1-s2.0-S0149291898800337-main

CLINICAL THERAPEUTICSVVOL. 20, NO. 1, 1998

Oropharyngeal Candidiasis: A Review of Its Clinical Spectrum and Current Therapies

Joel B. Epstein, MSD, DMD, and Bruce Polsky, MD2 Department of Dentistry, Vancouver Hospital & Health Sciences Centen the British Columbia Cancer Agency, University of British Columbia, Vancouvel; British Columbia, and University of Washington, Seattle, Washington, and 2The Infectious Disease Service, Memorial Sloan-Kettering Cancer Center and Cornell University Medical College, New York, New York

ABSTRACT

With the increased use of antibiotics and immunosuppressive agents, oropharyngeal candidiasis is becoming more common. This infection is also associated with such advances in medical management as chemotherapy and organ transplantation and with human immunodeficiency virus infection. Various topical and systemic agents are available to treat patients with candidiasis, but optimal management can be elusive. Treatment of uncomplicated oropharyngeal candidiasis in the immuno- competent patient involves selecting a par- ticular formulation of a topical medication based on oral conditions, length of contact time, and taste, texture, and cost of the medication. Treatment of severe oropharyngeal candidiasis, particularly in patients with a compromised immune system, is often more difficult, and relapses are common. Reports of resistance to systemic agents, particularly in patients needing recurrent therapy, are increasing. Ampho-

tericin B, long used as an intravenous agent, is now available as an oral suspension that may offer therapeutic benefits comparable to those of systemic therapy without the toxicity associated with systemic absorption. Key wonEs: amphotericin B oral suspension, oropharyngeal candidiasis, Candida albicans, oral mucosa.

INTRODUCTION

Candida, a yeastlike fungus, is commonly part of the normal flora of the skin, mouth, intestinal tract, and vagina and is present in the oral cavity in 40% to 60% of the population. 1,2 Candida albicans is the most commonly isolated species1*2 and is the species most likely to cause disease in humans3 Other Candida species include Candida tropicalis (prevalent in immuno- suppressed patients), Candida krusei, Candida guilliermondii, and Candida parapsilosis (of limited pathogenicity but particularly associated with infection of indwelling vascular access devices).

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J.B. EPSTHN AND B. POLSKY

Both superficial and invasive candidiasis are occurring more frequently because of increased use of antibiotics and immunosuppressive agents and such advances in medical management as chemotherapy, organ transplantation, parenteral nutrition, and invasive surgical procedures.4 In addition, candidiasis of the oropharynx and esophagus is associated with human immunodeficiency virus (HIV) infection and is a clinical predictor of disease progression in HIV-infected patients, with acquired immunodeficiency syndrome (AIDS) developing as early as 1 to 3 years after the appearance of oropharyngeal candidiasis.5s6

Despite the various topical and systemic agents available to treat patients with oropharyngeal and systemic candidiasis, optimal management can be elusive in some instances. Topical therapy (eg, nystatin, miconazole, clotrimazole, amphotericin B) generally is effective in patients with uncomplicated mucocutaneous candidiasis; however, the optimal treatment for immunocompromised patients and patients with chronic or recurrent in-

fection remains to be elucidated. Budtz- Jorgensen4 has given a general overview of the etiology, pathogenesis, and treatment of candidiasis.

The present review considers local and systemic risk factors for oropharyngeal candidiasis, reviews the clinical manifestations and diagnosis of infection, and dis- cusses current approaches to management.

RISK FACTORS

Both local and systemic risk factors can increase an individuals susceptibility to candidiasis, as may characteristics of the organism itself. Host factors include age (ie, neonates, advanced age), diabetes, wearing of dentures, use of broad-spectrum antibiotics or steroids, impaired salivary gland function, disruption of oral mucosa, dietary factors (eg, high-carbohydrate diet, iron-deficiency anemia4), cancer, cancer therapy, and HIV infection (Table I). Certain patient populations with severe underlying illness may have multiple factors that predispose them to candidiasis.

Table I. Risk factors for development of oropharyngeal candidiasis.

Local factors Xerostomia (eg, because of radiotherapy, chemotherapy, Sjogrens syndrome) Use of broad-spectrum antibiotics or steroids High-carbohydrate diet Leukoplakia, oral cancer Dentures (eg, poor fit, trauma, uncleanliness) Cigarette use

Systemic factors Neonate, advanced age Diabetes Nutritional deficiencies (eg, iron, folate, or vitamin B,, deficiency) Malignancies (eg, leukemia, agranulocytosis) Immunosuppression (eg, acquired immunodeficiency syndrome, steroid use)

Adapted with permission from Budtz-JBrgensen.4

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CLINICAL THERAPEUTICS

Pathogen factors that have been impli- cated in the development of oropharyngeal candidal infections include cell-wall components that enhance adhesion to epithelial cells, hydrophobic@ of the organism, germ tube formation, presence of mycelia, abil- ity to persist within epithelial cells, production of endotoxins, induction of tumor necrosis factor, production of acid pro- teinase, and phenotypic switching.7

Neonates

Neonates are susceptible to oropharyngeal candidiasis because of their immature immune system.2 Infection usually is acquired during birth to a mother with vaginal candidiasis and becomes obvious within the first week. Exposure to C albicans from infected bottle nipples or the skin of nurses or the mother may also lead to oropharyngeal candidiasis.2 Such infection usually is benign and generally can be treated effectively with topical agents.*

Diabetes

Diabetic patients are at increased risk for oropharyngeal candidiasis.2 Although the mechanism has not been fully elucidated, higher-than-normal numbers of C albicans have been cultured from the saliva of patients with diabetes.5*7 Elevated glucose levels and a reduced chemotactic factor in saliva, altered neutrophil function, and reduced saliva volume may play a role in the pathogenesis of candidiasis.2

Wearing of Dentures

Oropharyngeal candidiasis afflicts as many as 65% of older patients wearing full upper dentures.3 Denture wearers susceptibility to oropharyngeal candidiasis

may be due to enhanced adherence of Cundidu species to acrylic, reduced saliva flow under the surfaces of denture fittings, improperly fitted dentures, or poor oral hygiene.v2

Broad-Spectrum Antibiotic and Steroid Use

Broad-spectrum antibiotics that alter the oral flora may create a favorable en- vironment for the proliferation of Cun- didu species.9 A study by Burton et allo found that antibiotic therapy, especially with steroid use, may lead to fungal overgrowth. Other studies have shown that chronic use of steroid inhalers also in- creases the risk of oropharyngeal candidiasis, possibly by suppressing cellular immunity and inhibiting phagocytosis.2 Local mucosal immunity and oral flora return to the pretreatment state once therapy is discontinued.

Impaired Salivary Gland Function

Patients with impaired salivary gland function are susceptible to Candida infections of the oral cavity.s7 Low secretion rate and low pH in saliva may contribute to the development of candidiasis.12 Saliva protects against candidiasis in several ways. Its secretion causes a dilutional effect and its movement clears organisms from mucosal surfaces. Antimicrobial pro- teins in the saliva, including lactoferrin, sialoperoxidase, lysozyme, histidine-rich polypeptides, and specific anticandida an- tibodies, interact with the oral mucosa and prevent overgrowth of Cundidu. A study by Nikawa et all3 found that lactoferrin, a nonspecific defense factor in saliva and mucosal secretions, appears to have fun- gicidal activity against Cundidu species.

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J.B. EPSTEIN AND B. POLSKY

Drugs that cause xerostomia can predispose patients to oropharyngeal candidiasis. Patients with head and neck cancer and those who have received radiation to the head and neck can have disturbances of major or minor salivary glands.7 Bone marrow transplant recipients and patients receiving chemotherapy can also experience salivary gland dysfunction.7

Disruption of the Oral Mucosa

Disruption of the oral mucosa can increase a persons risk for oropharyngeal candidiasis. 1*7 The oral epithelium protects against Cundida infections by main- taining a physical barrier that prevents in- vasion of microorganisms, and epithelial turnover helps clear organisms from the mouth. Patients receiving chemotherapy for acute leukemia have an altered rate of mucosal regeneration, making them more vulnerable to infection.7 Patients with mucositis, especially those with a compromised immune system, are at high risk for candidiasis.14

Cancer and Cancer Therapy

Patients who have cancer are particularly at risk for developing oropharyngeal candidiasis.3~6*15-21 Advances in the use of radiotherapy and chemotherapy have also been associated with an increase in opportunistic fungal infections.15 Bergmann noted that transient xerostomia caused by chemotherapy may induce acute oropharyngeal infections, although transmission of potentially pathogenic mi- crooraanisms occurs mainly after antibi-

due to esophagitis, fever) and carries a considerable risk of mortality. 19,20,23 One study found that in addition to the risk of mortality, oropharyngeal candidiasis is associated with long-lasting fever and decreased bone marrow function in patients with leukemia.23

Oropharyngeal candidiasis is reported in up to one third of leukemic patients.1T3*4*9J9*20 The intensive radiation and chemotherapy used to treat these cancer patients can disrupt the oral mucosa and change the bacterial milieu of the mouth to favor the overgrowth of C albicans.22 Frequent treatment with broad-spectrum antibiotics in neutropenic patients also al- ters the normal oral flora and predisposes patients to oropharyngeal candidiasis.15

Candidu infections, although generally superficial, can become invasive or systemic in these patients and may result in mortality.17~19 It has been reported that systemic candidiasis develops more frequently in leukemic patients who have oropharyngeal candidiasis than in those patients who do not and is most frequently associated with prolonged neutropenia as the principal immune defect.17yN Cundida is present in approximately 90% of patients with acute leukemia who arc undergoing chemotherapy>4 In radiotherapy, the presence of clinical oropharyngeal candidiasis may complicate oral mucositis; in these patients, risk factors include xerostomia, the presence of oral prostheses, and continuing tobacco and alcohol use during treatment.21

HIV Infection and AIDS

otic treatment. Candidiasis in patients with Patients with depletion of CD4+ lym- leukemia and those undergoing bone mar- phocytes due to HIV infection are at high row transplantation causes morbidity (eg, risk for oropharyngeal candidiasis,25 altered taste, oral sensitivity, dysphagia which is so common in HIV-infected pa-

43

tients that it is included in several stag- ing classifications for AIDSz6 Oropha- ryngeal candidiasis is the most prevalent opportunistic oral infection in this group, occurring in as many as 95% of patients.5*6*18*2628 It is also a predictor of disease progression in HIV-infected patients, with AIDS developing as early as 1 to 3 years after oropharyngeal candidiasis occurs.5*6 In patients in whom candidiasis has been controlled with therapy, progression or recurrence of the candidiasis is commonly seen in advanced HIV disease.

The clinical manifestations of oropharyngeal candidiasis in AIDS patients may vary over time and typically include the pseudomembranous and erythematous forms and angular cheilitis.5,28 Pollock et al29 hypothesized that once HIV infection is established, an alteration in salivary gland function may trigger defective antifungal activity. The pain and loss of taste that often accompany this infection can lead to poor appetite, weight loss, and inanition.18 Because oropharyngeal candidiasis can extend into the esophagus, causing gastrointestinal bleeding and serious systemic infection,18 treatment must not only eradicate oropharyngeal Can- dida but also prevent its extension into the esophagus.30

Even aggressive treatment frequently is unsatisfactory, and further studies are needed in HIV-infected patients.27 The in-


adequacy of therapy may be reflected in a lack of host response to help combat the infection, frequent relapses, persistent infection requiring prolonged therapy, antifungal drug resistance, and adverse drug effects.6 Accurate diagnosis and treatment are needed to prevent complications and maintain patients quality of life.3

CLINICAL PRESENTATION

Oropharyngeal candidiasis can be classi- fied clinically in several ways (Table II).3,32,33 Terminology including the de- scriptors acute and chronic should be avoided because, particularly in individuals with chronic immunosuppression, oropharyngeal manifestations can persist for extended periods regardless of the clinical findings. Symptoms that may be associated with the infection include burn- ing, sensitivity, altered taste, and change in the sense of smell. If involvement ex- tends to the oropharynx, dysphagia and odynophagia may occur.

The classic form of candidiasis is the pseudomembranous form (thrush), which is characterized by soft, yellowish-white plaques on the oral mucosa that can be re- moved with vigorous rubbing and may leave red or bleeding sites after re- mova1.3*32 Those at risk for this form of oropharyngeal candidiasis include neonates, the debilitated elderly, patients with cancer or undergoing therapy for cancer,

Table II. Classification of oropharyngeal candidiasis.

Pseudomembranous (thrush) Brythematous Denture stomatitis (atrophic) Angular cheilitis Leukoplakia due to hyperplastic candidiasis

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and HIV-infected individuals. Antibiotic therapy, dry mouth, use of steroid inhalers, and smoking are also risk factors.%

Another form of orophatyngeal candidiasis is the erythematous type, which frequently develops in patients taking antibiotics or using steroid inhalers and in patients with HIV33 The dorsal aspect of the tongue and the palate are generally involved, and the patient presents with red mucosa with loss of papillae on the tongue and patchy red changes in the palate, although any portion of the oral mucosa can be affected.% This type of candidiasis is characterized by sensitive and painful erythematous mucosa with few, if any, white plaques.9

In denture stomatitis, or denture sore mouth (atrophic candidiasis), the palatal mucosa in contact with the dentures becomes affected and is chronically erythematous and edematous, and a hyperplastic response may be seen, although patients generally experience no symptoms.3 Treatment includes correction of denture faults, careful cleaning of dentures, and antifungal therapy.35

Angular cheilitis, an inflammatory re- action at one or both corners of the mouth, is characterized by painful red fissures. C albicans is a common pathogen, and infection is frequently accompanied by Staphylococcus aureus infection.3 Den- ture wearers and patients with HIV are predisposed to this type of presentation. Although denture stomatitis and angular cheilitis usually do not indicate serious disease, severe infections may occur in immunocompromised individuals.4

Leukoplakia due to hyperplastic candidiasis may represent a precancerous condition that presents as bilateral, elevated, white mucosal lesions on the buccal mucosa, tongue, lips, and bottom of the mouth.3,31 Candida species are frequently

cultured from the mouth of patients with common and speckled oral leukoplakia, although they may not be the cause of the lesions. The presence of these organisms may be superficial, and they are thought to be secondary invaders in the epithelial portion of the lesions.3 Clinical signs and symptoms range from painless plaquelike white patches to nodular erythroplakic lesions that cause the patient discomfort. Smoking appears to be the main risk factor for development of hyperplastic candidiasis.

Systemic Infection

Systemic Candidu infection is usually caused by C albicans and less frequently by C krusei and C tropicalis in immuno- suppressed patients. Patients with neutropenia due to leukemia or from treatment of their malignancy, those with indwelling intravascular lines, and those receiving antibiotics or parenteral nutrition are at risk for Candida septicemia. Candida endocarditis is related to intravascular trauma (eg, cardiac catheteri- zation, surgery) and is more common on prosthetic valves. Candidiasis involving the esophagus, trachea, bronchi, or lungs is an AIDS-defining condition.30

All forms of systemic disease are serious, progressive, and potentially dead- ly. Amphotericin B administered intravenously is the treatment of choice, although ketoconazole or fluconazole is preferred for chronic mucocutaneous candidiasis.36

DIAGNOSIS

Candidiasis may be diagnosed by examining smears from the lesions using Grams stain or a potassium hydroxide preparation. A culture from the skin,

45


mouth, vagina, urine, sputum, or stool is obtained if identification of the species or strain is desired.5*37 However, it must be remembered that oropharyngeal candidiasis cannot be diagnosed solely by detec- tion of the presence of Candida species because the organism is a common com- mensal in the human flora.4 Studies have shown that high colony counts of Can- dida species from saliva collections cor- relate with the presence of clinical infection.38 To confirm the diagnosis, a characteristic clinical lesion, exclusion of other causes, and, occasionally, histologic evidence are necessary. Frequently the diagnosis is confirmed by response to antifungal therapy.

TREATMENT

Susceptibility Testing: Ident@cation of Resistbt Strains

Susceptibility testing of fungi in general is not as standardized as that of bac- teria, but it is evolving. The National Committee for Clinical Laboratory Stan- dards is developing guidelines for antifungal susceptibility testing.39 Barchiesi et a140 note that the current applicability of in vitro antifungal susceptibility tests is limited by inadequate standardization and insufficient correlation of in vitro test results with clinical outcome. The absence of standard guidelines may also be related to the limited indications for performing susceptibility testing, the small number of antifungal agents available, and technical difficulties associated with the testing of yeasts.41-3 Antifungal susceptibility studies may help clarify which strains are likely to develop resistance during long- term therapy.44

Approach to Management

Topical therapies should be the first choice for local and regional infection. In the authors opinion, when systemic therapy is deemed necessary, topical medications should be continued in suspected oropharyngeal infections, because this may allow a lower dose or shorter duration of systemic therapy. Because few medications remain in contact with oral tissue for prolonged periods, frequent applications of topical therapies are necessary.

The medication chosen should reflect the conditions in the oral cavity and take cost into consideration. Such factors as taste and texture and whether sucrose or alcohol is a component of the medication should be considered when selecting a medication and formulation. Many of the oral products include high concentrations of sucrose and thus have a high cariogenic potential, which is particularly important in dentate patients with dry mouth. In patients with dry mouth, tablets given to dissolve in the mouth may be poorly soluble and present a rough surface to the oral soft tissue that could become irritating; oral suspensions may be a good choice for such patients. Cream forms of appro- priate medications may be readily applied to the tissue surface of dentures, but their taste and texture may not be tolerated if they are applied without an occlusive ap- pliance. Creams are easily applied to the comers of the mouth. A single-dose trial will provide some information on product acceptability.

History of Treatment

Treatment of superficial fungal infections in the early 1900s was nonspecific and of questionable efficacy.45 Systemic

46


antifungals were nonexistent. Among the older topical preparations was gentian violet, which was used until the first polyene antibiotic, nystatin, was discovered in 195 1 .45 The antifungal activity of amphotericin B was reported in 1956, and this agent was the first available antifungal to be effective in treating systemic infection.45 Because of its enduring success in treating fungal infections, amphotericin B is the standard against which newer therapies are compared.

The first azole, benzimidazole, was discovered in 1944.45 The azoles include the imidazoles and the triazoles. Many imidazoles have been assessed, including miconazole and clotrimazole (both identified in 1969) and ketoconazole (1977). The antifungal activity of the triazoles, including fluconazole and itraconazole, was first reported in the mid-1980s.

Deatment Approach

Various systemic and nonsystemic (topical) agents are available to treat oropharyngeal candidiasis (Table lII)!*46 Topical agents have been the mainstay of therapy, particularly in uncomplicated cases. If pos- sible, topical preparations should always be used before systemic antifungal drugs!7 Because they are not absorbed systemically, topical drugs lack the systemic adverse effects and drug interactions of the systemic agents.9 However, salivary action may dilute and rapidly eliminate topical drugs from the oral cavity, thus ren- dering them ineffective.48 Topical agents are available in an assortment of formula- tions, including oral rinses, troches, powder, vaginal tablets, and creams. Systemic agents have been used when topical therapy has been ineffective or not tolerated,

Table III. Routes of action of antifungal agents for the treatment of oropharyngeal candid&is.

Route of Action

Class and Agent Topical systemic

Polyenes Nystatin Amphotericin B

Imidazoles Clotrimazole Miconazole Ketoconazole

Triazoles Pluconazole Itraconazole

Other Chlorhexidine gluconate 0.2% (antiseptic for denture disinfection)

Denture cleansers

X

X X

X

X

X

X

X

X

X

Adapted with permission from Budtz-J6rgensen.4

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primarily in immunocompromised patients with cancer or HIV infection. Topical and systemic medications are used to attempt prophylaxis in patients receiving bone marrow transplantation.

Topical Therapy

Gentian violet, an aniline dye, was commonly used to treat orophatyngeal candidiasis until the polyene antifungals be- came available in the 19~50s.~~ Gentian violet was quickly replaced by the polyenes because of emerging resistance and annoying side effects such as staining of the oral mucosa and skin irritation.45T49 Although approximately 87 polyenes have been investigated, only three-nystatin, amphotericin B, and natamycin-are commercially available. Natamycin is used only for ocular infection.

Both nystatin and amphotericin B are produced by Streptomyces species. These agents act by binding to ergosterol and possibly other sterols in the cell membrane of fungi, altering cell-membrane permeability by causing the formation of aqueous pores or channels that leak cellular components and bring about cell death.45vJo

Nystatin is the agent most widely used for the initial treatment of patients with oropharyngeal candidiasis. 1,2 It is available as an oral rinse, topical cream, oral pastille, vaginal tablet, and powder. lv2v5 Nystatin is not absorbed systemically and therefore lacks serious toxicity. Adverse events generally involve the gastrointestinal tract and include nausea, vomiting, and diarrhea.45 This can be a problem for cancer patients already nauseated from chemotherapy.1,9 The oral rinse is heavily sweetened with sucrose and may be useful in patients with xerostomia who are eden-

tulous, for whom the tablets can be difficult to dissolve and irritating to the oral mucosa, particularly if the oral mucosa is friable. AIDS patients and patients receiving radiotherapy21 frequently experience this complication. Although nystatin is commonly used as prophylaxis for or treatment of oropharyngeal candid&is in AIDS and cancer patients, several reports have cited disappointing results in these patients, with frequent treatment failures and early relapses.6J0J6J7~20

Two studies examining the compatibil- ity of nystatin with chlorhexidine digluconate, an antiseptic used to disinfect dentures, in the treatment of patients with oropharyngeal candidiasis found that both drugs become ineffective when combined.51,52 Therefore, care must be taken in combination therapy. Several studies have compared various topical and systemic agents (eg, nystatin and amphotericin B with fluconazole or ketoconazole) to determine what is best tolerated, most effective, and least expensive in different patients.20*53-56

The azoles are fungistatic and interfere with the synthesis of ergosterol, causing a change in the permeability of the cell membrane, leakage of cellular contents, and cell death.s9 Clotrimazole, an imidazole, was the first broad-spectrum antifungal of its class. Clotrimazole troches are more palatable than nystatin oral suspension and may be used in patients who cannot tolerate the taste of nystatin.g5 Clotrimazole has been reported to be effective for prophylaxis and treatment of oropharyngeal candidiasis in cancer patients, in whom it may prevent the development of esophagitis,58 but it appears to be less effective than fluconazole in treating HIV-infected patients with oropharyngeal candidiasis.5y59 In addition, like ny-

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statin oral troches, clotrimazole troches may be poorly tolerated by AIDS patients or patients with xerostomia from cancer therapy.7 Miconazole has also been shown to be effective in patients with oropharyngeal and esophageal candidiasism

When topical agents cannot effectively control oropharyngeal candidiasis, com- bining topical therapy with a systemic agent may eradicate the infection while allowing a lower dose and shorter course of the systemic agent.

Systemic Therapy

Systemic therapy may be necessary in patients with oropharyngeal candidiasis that is refractory to topical treatment, those who cannot tolerate topical agents, and those at high risk for systemic infection.

Amphotericin B The polyene antifungal amphotericin B

has been shown to be effective when given intravenously to patients with severe oropharyngeal candidiasis or those with infection refractory to other agents.2T6 One study assessed its usefulness given prophylactically in low doses to neutropenic autologous bone marrow transplant recipients and found that it may be useful in certain high-risk patients. Antifungal agents may also be used prophylactically in solid organ transplant recipients.62

Amphotericin Bs primary use is in patients at risk for progressive and potentially fatal fungal infections, and its routine use for oropharyngeal candidiasis has been limited by its toxic side effects. The potential for toxicity with systemic use of amphotericin B is considerable. Toxicities affect many organ systems and include general toxicities (fever, shaking, chills, malaise, weight loss), renal toxicity, gas-

trointestinal effects (nausea, vomiting, diarrhea, cramping, altered liver function), neurologic symptoms (headache, hearing loss, dizziness, visual changes, peripheral neuropathy), muscle/joint pain, dermato- logic reactions (rash, itching), hemato- logic effects (anemia), and cardiovascular and pulmonary toxicities.

Azoles The azoles (ie, miconazole, clotrima-

zole, ketoconazole, fluconazole, and itraconazole) have been widely used to treat patients with both superficial and systemic fungal infections. Ketoconazole was the first imidazole found to have systemic activity. Although it has been effective in the treatment of oropharyngeal candidiasis in patients with cancer and HIV infection, several studies have shown ketoconazole to be less effective than fluconazole in patients with HIV infection.5,15,34,63@ A study by Donnelly et al55 found ketoconazole to be no more effective than amphotericin B in preventing yeast infections in neutropenic patients with leukemia, and its routine use is not recommended.65 Ketoconazole requires gastric acidity for absorption, which may reduce its effectiveness in patients with AIDS or other gastrointestinal disorders and poor food intake. 1,9 The most frequent adverse events described for ketoconazole include nausea, vomiting, abdominal pain, and itching. 1,63 However, the adverse event of greatest concern is hepatotoxicity,9,42 and long prophylactic courses should be avoided.47 Asymptomatic in- creases in serum transaminase levels have been reported in 2% to 10% of patients, with resolution after discontinuation of therapy or spontaneous resolution during therapy.45 Hepatitis with jaundice and, rarely, hepatic failure have occurred. 1,45

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CLINICAL THERAPEUTICSm

The incidence of hepatotoxicity is reported to be in the range 1: 10,000 to 1:2000.45,63

Two triazoles, fluconazole and itraconazole, are the newest azoles to become available. Fluconazole is particularly useful in patients requiring prolonged antifungal therapy, because it is relatively well tolerated and is taken only once a day.27 Both fluconazole and itraconazole have been shown to be effective in the treatment of orophatyngeal candidiasis in patients with cancer and HIV infection, and they are widely used in these patients.16.34,54*56@,66 Itraconazole has now been introduced as an oral suspension. A recent study of fluconazole in the prophylaxis of candidiasis in patients with leukemia and bone marrow transplantation demonstrated the potential of fluconazole to reduce oropharyngeal colonization by C albicans, but an effect on systemic infection was not seen.19 C krusei is intrinsically resistant to fluconazole and, therefore, the observed increase in infection by C krusei in leukemia patients mandates caution in the use of fluconazole in these patients.19 Further studies are needed to establish optimal doses in patients with HIV infection and different types of oropharyngeal candidiasis27 and the usefulness of fluconazole in leukemia and bone marrow transplant patients.19

Resistance to Treatment

Resistance of Candida to polyenes is virtually unknown despite years of clinical use.13*67 However, reports of resistance to the azoles, particularly among AIDS patients, are appearing with increasing frequency.28*66*68-76 Therapeutic failure due to fluconazole-resistant strains in AIDS patients is increasingly reported in

the literature,28,68,69,73-76 although one study found fluconazole effective when other agents were not.77 In many situations, this resistance appears to develop in patients with advanced HIV disease or after repeated or long-term therapy.28,68*69*73 Resistant species, specifically C krusei, have been identified in bone marrow transplant patients and patients with leukemia.i9 This clinical scenario has also been described with ketoconazole.68 A study by Fan-Havard et al,78 however, did not find large-scale resistance in the Can- dida populations isolated from patients receiving long-term therapy. There have also been reports of fluconazole selecting for more resistant strains of Candida species and of cross-resistance between the azoles.34*49*63,72,79 More antifungal susceptibility studies are needed.44 In addition, the optimal management of fungal infections in HIV-infected children remains to be defined.80

It must be noted that all the azoles, particularly ketoconazole, can interact with many other agents, including antacids, omeprazole, histamine2 antagonists, ri- fampin, phenytoin, astemizole, oral anti- coagulants, insulin, cyclosporine, and cor- ticosteroids.5*45s63 Such interactions may result in either increased or decreased blood levels of these agents, thus altering their potential efficacy or toxicity.

New Therapies

Amphotericin B, an agent that has long been the reference standard for serious fungal infections,9 has recently been introduced as a nonsystemic oral rinse for the topical treatment of patients with oropharyngeal candidiasis. An amphotericin B lozenge/chlorhexidine combination has been used in Scandinavia for

50


years to treat patients with denture stomatitis.81 Amphotericin B lozenges are effective in patients susceptible to Candida infection, because long-lasting concentrations of the drug can be achieved in the saliva.82T83 Unlike many other antifungal agents, resistance to amphotericin B rarely develops during therapy.9*43 The drugs principal limitation is its toxicity when used systemically.43*84

The use of amphotericin B oral suspension as a topical antifungal was first studied nearly 40 years ago. This formulation has been available commercially in Europe for a number of years for the treatment of patients with oropharyngeal candidiasis.5,9*49*50 In vitro studies have shown that amphotericin B is more active than nystatin against C albicans.85-87 It has proved to be safe and effective in all age groups, including premature infants and elderly patients.49*88-90 Because virtually no amphotericin B oral suspension is absorbed systemically, the toxicity con- cerns associated with intravenous amphotericin B use are eliminated.91,92 The oral preparation is well tolerated by patients, with only infrequent reports of mild nausea, diarrhea, and vomiting.49,63*64*66 Some tissue conditioners (used in dental pros- thetics) will inhibit the antifungal activity of amphotericin B oral suspension, however, and all combination therapy should be scrutinized closely.52

DISCUSSION

Oropharyngeal candidiasis is increasingly common because of the AIDS epidemic and advances in medicine that allow patients with cancer and other debilitating diseases to live longer, although in an immunocompromised state. Use of broad- spectrum antibiotics and topical and sys-

temic steroids has led to increased oropharyngeal colonization and subsequent infection. Patients with xerostomia, those who smoke tobacco, and those who wear dentures are also at increased risk for candidiasis. The clinical presentation of this infection may vary. Patients may be asymptomatic or may have severe, persistent symptoms. Oral findings may include white plaques that can be wiped off, leukoplakia, and erythema. Without proper treatment, oropharyngeal candidiasis in an immunocompromised patient can lead to serious systemic infection.

Treatment of uncomplicated oropharyngeal candidiasis in the immunocompe- tent patient is usually straightforward. However, selecting the form of a topical medication requires consideration of the oral condition, the length of contact time with the medication, and the taste, texture, and cost of the product. In patients with severe oropharyngeal candidiasis, particularly those with a compromised immune system, or in patients with refractory oropharyngeal candidiasis, treatment is often more difficult. Relapses are common, and unless the underlying conditions predisposing to infection are managed effectively, long-term or frequent intermit- tent therapy is often required.

Topical agents are generally effective in uncomplicated cases but may be inadequate in certain clinical situations, including complicated infections in patients with AIDS or cancer. The most effective regimen for fungal prophylaxis in patients with protracted neutropenia has yet to be determined.54 Systemic agents such as ketoconazole, fluconazole, and itraconazole have been used extensively in these patients. A major concern with these agents, particularly with fluconazole, is the increasing number of reports of resistance,

51

particularly in patients requiring long- term or recurrent therapy. Strategies must be developed for preventing and manag- ing the increasing prevalence of more resistant strains of C albicans.

Intravenous amphotericin B is a time- tested agent with an excellent record in the treatment of patients with systemic my- cases and, occasionally, those with refractory oropharyngeal candidiasis. Its routine use for orophatyngeal candidiasis is limited by its toxicity. Amphotericin B oral suspension may have the benefits of an intravenous formulation without the toxic effects associated with systemic absorption.

ACKNOWLEDGMENT

Preparation and publication of this paper were supported by a grant from Bristol- Myers Squibb, Princeton, New Jersey.

Address correspondence to: Joel B. Epstein, MSD, DMD, Department of Dentistry, Vancouver Hospital & Health Sciences Center, 855 West 12th Avenue, Vancouver, BC V5Z lM9, Canada.

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