, nasopharyngeal steroids, or oral cancer. Impaired systemic immunity is another major cause of infection, notably in patients who are on immunosuppressive therapy, infected by HIV, or have diabetes.[7, 8]

C albicans is the predominant causal organism of most candidiasis. Other species, such as Candidatropicalis and Candidastellatoidea, more often appear in persons who are severely immunocompromised.

Secreted aspartyl proteinases (SAPs) are proteins secreted by Candida that contribute to virulence by facilitating invasion and inflammation. The prevacuolar protein sorting gene, VPS4, is required for extracellular secretion of SAPs, and it is a key component of the virulence of Candida.[9] Additionally, studies have shown that women with vulvovaginal candidiasis have higher levels of SAPs in their vaginal fluid.[10]

In those with dental devices, Candida, upon attachment, can form a small subcolony of persister cells. These cells have been shown to be highly resistant to antimicrobials, and they provide a mechanism for the recurrent formation of biofilms.[11]

Chronic mucocutaneous candidiasis

Chronic mucocutaneous candidiasis (CMC) describes a group of rare syndromes, in which persistent mucocutaneous candidiasis responds poorly to topical treatment. It is associated with immune defects, particularly in T-cell, dendritic cell, and T-helper 17 (Th17) cell function. Studies have demonstrated specific signals that when compromised, cause defects in the response to candidal antigens. Identified defects include overproduction of IL-6, underproduction of IL-23, and deficiency of IL-17.

There are many risk factors that increase the incidence of candidiasis. Immunosuppression is the most significant of these, and it can be due to diabetes, antibiotics, immunosuppression, systemic steroid use, and HIV infection, among others.

• Immunocompromise: Increased carriage rates are seen in several conditions, including HIV infection, diabetes, systemic steroid use, aerosolized steroid use, immunosuppression, and malignancy
• Hyposalivation: Increases carriage of Candida and can be due to drug effects (antipsychotics), Sjögren syndrome, radiotherapy, or chemotherapy
• Poor oral hygiene: Candida counts increase during sleep but are reduced by eating and brushing the teeth
• Dentures: Removal and reinsertion of dentures cause increases in salivary candidal counts, suggesting that plaque on the dentures harbors C albicans
• Missing teeth: Being edentulous increases the overlap of skin at the corners of the mouth, increasing the risk for angular cheilitis formation
• Smoking: Increases Candida carriage by 30-70%
• Antibiotic use: Increases carriage of Candida
• Vitamin deficiencies: Higher association of candidiasis with vitamin B-12 and iron deficiency

The prognosis is good for most infections in the immunocompetent host, but in patients who are immunocompromised, antifungal resistance is commonplace. Oral candidiasis may predispose individuals to esophageal spread. Systemic spread is rare, but can occur in the severely immunocompromised.

For patient education resources, see the following:

• Overview of oropharyngeal thrush from the Centers for Disease Control and Prevention (CDC): Candida infections of the mouth, throat, and esophagus
• Overview of vulvovaginal candidiasis from the CDC: Vaginal Candidiasis
• Overview of balanitis from the University of Maryland Medical Center: Balanitis
• Candidiasis (Yeast Infection)

Acute pseudomembranous candidiasis (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 that when removed, reveal a raw, erythematous, and sometimes bleeding base.

Chronic hyperplastic candidiasis

This is characterized by thick, white plaques on the buccal mucosa or the tongue that are hard or rough to the touch. Unlike the lesions of acute pseudomembranous candidiasis (thrush), the lesions of chronic hyperplastic candidiasis are more adherent and difficult to scrape off.[5]

Homogeneous or speckled areas, which do not rub off (nodular lesions), can be seen. Speckled leukoplakia accounts for 3-50% of candidal leukoplakias.[12]

Acute atrophic (erythematous) candidiasis

Erythematous areas on the dorsum of the tongue, palate, or buccal mucosa are characteristic. Lesions on the dorsum of the tongue present as depapillated areas. Angular stomatitis may also be present. In those taking antimicrobials, a sore red mouth, especially of the tongue, may be present.

Chronic atrophic candidiasis (denture stomatitis)

Chronic erythema and edema of the mucosa that contact the fitting surface of the denture are characteristic, causing soreness and burning. The mucosa below the lower denture rarely is involved. It may co-present with angular cheilitis.

Denture-related stomatitis is classified into three clinical types as follows:

• Localized inflammation or a pinpoint hyperemia
• Generalized erythema involving a part of, or the entirety of, denture-covered mucosa
• Granular type (inflammatory papillary hyperplasia) commonly involving the central part of the hard palate and the alveolar ridge: Hyperplasia of oral mucosa can be seen

Angular stomatitis (perlèche, angular cheilitis)

This is a subset of erythematous candidiasis. Lesions affect the angles of the mouth, causing soreness, erythema, and fissuring. Both yeasts (candidal) and bacteria (especially Staphylococcus aureus) may be involved. 

Angular cheilitis is not specific for mucosal candidiasis. It can also be seen with vitamin B-12 or iron deficiency, Down syndrome, orofacial granulomatosis, Crohn disease, HIV infection, or diabetes.

Median rhomboid glossitis (glossal central papillary atrophy)

This is also a subset of erythematous candidiasis. Median rhomboid glossitis is an erythematous, atrophic lesion on the dorsum of posterior tongue. It is most frequently seen in those who smoke or have HIV infection.

Diagnosis begins with a thorough history and physical examination.

Patients should be asked about immunosuppressive agents (local and systemic), antibiotics, other opportunistic infections, risky sexual contact, and dental procedures. Patients should be asked about difficulty or pain with swallowing, which can be an indication of esophageal spread. During the physical examination, directly visualize the lesions by examining all areas of the mouth or genitals.

Depending on the severity of the infection, potassium hydroxide (KOH) preparation, culture, and antimicrobial sensitivities should be done to confirm the diagnosis.

The initial test for Candida infection is usually cytologic examination by scraping a lesion and placing the sample on a slide. Application of 10% KOH and applying gentle heat lyses host cells and allows for visualization of the organism. Candida presents with pseudohyphae and budding yeasts. In patients with chronic or recalcitrant disease, culture may be performed to confirm the diagnosis and identify resistant organisms. Susceptibility to antifungals can also be obtained and may be useful in the cases of treatment-resistant, recurrent, or immunosuppressed-associated infections.[13]

As tests of humoral immunity, the Candida agglutinin test, Candida complement-fixation test, Candida precipitin test, immunofluorescence, and enzyme-linked immunoassay (ELISA) are available options. Immunity in superficial candidiasis and in oral candidiasis is predominantly cell mediated. Delayed skin hypersensitivity to antigens and in vitro tests of cellular immunity can demonstrate cell-mediated immunity to candidal antigens.

In suspected cases of chronic mucocutaneous candidiasis (CMC), testing for HIV disease, diabetes, folate, vitamin B-12, ferritin, hemoglobin, and blood cell counts should be performed. Tests of thyroid or adrenocortical function are warranted in selected individuals, since endocrine disorders can be associated with oral candidiasis or CMC.

Medical therapies

Medications used to treat candidiasis can be topical or systemic agents, and, in most cases, therapy is initiated with topical medications. However, severe disease, esophageal involvement, or inadequate response to topical medications may warrant systemic therapy. The following treatment recommendations are adapted from the Clinical Practice Guideline for the Management of Candidiasis from the Infectious Diseases Society of America (IDSA).[14]

Oropharyngeal treatment is as follows:

• Mild: Nystatin suspension four times a day for 1-2 weeks, or 10 mg clotrimazole troche five times a day for 1-2 weeks
• Moderate to severe: 100-200 mg oral daily fluconazole for 1-2 weeks
• Refractory to fluconazole: 200 mg itraconazole solution once a day for up to 4 weeks
• HIV patients: Antiretroviral therapy strongly recommended
• Dentures: Disinfect dentures along with antifungal therapy
• Chlorhexidine oral rinses may be of some benefit in the control of oral candidiasis, as may some essential oils ^[15]

Esophageal treatment is as follows:

• Requires systemic therapy; empiric treatment is acceptable prior to endoscopy
• Initial therapy: 200-400 mg oral daily fluconazole for 2-3 weeks
• Unable to tolerate oral medication: 400 mg daily intravenous fluconazole, or an echinocandin (eg, 150 mg daily intravenous micafungin), then deescalate when tolerable to 200-400 mg oral daily fluconazole
• Refractory to fluconazole: 200 mg itraconazole solution once a day, or 200 mg oral or intravenous voriconazole twice a day for 2-3 weeks
• Recurrent: Long-term therapy with 100-200 mg oral fluconazole three times per week

Vulvovaginitis treatment is as follows:

• Uncomplicated: Any topical azole or a single dose of 150 mg oral fluconazole
• Severe or immunosuppressed: 2-3 doses of 150 mg oral fluconazole every 72 hours
• Candida glabrata infection, unresponsive to azoles: 600 mg intravaginal boric acid capsule nightly for 10-14 days, ^[16] or intravaginal nystatin ^[17]
• Recurrent: Induction therapy with 2 weeks of a topical agent or oral fluconazole, followed by weekly 150 mg oral fluconazole for 6 months

Balanitis treatment is as follows:

• Mild: Topical imidazole twice a day for 1-2 weeks
• Severe or recurrent: 50-100 mg oral fluconazole once a day for 2 weeks

Chronic mucocutaneous candidiasis treatment is as follows:

• Patients with associated endocrine abnormalities, such as those involving the parathyroid, should have electrolytes monitored and corrected as necessary
• Initial: 400-800 mg oral fluconazole once a day for 4-6 months
• Maintenance: 200 mg oral fluconazole once a day

Resistance of fungi to azoles is rare, but some Candida species, such as C glabrata and C krusei, are innately less susceptible to azoles. C albicans can acquire azole resistance.[18]

Boric acid

This can be compounded by a pharmacist or purchased online. Patients may also make their own capsules using boric acid powder and gelatin capsules. They should fill the narrow half of the capsule, and then cap it with the wider half. To prevent recurrence, boric acid can be used twice a week. The mechanism by which topical boric acid is effective in vulvovaginitis due to Candida is not well understood, but one theory is that it may inhibit oxidative metabolism or impair virulence. Adverse effects can be mild, such as local irritation. Systemic adverse effects can also occur and can include fever, vomiting, and seizures. Patients should be warned that boric acid capsules can be fatal if swallowed, and they should not be used during pregnancy.

Treating underlying causes

Attention to the underlying cause helps avoid prolonged or repeated courses of treatment. If antibiotics or corticosteroids (oral or inhaled) are the underlying 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.

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. Denture soak solutions with benzoic acid eradicate C albicans from the denture surface by being taken up by the acrylic resin and eliminating the organism from the internal surface of the prosthesis. Oral rinses containing 0.12% chlorhexidine gluconate eliminate C albicans on the acrylic resin surface of the denture, and they reduce palatal inflammation. Protease-containing denture soaks (alkalize protease) remove denture plaque, especially when combined with brushing.

Xerostomia causing candidiasis can benefit from keeping the mouth moist through hydration, ice chips, or lozenges. If the dry mouth is the anticholinergic adverse effect of another medication, consider switching to another medication or changing the dosage. Treatment with cholinergic agents may also be considered.

Patients should be counseled about smoking, and they should be warned about the risk of developing mucosal candidiasis after taking medications that impair salivation, antibiotics, corticosteroids, and other immunosuppressants.

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Class Summary

Azoles are synthetic antifungals with broad-spectrum fungistatic activity against yeasts and fungi, including candidal species. By blocking fungal cytochrome P450-dependent enzymes, azoles disrupt the synthesis of ergosterol, which is the principal sterol in fungal cell membranes. The two subclasses of azoles are imidazoles (eg, clotrimazole, miconazole, econazole, ketoconazole) and triazoles (eg, fluconazole, itraconazole).

The most common adverse effect of topical azoles is local skin and mucous membrane irritation. The most common adverse effects of systemic azoles are gastrointestinal distress, morbilliform rash, and hepatotoxicity. Most azoles have additional adverse effects specific to each drug, and these are listed below. Diazoles (eg, ketoconazole, miconazole) have a stronger effect on human cytochromes than triazoles (eg, fluconazole, itraconazole) and therefore tend to have more severe adverse effects.

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

Clotrimazole (Lotrimin, Mycelex, Femizole, Gyne-Lotrimin)

Clotrimazole is available as topical therapy. As a 10-mg troche, clotrimazole is effective against oral candidiasis in some patients who are immunocompromised. It is less effective than other azoles in patients with HIV infection. 

Fluconazole (Diflucan)

Fluconazole is available as systemic therapy. Compared with other azoles, it has lower toxicity while maintaining a half-life of 30 hours in patients with normal renal function. Fluconazole is active against most C albicans, although resistance is occasionally seen. It is less active against other species, such as C glabrata, and it has no activity against C krusei.

Itraconazole (Sporanox)

Itraconazole is available as systemic therapy. Itraconazole is active against all Candida species. Therefore, it may be advantageous in patients who are immunocompromised and in whom other antifungals may predispose to selection and overgrowth of resistant species. It may interact with terfenadine, astemizole, and cisapride to produce dysrhythmias and to increase the activity of anticoagulants, cyclosporine, midazolam, and sulfonylureas. Adverse effects include hepatotoxicity, hypokalemia, and peripheral neuropathy.

Voriconazole (Vfend)

Voriconazole is available as systemic therapy. It is effective against organisms that demonstrate resistance to fluconazole, including C krusei. The associated adverse effects include phototoxicity, arrhythmia, and visual disturbances.

Class Summary

This class of antifungals includes the drugs amphotericin B and nystatin. Amphotericin B is available as a systemic therapy, and nystatin is available as topical therapy. Polyenes irreversibly bind to the cell membrane sterol, ergosterol, causing disruption by increasing cell membrane permeability. They are fungistatic at low concentrations and become fungicidal at higher concentrations.

Amphotericin, in particular, is notorious for its adverse effects. It can cause fevers, electrolyte disturbances, nephrotoxicity, arrhythmias, as well as a number of skin eruptions. Severe reactions from amphotericin include seizures, agranulocytosis, and hepatotoxicity.

Amphotericin B deoxycholate (Amphotericin B (conventional), Fungizone)

This is one of the oldest antifungals and has been in use for more than 40 years; it is the criterion standard of antifungal therapy. Lipid formulations have been developed. The total dose must be adjusted depending on the type of candidal infection being treated. Most patients receive a total dose of 0.5-1.5 g.

Nystatin (Mycostatin, Nilstat, Nyamyc)

This is a fungicidal and fungistatic antibiotic obtained from Streptomyces noursei. It is effective against various yeasts and yeastlike fungi. It changes the permeability of the fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak. Membrane channel activity is increased at lower doses, and pores are formed at higher concentrations.