Oropharyngeal candidiasis in adults

INTRODUCTION — Candida species can be associated with infections involving mucosal membranes, including the oropharynx and esophagus. The majority of these infections are related to Candida albicans.

This topic will review the clinical manifestations, diagnosis, and treatment of oropharyngeal candidiasis in adults. Topic reviews that discuss esophageal and chronic mucocutaneous candidiasis, as well as those that provide an overview of candidal infections, are presented elsewhere. (See "Esophageal candidiasis in adults" and "Chronic mucocutaneous candidiasis" and "Overview of Candida infections" and "Candida infections in children" and "Clinical manifestations and diagnosis of Candida infection in neonates".)

MICROBIOLOGY — The causative agent of oropharyngeal candidiasis is usually C. albicans. Non-albicans species, such as C. glabrata, C. krusei, and C. tropicalis have also been isolated [1-4], but in most patients, these species are usually present along with C. albicans, which is the probable cause of the symptoms. However, in highly immunosuppressed patients, non-albicans species appear to cause disease [2].

RISK FACTORS — In adults, oropharyngeal candidiasis (also referred to as thrush) is seen in both immunocompetent and immunocompromised hosts.

●In immunocompetent patients, oropharyngeal candidiasis typically occurs in those who wear dentures [5,6], patients with xerostomia (dry mouth), and those treated with antibiotics or inhaled corticosteroids.

●In immunocompromised patients, oropharyngeal candidiasis is usually seen in those in those with cellular immune deficiency states, such as patients who have acquired immunodeficiency syndrome (AIDS) or hematologic malignancies, as well as those who have received a transplant. However, it can also occur in patients receiving chemotherapy, corticosteroids, or radiation therapy to the head and neck [7].

CLINICAL MANIFESTATIONS

Signs and symptoms — Many patients with oropharyngeal candidiasis are asymptomatic. However, when symptoms do occur, patients commonly experience a cottony feeling in the mouth, loss of taste, and, in some cases, pain during eating and swallowing. Patients who have denture stomatitis usually experience pain.

Immunocompromised patients with oropharyngeal candidiasis often have concurrent Candida esophagitis or occasionally laryngeal candidiasis. Laryngeal candidiasis may be suspected in a patient with evidence of oropharyngeal infection who presents with hoarseness. A detailed discussion of Candida esophagitis is presented in a separate topic review. (See "Esophageal candidiasis in adults".)

Candida species also cause angular cheilitis, a painful fissuring at the corners of the mouth. (See "Cheilitis", section on 'Angular cheilitis'.)

Physical exam — There are two major forms of oropharyngeal candidiasis:

●The pseudomembranous form is the most common and appears as white plaques on the buccal mucosa, palate, tongue, and/or the oropharynx (picture 1). The disease can be characterized as mild, moderate, or severe based on the extent of the lesions:

•Mild disease: scattered, nonconfluent lesions >2mm in size

•Moderate disease: multiple lesions >2mm in size

•Severe disease: extensive, confluent lesions

Patients who have only a white coating on their tongue rarely have candidiasis; this condition is usually caused by hypertrophic papillae. Smokers can have a yellow-brown coating on their tongue from this same cause. (See "Oral lesions", section on 'Tongue lesions'.)

●The atrophic form, also called denture stomatitis, is seen in older adults who wear upper dentures. It is found under upper dentures and is characterized by erythema without plaques (picture 2) [8].

Angular cheilitis manifests as bilateral, bright red erythematous fissures at the angles of the mouth [9]. This is discussed in detail elsewhere. (See "Cheilitis", section on 'Angular cheilitis'.)

DIAGNOSIS — The diagnosis of oropharyngeal candidiasis is usually made clinically in patients with risk factors for infection and characteristic findings on exam. (See 'Risk factors' above and 'Clinical manifestations' above.)

However, testing may be warranted in the following settings:

●If there is a doubt as to whether the exam findings are consistent with thrush; or

●If the patient does not have the classic risk factors for thrush. The presence of thrush in a person with no obvious risk factors should raise the suspicion of human immunodeficiency virus (HIV) infection, and testing for HIV should be performed. (See "Screening and diagnostic testing for HIV infection".)

The diagnosis can be made by simply scraping the lesions with a tongue depressor and performing a Gram stain or potassium hydroxide preparation on the scrapings, which will reveal budding yeasts with or without hyphae. Alternatively, a culture can be obtained by rubbing a swab over a lesion; however, many people have oropharyngeal colonization by Candida; thus, the clinical picture has to be compatible with thrush if the culture is to be helpful.

TREATMENT — The initial choice of therapy is typically based upon the severity of disease and whether the patient is pregnant (table 1). Other considerations include the ease of administration, anticipated adherence, gastric acidity (which may affect absorption of some drugs), drug-drug interactions, and cost.

Indications — Patients with clinical evidence of oropharyngeal candidiasis should be treated. Treatment improves symptoms and, in immunocompromised patients, may also reduce the risk of developing esophagitis. Data supporting the efficacy of antifungal treatment are reviewed below. (See 'Initial therapy in nonpregnant patients' below and 'Patients with recurrent disease' below and 'Poor response to initial therapy' below.)

Initial therapy in nonpregnant patients

Patients with mild disease — For most patients with mild oropharyngeal candidiasis, we suggest topical therapy for 7 to 14 days [5,10,11]. Most patients demonstrate signs of improvement after three days. We prefer topical rather than oral therapy to reduce the risk of drug interactions and systemic toxicity. However, oral fluconazole may be preferred for certain patients, such as those who cannot use troches or suspension because of aspiration risk or inability to follow directions and certain immunocompromised patients at risk for disseminated disease due to severe mucosal breakdown (eg, patients with hematologic malignancies). Other experts also prefer initial therapy with fluconazole for all patients with HIV, regardless of CD4 count or disease severity [12].

●Preferred topical agents – Our preferred topical options include:

•Clotrimazole troches (one 10 mg troche dissolved in the mouth five times daily)

•Miconazole mucoadhesive buccal tablets (50 mg once daily applied to the mucosal surface over the canine fossa)

•Nystatin swish and swallow (400,000 to 600,000 units four times daily)

We prefer clotrimazole troches or miconazole mucoadhesive buccal tablets. Clotrimazole troches and fluconazole appear to be clinically equally effective for the initial treatment of thrush in patients with AIDS. In a trial of 334 patients with HIV and oral candidiasis who received either oral fluconazole (100 mg daily) or clotrimazole troches (10 mg five times), almost all patients were cured or showed clinical improvement regardless of which treatment they received [13]. Miconazole mucoadhesive buccal tablets were found to be as effective as clotrimazole troches used five times daily in a randomized study of 578 patients with HIV [14]; however, these are more expensive than clotrimazole.

Nystatin suspension is another option, but it is not always palatable to patients [15], and it contains sucrose, which can cause dental caries when used over prolonged time periods [16]. In addition, nystatin may be less effective than clotrimazole or miconazole. Unlike clotrimazole, nystatin was found to be less effective than fluconazole in a trial of 167 patients with HIV, in which clinical resolution was seen in 87 and 52 percent of patients who received fluconazole (100 mg once daily) or liquid nystatin (500,000 units four times daily), respectively [17]. In addition, there were fewer relapses at day 28 in those who received fluconazole (18 versus 44 percent), although this difference did not persist over time.

Gentian violet is another topical therapy, but we rarely use this since it is messy and does not appear to be more effective than the other options.

Successful therapy with topical agents depends upon adequate contact time between the agent and the oral mucosa [16]. Thus, patients should be able to follow instructions for use.

●Preferred systemic agents – For patients with mild disease who require systemic therapy, we typically use fluconazole (200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days) (table 1). Data supporting the use of fluconazole are described below. (See 'Patients with moderate to severe disease' below.)

Patients with moderate to severe disease — In patients with moderate to severe disease, we suggest systemic therapy with fluconazole (200 mg loading dose, followed by 100 to 200 mg daily for 7 to 14 days) rather than topical therapy (table 1). Patients typically improve clinically within a few days after initiating therapy, and in one report, clinical symptoms and signs resolved by the end of treatment in more than 90 percent of patients taking fluconazole [18]. Although the rate of clinical cure appears similar for fluconazole and certain topical therapies, we prefer fluconazole in this group of patients because it was associated with superior mycological cure rates, lower risk of relapse, and longer disease-free interval [17,19]. In addition, fluconazole is more convenient than most topical regimens, which may enhance adherence.

Other oral azoles (eg, itraconazole oral solution, posaconazole suspension, voriconazole) also appear to be effective for initial therapy [12,15,20-24]; however, we prefer fluconazole due its ease of administration, low side effect profile, lower risk of drug interactions, and cost. These other agents are typically used for treatment of refractory disease. (See 'Poor response to initial therapy' below.)

Echinocandins and intravenous amphotericin B deoxycholate can also be used as treatment of thrush, but these are rarely indicated.

Poor response to initial therapy — For those who have persistent symptoms after several days of therapy, we typically modify the treatment regimen. The approach depends upon the initial choice of therapy.

●Poor response to topical treatment – If the patient does not respond to topical therapy, the preferred therapy is oral fluconazole (200 mg loading dose, then 100 to 200 mg daily) for a total of 7 to 14 days [1,10,11,25].

●Poor response to fluconazole – For patients who do not respond to initial therapy with 100 to 200 mg of fluconazole, the next step is to double the dose of this agent. If this is not successful, a culture should be performed because the symptoms may be due to a species of Candida that is intrinsically resistant to fluconazole or to an isolate of C. albicans that has developed resistance to fluconazole [1].

Pending the culture results, we typically switch to itraconazole, posaconazole, or voriconazole since there are data supporting the use of these agents in patients who have thrush refractory to fluconazole [26-28]. We usually favor itraconazole solution rather than other agents because there are more clinical data for this approach.

For patients with refractory disease, we typically treat with one of the following azoles for 14 to 28 days:

•Itraconazole solution – Itraconazole solution (200 mg once daily) is a suitable option for patients who do not respond to fluconazole therapy [10,12,26]. Itraconazole capsules should not be used; although they are more palatable than the solution, they are less effective. In a study of patients with AIDS, itraconazole solution was effective in treating thrush that had become resistant to fluconazole, and it was thought this was likely both a local effect, bathing the mucosa, as well as a systemic effect [26].

•Posaconazole suspension – Posaconazole suspension may be an effective alternative for patients with refractory disease [12]. For such patients, posaconazole suspension should be administered (400 mg twice daily for three days and then once daily). In an open-label trial in 149 patients with HIV who were treated with posaconazole suspension for oropharyngeal candidiasis refractory to fluconazole or itraconazole, clinical cure or improvement occurred in 74 percent of patients [27].

Studies demonstrating the efficacy of posaconazole for thrush were performed with the oral suspension. An extended-release tablet is now available, and most physicians have switched to the tablet formulation for treatment of invasive fungal infections and prophylaxis in immunosuppressed hosts. However, it is unclear how the use of the tablet formulation will impact the efficacy of posaconazole for oropharyngeal candidiasis because it is not known if serum concentrations determine the response of thrush to therapy or if there is a benefit from the local effects of the suspension.

•Voriconazole – Voriconazole (200 mg orally twice daily) can be used if needed to treat oropharyngeal infection caused by Candida species that are resistant to fluconazole [10]. However, data are limited [28], and voriconazole is inherently more toxic than fluconazole. If voriconazole is given for more than two weeks, serum levels should be measured to avoid dose-dependent toxic effects. (See "Pharmacology of azoles", section on 'Voriconazole'.)

Echinocandins and intravenous amphotericin B can also be used as treatment for refractory thrush (table 1) [10], but these are rarely indicated. Amphotericin B deoxycholate oral suspension is also available in some countries for treatment of refractory thrush; however, it is not available in the United States and has to be compounded by a pharmacy.

Patients with recurrent disease — Recurrent disease is common if the underlying risk factors are still present (eg, ongoing steroid/chemotherapy use or persistently low CD4 counts). Recurrences are treated in the same manner as the initial episode unless therapy is no longer effective. (See 'Poor response to initial therapy' above.)

For patients with multiple closely spaced recurrences, suppressive therapy with oral fluconazole (eg, 100 mg daily or 100 mg three times weekly) can be effective at aborting these events [1,3,10,11]. We generally prefer once-daily dosing to reduce the risk of developing resistance, particularly in patients with sustained immunosuppression.

We do not use topical therapy as suppression because patients tire of using troches and lozenges, and most prefer a single oral tablet.

As soon as the underlying defect in cell-mediated immunity can be corrected (eg, when CD4 count is >200 cells/microL), suppressive therapy should be stopped in favor of intermittent treatment of each episode, given the effectiveness of fluconazole for treatment of acute disease, the low mortality associated with mucosal candidiasis, the potential for azole resistance and drug interactions, and the associated cost [12]. The risk of developing fluconazole resistance in the setting of azole therapy was demonstrated in a randomized trial of patients with HIV that compared continuous versus episodic fluconazole therapy; in this study, fluconazole resistance was detected in 45 and 36 percent of those who received continuous and episodic therapy, respectively, although there was no statistically significant difference between the arms [29].

Additional considerations

Pregnancy — Oral azoles are teratogenic and should not be used during the first trimester for the treatment of mucosal candidiasis. However, clotrimazole troches, miconazole buccal tablets, and nystatin swish and swallow topical therapies can be used. (See 'Patients with mild disease' above and "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)

For patients who have severe thrush in the first trimester, intravenous amphotericin B can be used [12], but this is rarely needed. There are no data regarding the use of echinocandins in pregnancy.

In the second and third trimester, topical therapy is still preferred; however, for those with refractory disease, the decision to use an azole must be determined on a case-by-case basis. A detailed discussion of the risks of using azoles during pregnancy is presented in a separate topic review. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)

Denture stomatitis — Treatment of denture stomatitis requires treatment of the device, in addition to antifungal therapy with fluconazole, to avoid relapse (table 1) [18]. The dentures must be removed before going to bed, brushed vigorously, and then soaked in a solution of chlorhexidine gluconate or a dilute solution of bleach (10 drops in a denture cup filled with water). Other over-the-counter denture care products can be used, but they do not appear to be as effective [5,6,10].

Angular cheilitis — Topical therapies, such as antifungal creams, are suitable for the treatment of angular cheilitis, which can be seen as a manifestation of Candida infection. (See "Cheilitis", section on 'Angular cheilitis'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis" and "Society guideline links: Opportunistic infections in adults with HIV".)

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●Basics topic (see "Patient education: Thrush in adults (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Microbiology − Oropharyngeal candidiasis, or thrush, is a common local infection usually caused by Candida albicans. (See 'Microbiology' above.)

●Risk factors − Disease is typically seen in immunocompetent adults who wear dentures, have received antibiotics, or are being treated with inhaled corticosteroids. In immunocompromised patients, oropharyngeal candidiasis is typically seen in those with cellular immune deficiencies (eg, patients with AIDS, hematologic malignancies, and transplant recipients), those receiving chemotherapy or radiation therapy to the head and neck, and those receiving corticosteroids. (See 'Risk factors' above.)

●Clinical manifestations and determining severity of infection

•Clinical manifestations – Oropharyngeal candidiasis most commonly appears as white plaques on the buccal mucosa, palate, tongue, and/or oropharynx (picture 1). Patients may be asymptomatic or experience a cottony feeling in the mouth, loss of taste, or pain during eating and swallowing. Patients who have denture stomatitis usually experience pain. (See 'Signs and symptoms' above and 'Physical exam' above.)

•The extent of disease – The extent of disease influences treatment: 

-Mild disease – Scattered, non-confluent lesions >2 mm in size 

-Moderate disease – Multiple lesions >2 mm in size  

-Severe disease – Extensive, confluent lesions 

●Diagnosis − In patients with characteristic findings and risk factors for infection, the diagnosis is typically based upon clinical findings. Diagnostic testing (identification of yeast forms on Gram stain or potassium hydroxide preparation, or via culture) should be performed if there is doubt as to whether the exam findings are consistent with thrush or if the patient does not have the classic risk factors for thrush. (See 'Diagnosis' above and 'Risk factors' above.)

●Treatment

•Goals of treatment − Treatment improves symptoms and, in immunocompromised patients, may also reduce the risk of developing esophagitis. Treatment options for nonpregnant patients typically include topical agents or azole therapy (table 1).

•Duration of therapy − Patients with oropharyngeal candidiasis should be treated with antifungal therapy for 7 to 14 days, except in refractory disease when duration can be extended up to 28 days. (See 'Initial therapy in nonpregnant patients' above.)

•Mild disease − For most patients with mild disease, we suggest topical therapy (clotrimazole troches or miconazole buccal tablets) rather than systemic therapy (table 1) (Grade 2C). Topical therapy is effective and has less toxicity and fewer drug interactions. We treat with topical therapy for 7 to 14 days. Most patients begin to improve within three days. Systemic therapy with oral fluconazole may be preferred for certain patients with mild disease, such as:  

-Aspiration risk

-Immunocompromised patients at risk for disseminated disease due to mucosal breakdown

-Patients who do not respond to topical treatment after five to seven days

•Moderate to severe disease − For patients with moderate to severe disease, we suggest systemic treatment with fluconazole rather than other systemic or topical therapies (table 1) (Grade 2B). Treatment with fluconazole is associated with superior mycological cure rates, lower risk of relapse, and longer disease-free intervals. We treat with fluconazole for 7 to 14 days. (See 'Patients with moderate to severe disease' above.)

•Refractory disease − For patients refractory to oral therapy with initial fluconazole treatment (100 to 200 mg daily), we increase the fluconazole dose to 200 to 400 mg daily. If there is still no response after several days, we obtain fungal cultures and switch to an alternative agent (table 1); we usually favor itraconazole over other agents because there is more evidence supporting this approach. For patients with refractory disease, systemic treatment is continued until clinical resolution, up to a maximum of 28 days. (See 'Poor response to initial therapy' above.)

•Recurrent disease – Recurrent disease is common if the underlying risk factors (ie, immunosuppression) are still present; recurrences are treated in the same manner as the initial episode unless therapy is no longer effective. 

-For most patients with recurrent oropharyngeal candidiasis, we suggest intermittent therapy rather than continuous suppressive therapy (Grade 2B). Intermittent therapy is effective and minimizes the risk of resistance and drug interactions. 

-For patients who have several recurrences within a few months, suppressive therapy may be reasonable; it should be discontinued as soon as the underlying immunodeficiency has resolved.

•Pregnancy considerations – The preferred treatment of oropharyngeal candidiasis varies during the course of pregnancy: 

-First trimester – Oral azoles (eg, fluconazole, itraconazole) are teratogenic and should not be administered during the first trimester. Topical therapy (clotrimazole troches, miconazole buccal tablets, or nystatin swish and swallow) is preferred (table 1). For severe or refractory disease, intravenous amphotericin B may be used (though is rarely necessary).

-Second and third trimester – Topical therapy is preferred. For severe or refractory disease, the decision to use an azole should be made on a case-by-case basis.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren Marr, MD, who contributed to an earlier version of this topic review.