eMedicine Specialties > Dermatology > Diseases of the Oral Mucosa

Noncandidal Fungal Infections of the Mouth

Crispian Scully, MD, PhD, DSc, FRCPath, MRCS, CBE, MDS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FMedSci, FHEA, FUCL,DSc, DChD, DMed(HC), Dr hc., Professor, Director of Special Projects, Eastman Dental Institute for Oral Health Care Sciences; Professor, Special Needs Dentistry, University College; Professor, Oral Medicine, Pathology and Microbiology, University of London
Maria Regina Sposto, DDS, PhD, MDSc(Dental Science), PhD(Dentistry), Associate Professor of Oral Diagnosis and Oral Medicine, Consulting Staff, Department of Oral Surgery and Diagnosis, Faculdade de Odontologia de Araraquara, UNESP-Universidade Estadual Paulista, Brazil

Updated: Sep 23, 2008

Introduction

Background

Candidiasis is the most common fungal infection of the mouth. This article, however, focuses on noncandidal oral fungal infections. A few eMedicine articles on candidiasis include Candidiasis, Chronic Mucocutaneous; Candidiasis, Mucosal; and Candidiasis, Cutaneous.

This article discusses 6 noncandidal oral infections: aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, and mucormycosis. Although these noncandidal fungal infections are considerably less common than oral candidiasis, they commonly produce subclinical infection, especially pulmonary infections.

In rare cases, these infections can produce clinical disease in healthy persons. Systemic mycoses in healthy individuals are more common in endemic areas than elsewhere, and they are often asymptomatic and may spontaneously resolve. In otherwise healthy persons, acute pulmonary and primary mucocutaneous symptomatic lesions may resolve without treatment. However, chronic pulmonary infection tends to progress and disseminated infections can be fatal. Immunocompromised persons are at particular risk from these mycoses, and clinical manifestations of infection by these organisms often suggest impaired immune competence.¹ Patients at greatest risk include those with leukemia, leukopenia, solid tumors, transplants,² or HIV disease.^3,4 Also at risk are premature infants.

Noncandidal fungal infections have the potential for serious injury to the oral cavity and sometimes also the paranasal sinuses, the orbit, and the cranial base. Orofacial lesions caused by the main systemic mycoses may occasionally be seen in isolation, but they are typically associated with lesions elsewhere, often in the respiratory tract. The oral lesions associated with these deep fungal infections are chronic, may mimic neoplasms, and progress to form solitary, chronic deep ulcers with the potential for local destruction and invasion and systemic dissemination.

Chronic oral ulceration, chronic maxillary sinus infection, or bizarre mouth lesions, especially in patients with HIV disease, those with lymphoproliferative disorders, persons with diabetes mellitus, or those who have been in endemic areas, may suggest the diagnosis and patients should be treated in consultation with a physician with appropriate expertise.

Most of these mycoses are diagnosed on the basis of a history of foreign travel or an immunocompromised state. Investigations include smears, biopsy, staining with periodic acid-Schiff (PAS) or Gomori methenamine silver, culture of the affected tissues, serodiagnosis (sometimes), physical examination, and chest radiography. Unfortunately, specific immunostaining for an accurate diagnosis of most mycoses is available only in a few laboratories.

Definitive diagnosis is achieved by means of microbiologic or histologic identification and serodiagnosis. DNA probes are available for several species. Prompt identification and treatment, usually with systemic antifungal drugs, are essential; delayed treatment or no treatment can result in considerable orofacial destruction, systemic dissemination, or death.

Most systemic mycoses can be treated with systemic amphotericin. Azoles are often considered better, but their cost is prohibitive where they are most needed, that is, in the developing world.

The Medscape Immune Reconstitution Resource Center and Emerging and Reemerging Infectious Diseases Resource Center may be of interest.

Pathophysiology

Aspergillosis

More than 160 species and variants of Aspergillus organisms have been discovered, although only 10 are pathogenic in humans. Aspergillus fumigatus is the most common pathogen, but Aspergillus flavus, Aspergillus glaucus, Aspergillus nidulans, Aspergillus terreus, Aspergillus repens, Aspergillus parasiticus, and Aspergillus niger are also encountered. A flavus is the most virulent.

Aspergillus species are the most common environmental fungi, being prolific saprophytes in soil and decaying vegetation. Inhalation of the conidia is very likely extremely common, but, unless the inhalation is massive or unless the host is immunocompromised, clinical disease is rare. Nevertheless, aspergillosis is found worldwide. Its prevalence is increasing, and this is the most prevalent mycosis second only to candidosis.

The organisms exist as prolific saprophytes in soil and decaying vegetation. Inhalation of the organisms allows for their germination and colonization in the mucosa of the respiratory tract, including the mouth. Lesions may be established primarily in the oral mucosa, but they more commonly begin in the mucosa of the maxillary sinus. They may appear in the oral cavity after local invasion and/or destruction of the surrounding structures. Inhalation of the spores is common, although clinical disease is rare unless the individual is immunocompromised by medication (eg, chemotherapy,⁵ organ transplantation immunosuppression) or disease (eg, HIV infection, leukemia, lymphoma).

Blastomycosis

Blastomycosis is a term sometimes used to include a range of granulomatous systemic mycoses, including North American blastomycosis (Gilchrist disease), South American blastomycosis (paracoccidioidomycosis or Almeida disease), coccidioidomycosis, and cryptococcosis. However, the nomenclature is now restricted mainly to the North American and South American forms of blastomycosis, which involve the viscera, lymph nodes, and mucocutaneous tissues.

Blastomyces dermatitidis causes the North American form, whereas Paracoccidioides brasiliensis causes the South American form. As expected, North American blastomycosis is seen predominantly in North America, in the Mississippi, Missouri, and Ohio River valleys in the United States and in southern Canada. However, it is also seen in Africa, India, the Middle East, and Australia.

B dermatitidis, which is found in soil and spores, may be inhaled to produce respiratory tract and sometimes disseminated disease. Serotype 1 is seen in North America, and serotype 2 is seen in Africa. Outdoor workers are particularly affected, but blastomycosis is increasingly recognized in persons with HIV disease.

Coccidioidomycosis

Coccidioidomycosis is seen mainly in arid parts of the Western hemisphere, such as the southwestern United States, Mexico, Central America, and parts of South America. Inhalation of spores of Coccidioides immitis, found in soil, produces subclinical infection in up to 90% of the population in such areas.

Cryptococcosis

Cryptococcosis is seen worldwide in humans and animals. Aspiration of Basidiobolus spores, mainly capsular serotype A but sometimes serotype D of Cryptococcus neoformans (a ubiquitous yeast found especially in pigeon feces and present in soil), may lead to infection. Two varieties have been described, which are C neoformans var neoformans (synonymous with capsular serotypes A, D, and AD) and the less common C neoformans var gattii (synonymous with capsular serotypes B and C). C neoformans var neoformans is found in excreta from pigeons, canaries, parrots, and budgerigars and in rotting fruit and vegetables. C neoformans var gattii is associated with a particular tree, the Red River gum tree (Eucalyptus camaldulensis).

Histoplasmosis

Histoplasmosis is the most frequently diagnosed systemic mycosis in the United States and has now been reported in approximately 30 countries worldwide. Histoplasma capsulatum, the causal organism, is a soil saprophyte found particularly in northeastern and central states such as Missouri, Kentucky, Tennessee, Illinois, Indiana, and Ohio (mainly in the Ohio and Mississippi valleys). The organism has also been found in Latin America, India, the Far East, and Australia. H capsulatum var duboisii is the type mainly found in equatorial Africa.

Histoplasma species are commonly found in bird and bat feces. In endemic areas, the organism is a soil saprophyte, and more than 70% of adults appear to be infected, typically with subclinical manifestations, as a result of inhaling spores.

Mucormycosis⁶

Mucor and Rhizopus species are the most common agents to cause zygomycosis. Fungi of the order Mucorales (of the class Zygomycetes) are responsible for most mucormycosis. However, in addition to Mucor and Rhizopus species, organisms from the genera Absidia, Apophysomyces, Mortierella, Saksenaea, Rhizomucor, and Cunninghamella may also be involved. Therefore, the condition is probably better termed zygomycosis.

These fungi are ubiquitous worldwide in soil, manure, and decaying organic matter. Classic zygomycosis occurs worldwide. In some warmer regions, other Zygomycetes such as Conidiobolus coronatus infect a range of animals and can also occasionally cause rhinofacial zygomycosis in humans. Most human cases have been recorded from the Caribbean, Latin America, and Central and West Africa.

Mucoraceae are commonly cultured from the nose, throat, mouth, and feces of many healthy individuals, but infection is virtually unheard of in otherwise healthy individuals.

Paracoccidioidomycosis

South American blastomycosis (paracoccidioidomycosis or Almeida disease) is found mainly in Colombia, Venezuela, Uruguay, Argentina, and particularly Brazil. In Brazil, the disease is endemic in the states of Sao Paulo, Rio de Janeiro, and Minas Gerais. P brasiliensis is responsible and is presumably being inhaled as spores. Subclinical infection is not uncommon in endemic areas.

Frequency

United States

Because of the ubiquitous presence of these fungi in the environment, exposure is common. However, clinical disease is uncommon except in persons with iatrogenic or pathologic immunosuppression.

International

Because of the ubiquitous presence of these fungi in the environment, exposure is common in endemic areas, and travelers may present with manifestations even years after exposure. However, clinical disease is uncommon except in persons with iatrogenic or pathologic immunosuppression.

Mortality/Morbidity

In a healthy individual, infection is typically self-limited, although latency is commonly established, rather than elimination. Reactivation of latent infection may subsequently occur if the infected individual becomes immunosuppressed.

• Primary infection or reactivation in individuals with impaired immune surveillance presents a different scenario in which the disease may continue as a locally invasive and destructive process. Once the organism breaks through local barriers and enters the blood or lymphoreticular system, dissemination is rapid and difficult to control.
• Untreated, these fungal infections can be fatal, and among patients who are immunosuppressed (eg, those with AIDS, diabetes, leukemia, lymphoma, or iatrogenic immunosuppression as in organ transplantation), death rates dramatically increase.
• Regional destruction of the maxilla by paranasal infections leads to considerable morbidity, including oroantral fistula with oronasopharyngeal insufficiency and orbital invasion, which may result in loss of the eye.

Race

The deep mycoses can affect individuals of all races; no racial predilection is recognized.

Sex

The mycoses affect both sexes equally.

Age

The deep mycoses can affect individuals of all ages, although they are more common in adults than in children. Elderly individuals may be at increased risk, although this is often secondary to impaired immunity.

Clinical

History

The following conditions may predispose individuals to infection. These conditions require an evaluation to determine whenever a deep fungal infection is established.

• Drug use
  • Use of corticosteroids
  • Use of cytotoxic agents
  • Use of immunosuppressants
• Immunodeficiency
  • Due to HIV
  • Due to AIDS
• Endocrinologic condition
  • Poorly controlled diabetes mellitus
  • Ketoacidosis
• Malignancy
  • Leukemia
  • Lymphoma
  • Others
• Other conditions
  • Neutropenia
  • Malnutrition
  • Old age

Physical

Patients with deep mycoses may present with a primary infection of the oral mucosa, but, more commonly, they present with an extension of an established paranasal infection. Therefore, by the time oral lesions are present, considerable destruction of the maxilla and maxillary sinus may have occurred.

In healthy individuals, the disease is usually self-limiting, but in individuals who are immunocompromised, extensive local destruction, fungemia, visceral and cerebral invasion, and death are substantial risks.

The most common presentation of oral deep fungal infection is a chronic, solitary ulcer or nodule. When infection involves the palate, this finding may be only the initial indication of considerable antecedent destruction of the maxilla and maxillary sinus. Extension and/or invasion into the orbital and cranial cavity are not uncommon. The condition may be indistinguishable from other causes of chronic oral ulcers (eg, tuberculosis, malignancy).

• Aspergillosis^7,8,9
  • Orofacial lesions caused by Aspergillus species include antral aspergilloma, invasive aspergillosis of the antrum, indolent chronic sinusitis, allergic sinusitis, and oral lesions. Aspergilloma of the maxillary antrum is uncommon and typically occurs in a healthy host as a hyphal ball in a chronically obstructed sinus.
  • Invasive sinus aspergillosis is rare and affects mainly immunocompromised hosts, although it is also seen in some apparently healthy individuals, predominantly in subtropical countries with a warm climate (eg, Sudan, Saudi Arabia, India). Patients with leukemia, lymphoma, HIV disease, or iatrogenic immunosuppression (eg, those undergoing bone marrow or renal transplantation) are at particular risk from such invasive sinus aspergillosis. Although A fumigatus is the usual cause of invasive sinus aspergillosis, A flavus appears to predominate in immunocompromised individuals. Rarely, other species (eg, A repens) are encountered, sometimes with other mycoses such as Microascus cinereus.
  • In invasive sinus aspergillosis, the antral wall is destroyed; this damage may be characterized by antral pain, swelling, sequelae from orbital invasion (eg, impaired ocular motility, exophthalmos, or impaired vision), or intracranial extension (eg, headaches, meningism).
  • Chronic sinus aspergillosis is uncommon, and patients present with a diffusely opaque antrum radiographically, sometimes with dense punctate radiopacities. This disease is unresponsive to treatment used for bacterial sinusitis. Allergic fungal sinusitis is also uncommon and is usually due to fungi other than Aspergillus organisms.
  • Interestingly, subclinical defects in cell-mediated immune responses to Aspergillus species have been observed in patients with sinus aspergillosis. Occasional cases of sinus aspergillosis arise as a result of metastasis from pulmonary aspergillosis or iatrogenic factors following dental procedures such as extractions, endodontics, or implants in the maxilla.¹⁰
  • Oral lesions of aspergillosis are seen predominantly in some immunocompromised patients with invasive aspergillosis. Yellow or black necrotic ulcers typically appear on the palate or occasionally on the posterior tongue.
• Blastomycosis
  • Blastomycosis may become disseminated to produce ulcerating lesions that affect the oral mucosa.
  • Mandibular involvement is rare.
  • Cutaneous blastomycosis may spread to affect the lips.
• Coccidioidomycosis
  • Oral lesions from coccidioidomycosis are rare, but when they occur, they typically are reported secondary to lung involvement.
  • They are verrucous lesions, sometimes occurring with infection of the jaw.
  • They have yet to be reported in a patient with HIV disease.
• Cryptococcosis
  • Oral cryptococcal infection manifests mainly as nonhealing extraction wounds or chronic ulceration on the palate or tongue.
  • Several cases of cryptococcal oral lesions have recently been reported in persons infected with HIV. In the past, rare cases have been reported in individuals with leukemia.
• Histoplasmosis
  • Oral lesions of H capsulatum infection have been recorded mainly in persons with pulmonary or disseminated histoplasmosis, especially in patients with HIV infection.¹¹
  • Oral lesions are sometimes isolated and have also been recorded in apparently healthy persons. Oral lesions are usually ulcerative or nodular; have been found on the tongue, palate, buccal mucosa, or gingiva; and rarely invade the mandible or maxilla.
  • Oral lesions in African histoplasmosis are generally localized, affecting the tongue, buccal mucosa, or jaws.
• Paracoccidioidomycosis¹²
  • Oral lesions of paracoccidioidomycosis are chronic, often granular or exophytic, and ulcerated.
  • Antral lesions are rare.
  • Oral lesions of paracoccidioidomycosis appear to be uncommon in persons with HIV disease, although involvement of the submandibular lymph nodes and the presence of lesions outside the head and neck have been reported.
• Rhinosporidiosis: Oral lesions of rhinosporidiosis are usually proliferative lumps, especially affecting the soft palate.
• Zygomycosis
  • Rhinocerebral zygomycosis is usually caused by Rhizopus oryzae or Rhizopus arrhizus. The disease typically commences in the nasal cavity or paranasal sinuses and causes pain, nasal discharge, and fever; the organisms may then invade the palate to produce black, necrotic oral ulcers.
  • Orbital invasion may produce orbital cellulitis, impaired ocular movements, proptosis, and ptosis.
  • Intracranial invasion follows penetration of ophthalmic vessels or the cribriform plate.
  • Zygomycosis occasionally commences in the palate.

Causes

• Aspergillosis -A flavus, A terreus, and A fumigatus
• Cryptococcosis -C neoformans
• Histoplasmosis -H capsulatum
• Blastomycosis -B dermatitidis
• Mucormycosis (zygomycosis) -Mucor species and Rhizopus species
• Paracoccidioidomycosis -P brasiliensis

Differential Diagnoses

Other Problems to Be Considered

Underlying undiagnosed disorder leading to immunosuppression
Dissemination of fungal infection
Extension into or invasion of the paranasal sinuses, the orbit, or the cranial cavity

The condition may be indistinguishable from other causes of chronic oral ulceration, such as tuberculosis, malignancy, and any of the other deep mycoses.

Workup

Laboratory Studies

• Tests can include cytology smears; biopsy and staining with PAS or Gomori methenamine silver stain; cultures; DNA probing, which is becoming increasingly available but at present is not sufficient alone; and, in some circumstances, serodiagnosis, which is available for aspergillosis (galactomannan antigen testing) and cryptococcosis (capsular polysaccharide antigen testing). However, serodiagnosis is not adequate without the other tests mentioned, which are confirmatory tests.
  • The diagnosis of aspergillosis is confirmed by smear results and lesional microscopy findings. Staining with PAS or Gomori methenamine silver shows regular, narrow (4 µm wide), branching, and septate hyphae of Aspergillus species. However, hyphae of Fusarium species, Mucor species, and Pseudallescheria boydii may cause confusion. Immunostains may help for definitive diagnosis. Culture of tissue or fluids on Sabouraud or Mycosel agar may return positive results, but this is not invariable. Furthermore, the organisms are ubiquitous; therefore, isolation of Aspergillus organisms is not proof of disease. Estimations of serum precipitin and immunoglobulin E–specific antibody levels may support the diagnosis.
  • The diagnosis of blastomycosis is based on smear or culture results. Biopsy may show Blastomyces species in the tissue, with granulomas. Staining with PAS, methenamine silver nitrate, or Fontana-Masson stain helps in the identification. The organism can be mistaken for H capsulatum, C neoformans, Bipolaris species, or Wangiella dermatitidis. Direct immunostaining is the most useful means of confirmation. DNA probes can yield an answer in 2 hours. Skin test and serology results are, unfortunately, unreliable, although serotesting has improved.
  • Coccidioidomycosis is diagnosed mainly by means of a thorough history and physical examination supported by histology findings that show granulomas with spherules containing endospores. DNA probes are now available. Also helpful are serology and the spherulin or coccidioidin skin tests. Culture, although useful, is potentially hazardous to laboratory staff.
  • Cryptococcosis is confirmed by microscopy or by staining with PAS, mucicarmine, or methenamine silver stain. The stains show granulomas. Smears may also be stained with India ink or nigrosin. The yeast cell is round or elliptical, 4-6 µm in diameter, clear, and capsulated. It also fluoresces in ultraviolet light. Culture and assay of serum or cerebrospinal fluid for capsular antigen and antibody (latex agglutination test) may help in diagnosis.
  • Histoplasmosis is confirmed with microscopy, which shows granulomas with PAS-positive spores with a narrow halo in macrophages and microabscesses with necrosis. DNA probes are now available. Culture results on Sabouraud agar are also confirmatory. Complement fixation tests may be of value; a titer greater than 1:32 indicates infection, but several other serotests are also available. The histoplasmin skin test result is of little importance in diagnosis.
  • A diagnosis of mucormycosis is confirmed with smears or the histologic demonstration of tissue invasion by broad (5-50 µm), irregularly wide, nonseptate, branching hyphae. These hyphae characteristically invade blood vessels and cause thrombosis, ischemia, infarction, and necrosis. Methenamine silver or PAS staining is best to show the fungi, which are difficult to culture from a swab sample.
  • Paracoccidioidomycosis is diagnosed using pus or scrapings from a lesion. Examined in potassium hydroxide, the samples may show the rounded, refractive cells of P brasiliensis, which have characteristic multiple budding. Biopsy is required for definitive diagnosis; it reveals suppurative granulomas with giant cells and blastospores, which are double-contoured, cystlike structures approximately 30 µm in diameter. These are often surrounded by daughter spores (Mickey Mouse appearance). Methenamine silver nitrate or PAS stain is particularly useful to demonstrate the organisms, and direct immunostaining with Blastomyces antiserum is less frequently used. Smear or culture can also be diagnostically useful, but P brasiliensis grows extremely slowly. Serologic examination by means of immunodiffusion, or particularly complement fixation, is useful in epidemiologic studies. Reliable skin tests are not available.

Imaging Studies

• Chest radiography
• Plain radiography, CT scanning, or MRI to evaluate the submucosal extent

Other Tests

• CBC count with differential (eg, to evaluate for neutropenia or lymphopenia)
• Immunologic testing
• Comprehensive metabolic panel (eg, to evaluate for diabetes or malnutrition)
• HIV serostatus testing

Procedures

• Incisional biopsy with special stains (eg, PAS, methenamine silver)
• Cytologic smears

Treatment

Medical Care

Amphotericin B is an effective treatment for all forms of oral deep fungal infection. Flucytosine and rifampin enhance the activity of amphotericin B and may be indicated when the response to amphotericin B is inadequate. However, other agents that are less cytotoxic may also be effective. Treatment variably continues for 6-12 weeks after culture results are negative.

Azoles are considered better but the cost is prohibitive where they are needed most, that is, in the developing world.

Surgical Care

In addition to medical therapy, surgical debridement may be required, particularly in cases of aspergillosis and mucormycosis (zygomycosis). Invasive aspergillosis should be treated by means of surgical debridement supplemented with intravenous amphotericin and, as some suggest, hyperbaric oxygen. Zygomycosis used to be almost uniformly fatal and still has a mortality rate approaching 20%; therefore, control of underlying disease is essential if possible, together with systemic amphotericin therapy and surgical debridement.

Surgery may be further indicated in cases of mycoses to correct any defects resulting from fungal destruction of the maxilla, orbit, and/or cranial base.

Consultations

Consultation with a respiratory medicine specialist or an immunologist may be helpful.

Medication

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

Antifungal agents

The mechanism of action usually involves inhibiting pathways (enzymes, substrates, transport) necessary for sterol and/or cell membrane synthesis or altering the permeability of the fungal cell membrane (polyenes).

Amphotericin B (Amphocin, Fungizone)

Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols, (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak, with subsequent fungal cell death.

Dosing

Adult

0.3-1.5 mg/kg/d IV

Pediatric

0.25-1.5 mg/kg/d IV

Interactions

Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor renal function, serum electrolytes (eg, magnesium, potassium), liver function, CBC counts, and hemoglobin concentrations; resume therapy at lowest level (eg, 0.25 mg/kg) when therapy is interrupted for > 7 d; hypoxemia, acute dyspnea, and interstitial infiltrates may occur in patients with neutropenia receiving leukocyte transfusions (separate time of amphotericin infusion from time of leukocyte transfusion); fever and chills are not uncommon after first few administrations; nephrotoxicity, thrombophlebitis, thrombocytopenia, anemia, and hypokalemia may occur; rare acute reactions may include hypotension, bronchospasm, arrhythmias, and shock

Caspofungin (Cancidas)

Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall.

Dosing

Adult

50 mg IV qd

Pediatric

Not established

Interactions

Coadministration with cyclosporin may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels; may decrease levels of tacrolimus

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in moderate hepatic dysfunction (decrease dose); may exacerbate preexisting renal dysfunction or myelosuppression; hepatotoxicity, hypokalemia, and blood dyscrasia may occur

Flucytosine (Ancobon)

Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against Candida and Cryptococcus species and is generally used in combination with amphotericin B. Treats aspergillosis.

Dosing

Adult

50-150 mg/d PO in divided doses q6h

Pediatric

Not established

Interactions

Amphotericin B may increase toxicity; cytosine may inactivate; along with rifampin, increases activity of amphotericin B

Contraindications

Documented hypersensitivity; impaired renal or hepatic function

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in bone marrow suppression; adjust dose in renal impairment; hepatotoxicity, hypokalemia, blood dyscrasia, hypoglycemia, or cardiopulmonary arrest may occur

Fluconazole (Diflucan)

Fungistatic activity. Synthetic oral antifungal (broad-spectrum bistriazole) that selectively inhibits fungal cytochrome P-450 and sterol C-14 alpha-demethylation, which prevents conversion of lanosterol to ergosterol, thereby disrupting cellular membranes.

Dosing

Adult

200 mg/d PO/IV

Pediatric

6-12 mg/kg/d PO/IV

Interactions

Levels may increase with hydrochlorothiazides; levels may decrease with long-term coadministration of rifampin; may increase concentrations of theophylline, phenytoin, tolbutamide, cyclosporin, glyburide, and glipizide; may increase effects of anticoagulants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adjust dose for renal insufficiency; closely monitor if rashes develop, and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) when taken with underlying medical conditions (eg, AIDS, malignancy) or while taking multiple concomitant medications; not recommended for mothers who are breastfeeding; hepatotoxicity and leukopenia may occur

Ketoconazole (Nizoral)

Fungistatic activity. Imidazole broad-spectrum antifungal; inhibits synthesis of ergosterol, causing cellular components to leak and resulting in fungal cell death.

Dosing

Adult

200 mg/d PO
200-400 mg/d PO, with food or soda

Pediatric

5-10 mg/kg/d PO

Interactions

Isoniazid may decrease bioavailability; coadministration decreases effects of rifampin or ketoconazole; may increase effect of anticoagulants; may increase toxicity of corticosteroids and cyclosporine (can adjust cyclosporine dosage); may decrease theophylline levels; decreases metabolism of repaglinide, increasing serum levels and effects

Contraindications

Documented hypersensitivity; fungal meningitis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May reversibly decrease corticosteroid serum levels (adverse effects avoided with dose of 200-400 mg/d); administer antacids, anticholinergics, or H2-blockers at least 2 h after taking; hepatotoxicity, leukopenia, and thrombocytopenia may occur

Miconazole (Monistat IV)

Damages fungal cell wall membrane by inhibiting biosynthesis of ergosterol. Membrane permeability is increased, causing nutrients to leak and resulting in fungal cell death. Interferes with mitochondrial enzymes.

Dosing

Adult

400-1200 mg IV q8h

Pediatric

5-40 mg/kg/d IV q8h

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Fever, chills, rash, itching, anorexia, thrombocytopenia, cardiac arrest, and anemia may occur

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting cytochrome P-450 – dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Dosing

Adult

50-400 mg/d PO
Alternatively, 200 mg/d IV

Pediatric

5 mg/kg/d IV

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 when high doses are used; rhabdomyolysis may occur with coadministration of HMG-CoA reductase inhibitors (eg, lovastatin, 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 levels (phenytoin metabolism may be altered)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in hepatic insufficiencies; hepatotoxicity and hypokalemia

Follow-up

Complications

• Drug resistance
• Drug interactions and adverse effects
• Structural defects or loss of function (eg, resulting from fungal destruction of the maxilla, orbit, and/or cranial base)

Prognosis

• Most fungal infections in apparently healthy individuals are self-limiting or subclinical and have a good prognosis.
• If a deep fungal oral lesion develops, the likelihood of self-limiting disease is significantly reduced, and the lesion likely represents a potentially serious underlying infection.
  • Although most deep fungal infections respond to aggressive antifungal therapy, infections can be fatal, particularly mucormycosis and aspergillosis.
  • Deep fungal infections should be viewed as serious and potentially life threatening.

Miscellaneous

Medicolegal Pitfalls

• Failure to diagnose the chronic oral ulcer is a pitfall.
• Any lesion that persists unexplained for more than 2 weeks must be evaluated using biopsy, culture, and/or imaging.
• Chronic oral ulceration, chronic maxillary sinus infection, or bizarre mouth lesions, especially in patients who have traveled to endemic areas or are immunocompromised in any way, should be treated with suspicion.

Multimedia

Media file 1: Aspergillosis. Note deep mucosal ulceration and nodular expansion of the hard palate. Courtesy of David Sirois, DMD, PhD.

Media file 2: Blastomycosis. Top image shows nonspecific papillary nodular lesion on the hard palate. Bottom image shows extensive ulceration involving the skin of the face and neck. Courtesy of David Sirois, DMD, PhD.

Media file 3: Histoplasmosis. Top image shows periodontal recession and deep ulceration with exposed necrotic alveolar bone (arrow). Bottom image shows solitary, deep ulceration of the gingivae also associated with necrotic bone (arrow). Courtesy of David Sirois, DMD, PhD.

Media file 4: Mucormycosis. Top left image shows multiple, deep ulcerations (arrows) of the hard palate. Top right image shows destruction of the palate and the floor of the orbit (failed skin graft of the right eye after orbital enucleation); this infection originated in the maxillary sinus. Bottom image shows similar deep, destructive ulceration of the left posterior maxillary alveolar bone and mucosa due to mucormycosis of the maxillary sinus. Courtesy of David Sirois, DMD, PhD.

Media file 5: Cryptococcosis. Left image shows solitary, destructive lesion resulting in necrosis of alveolar bone and palatal mucosa; note the superficial pseudomembranous candidiasis of the palate. Right image shows nonspecific chronic ulceration of the buccal mucosa due to cryptococcosis; this is associated with submucosal induration and regional adenopathy. Courtesy of David Sirois, DMD, PhD.

References

1. Marsot-Dupuch K, Quillard J, Meyohas MC. Head and neck lesions in the immunocompromised host. Eur Radiol. Mar 2004;14 Suppl 3:E155-67. [Medline].

2. Badiee P, Kordbacheh P, Alborzi A, Zeini F, Mirhendy H, Mahmoody M. Fungal infections in solid organ recipients. Exp Clin Transplant. Dec 2005;3(2):385-9. [Medline].

3. Scully C, de Almeida OP, Sposto MR. The deep mycoses in HIV infection. Oral Dis. May 1997;3 Suppl 1:S200-7. [Medline].

4. Hodgson TA, Rachanis CC. Oral fungal and bacterial infections in HIV-infected individuals: an overview in Africa. Oral Dis. 2002;8 Suppl 2:80-7. [Medline].

5. Dreizen S, Keating MJ, Beran M. Orofacial fungal infections. Nine pathogens that may invade during chemotherapy. Postgrad Med. Apr 1992;91(5):349-50, 353-4, 357-60 passim. [Medline].

6. O'Neill BM, Alessi AS, George EB, Piro J. Disseminated rhinocerebral mucormycosis: a case report and review of the literature. J Oral Maxillofac Surg. Feb 2006;64(2):326-33. [Medline].

7. Myoken Y, Sugata T, Kyo TI, Fujihara M. Pathological features of invasive oral aspergillosis in patients with hematologic malignancies. J Oral Maxillofac Surg. Mar 1996;54(3):263-70. [Medline].

8. Myoken Y, Sugata T, Myoken Y, Kyo T, Fujihara M, Mikami Y. Antifungal susceptibility of Aspergillus species isolated from invasive oral infection in neutropenic patients with hematologic malignancies. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. Feb 1999;87(2):174-9. [Medline].

9. Karabulut AB, Kabakas F, Berköz O, Karakas Z, Kesim SN. Hard palate perforation due to invasive aspergillosis in a patient with acute lymphoblastic leukemia. Int J Pediatr Otorhinolaryngol. Oct 2005;69(10):1395-8. [Medline].

10. Khongkhunthian P, Reichart PA. Aspergillosis of the maxillary sinus as a complication of overfilling root canal material into the sinus: report of two cases. J Endod. Jul 2001;27(7):476-8. [Medline].

11. Hernández SL, López De Blanc SA, Sambuelli RH, Roland H, Cornelli C, Lattanzi V, et al. Oral histoplasmosis associated with HIV infection: a comparative study. J Oral Pathol Med. Sep 2004;33(8):445-50. [Medline].

12. Almeida OP, Jacks J Jr, Scully C. Paracoccidioidomycosis of the mouth: an emerging deep mycosis. Crit Rev Oral Biol Med. 2003;14(5):377-83. [Medline].

13. Muzyka BC, Glick M. A review of oral fungal infections and appropriate therapy. J Am Dent Assoc. Jan 1995;126(1):63-72. [Medline].

Keywords

noncandidal infection of the mouth, fungal mouth infection, mycosis, mycoses, aspergillosis, cryptococcosis, histoplasmosis, blastomycosis, mucormycosis, zygomycosis, paracoccidioidomycosis, Aspergillus flavus, A flavus, Aspergillus terreus, A terreus, Aspergillus fumigatus, A fumigatus, Cryptococcus neoformans, C neoformans, Histoplasma capsulatum, H capsulatum, Blastomyces dermatitidis, B dermatitidis, Mucor species, Rhizopus species, Paracoccidioides brasiliensis, P brasiliensis, cryptococcal meningitis, meningoencephalitis, Gilchrist disease, Gilchrist's disease, Almeida's disease, Almeida disease, rhinosporidiosis

Contributor Information and Disclosures

Author

Crispian Scully, MD, PhD, DSc, FRCPath, MRCS, CBE, MDS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FMedSci, FHEA, FUCL,DSc, DChD, DMed(HC), Dr hc., Professor, Director of Special Projects, Eastman Dental Institute for Oral Health Care Sciences; Professor, Special Needs Dentistry, University College; Professor, Oral Medicine, Pathology and Microbiology, University of London
Crispian Scully, MD, PhD, DSc, FRCPath, MRCS, CBE, MDS, FDSRCS, FDSRCPS, FFDRCSI, FDSRCSE, FMedSci, FHEA, FUCL,DSc, DChD, DMed(HC), Dr hc. is a member of the following medical societies: Academy of Medical Science, British Society for Oral Medicine, International Association for Dental Research, and Royal Society of Medicine
Disclosure: Nothing to disclose.

Coauthor(s)

Maria Regina Sposto, DDS, PhD, MDSc(Dental Science), PhD(Dentistry), Associate Professor of Oral Diagnosis and Oral Medicine, Consulting Staff, Department of Oral Surgery and Diagnosis, Faculdade de Odontologia de Araraquara, UNESP-Universidade Estadual Paulista, Brazil
Disclosure: Nothing to disclose.

Medical Editor

Shyam Verma, MBBS, DVD, FAAD, Adjunct Clinical Assistant Professor, Department of Dermatology, University of Virginia, State University of New York at Stonybrook, Penn State University
Shyam Verma, MBBS, DVD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Drore Eisen, MD, DDS, Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati
Drore Eisen, MD, DDS is a member of the following medical societies: American Academy of Dermatology, American Academy of Oral Medicine, and American Dental Association
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Oslei Paes de Almeida, MD, to the development and writing of this article.

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)