Antifungal therapy in oropharyngeal mycotic infections

Antifungal therapy in oropharyngeal infections

mycotic

Joel B. Epstein, DMD, MSD,” Vancouver, British Columbia, Canada

Oral and pharyngeal candidiasis is a significant infection, particularly in immunosuppressed persons. Candidiasis may be Bvident as red or white lesions and may produce symptoms. In immunosuppressed persons, oral candidiasis may lead to extensive regional involvement and to systemic infection and can result in death. Because of the significance and prevalence of candidiasis. the recognition and management of infection are important. (ORAL SURC ORAL MED ORAL PATHOL 1990;69:32-41)

M

ucositis and pharyngitis secondary to fungal infection are common.‘-5 Candida species are reported to be present in the normal oral flora of from 40% to 60% of the population.6 Candida albicans is most common in the normal flora and most frequently implicated as the pathogen in oropharyngeal and systemic infection.6 Oropharyngeal candidiasis can be the source of regional and systemic dissemination, particularly in granulocytopenic and immunosuppressedpatients. In these patients, reduced or absent signs and symptoms of inflammation make diagnosis difficult.7 The primary pathogen is Candida albicans, but pathogens may also include other Candida species and other fungi, including aspergillus and mucormycosis. Candidiasis may arise as a result of local conditions that may lead to shifts in the bacterial flora, and favor Candida species, or as a result of changes in the systemic status of the host. Local factors

Local factors predisposing to candidiasis include the wearing of dentures, xerostomia, and changes in the oral environment. Nonspecific factors in oral defense include the epithelial barrier, the flow of saliva, the diluting effects of saliva, antimicrobial constituents in saliva, and microbial interactions.6 Lysozyme in saliva has antibacterial activity and

“Medical/Dental Staff, Cancer Control Agency of British Columbia, Vancouver, B.C.; Head, Division of Oral Medicine and Clinical Dentistry, Vancouver General Hospital, Vancouver, B.C.; L.LIIIILiil kub,bld.,ll L~IUI’CDb”‘, LllLvr2;lairj ul’ EiiLAii CuiuKibiJ., Vancouver, B.C.; Research Associate, Department of Oral Medicine, University of Washington, Seattle, Washington. 7/13/11133 32

may also possessactivity against Candida species.6 Lactoferrin has been shown to have antibacterial and antifungal effects, by binding iron required for microbial growth.8 Sialoperoxidase has antimicrobial activity at physiologic concentrations. Recently, histidine-rich polypeptides in saliva have been reported to inhibit growth and have bactericidal and fungicidal effects.9,‘* Salivary glycoproteins present in saliva may prevent attachment of microorganisms to epithelial cells by competition with cellular receptor sites and lead to clumping of organisms.6*L1 Microbial interactions include nutritional competition, alteration in the microenvironment, elaboration of toxic by-products, and competing for adherence sites on epithelial cells.12 Specific anti-Candida antibodies are present in saliva. Salivary antibodies may affect the growth of organisms in the oral flora. The antibody may lead to aggregation of organisms and/or prevent their adherence to mucosal epithelium, reducing or preventing colonization and infection.6*L3-‘6In the oral environment where epithelial renewal occurs continually, and the mucosal surface is continually bathed with a flow of secretions, the ability of an organism to attach to the surface is a significant factor in colonization and disease. Systemic factors

Systemic predisposing factors include diabetes, immunosuppression due to disease including leukemia, medical therapy induced immunosuppression (i.e., corticosteroids, immunosuppressive drugs), and acquired immunodeficiency due to human immunodeficiency virus (HIV) infection. The oral flora may be affected by the use of

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1. Pseudomembranous candidiasis; angular cheilitis.

broad-spectrum antibiotics that may result in a flora of more resistant bacteria or result in increase in fungi.“-I9 Treatments such as radiation therapy and cancer chemotherapy that are directly toxic to the oral mucous membrane may lead to disruption of the oral mucosa. Changes occur in the oral flora during radiation therapy with a shift from primarily aerobic and anaerobic gram-positive cocci and bacilli to a flora with predominantly gram-negative organisms and fungi20-22. Local factors including local physicai irritation, preexisting infection, oral hygiene, nutritional status, and individual sensitivity*’ may influence the degree of mucosal breakdown.24,25 Ulceration and loss of the epithelial barrier may predispose the patient to both local and systemic infection.

Table

I. The spectrum of candidiasis

Pseudomembranous Atrophic Myperplastic Ulcerative Mucocutaneous

(thrush)

(invasiw) (endocrine-moniliasis

syndrome)

Esophagitis Systemic

Candidiasis has been recognized as a frequent infection in patients with leukemia. In a study of patients with acute leukemia, Dreizen and coworkers]’ found approximately one half of all oral infection to be of fungal origin, primarily Candida species. Barrett) identified 30% of patients with leukemia studied as developing oropharyngeal candidiasis.

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Fig.

2. Atrophic candidiasiswith few Candida plaques.

Fig.

3. Hyperplastic candidiasis(Cundida leukoplakia).

In a study of patients who were receiving chemotherapy for solid tumors, oral infection developed in lo%, with more than two thirds of fungal origin.26 In patients with neutropenia, the first sign of infection may be fever. 27*28The development of new fever in patients with granulocytopenia represents infection in approximately 60% of patients.29 Disseminated Candida is a life-threatening disease and can be difficult to diagnose, inasmuch as blood cultures may be negative, and the diagnosis is frequently made postmortem.4 Multiple sites of positive Cundida cultures should be considered as presumptive oi systemic infection in patients who are febrile while on antibiotic coverage.

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ORALPATHOL January 1990

In patients treated with chemotherapy, alteration in saliva flow and composition may also contribute to the change in the oral flora.13+‘6*30.31In the compromised host, mucositis and pharyngitis are associated primarily with gram-negative bacilli and fungi. Changes in the oral flora are conditioned by the use of antibiotics and due to acquisition of organisms from the environment.32 The patient’s underlying disease is a critical factor in determining the risk for infection. Infections are common in association with HIV iniecrion.“.‘” GIuyLdi yii&d GGi:i&ZSiS ia the most common oral infection in HIV infection; more than half of patients with the acquired immunodeficiency

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4. Invasive candidal

syndrome (AIDS), and AIDS-related complex (ARC) have signs and symptoms of candidiasis.33v35 The presence of oral candidiasis may be the first sign of immunosuppression due to HIV infection and may reflect increasing immunosuppression with progression of the disease. MANIFESTATIONS

(Table

mycotic infections

35

._“_, .-. Fig.

CLINICAL

therapy in oropharyngeal

I)

Candidiasis may be evident as pseudomembranous candidiasis with adherent white plaques that can be wiped off (Fig. 1). The mucosa is erythematous, and the presentation may be associated with a burning sensitivity and altered taste. Candidiasis may be evident as an atrophic form with moderate-to-intense erythema and symptoms (Fig. 2). Candidiasis may also become more invasive into the epithelium, resulting in hyperplastic candidiasis, which can be seen as a leukoplakia-like plaque that cannot be removed from the surface (Fig. 3). Candida leukoplakia may be associated with a systemic condition termed Candida-endocrine syndrome. Invasive, chronic ulcers may be associated with candidiasis in immunosuppressed patients (Fig. 4). Diagnosis is based on clinical signs and symptoms and microbiologic study; occasionally, biopsy is required. Aspergillus species may cause infection in patients with neutropenia. The most common site of infection has been determined to be the upper respiratory passages including the nasal passages or sinuses; the oral cavity has been reported to be involved.36 Mucormycosis follows a pattern similar to Aspergillus but is less common. Candidiasis is of particular importance in patients with progressive immunosuppression due to HIV

Table

ulcer of lip. II. Antifungal

medications

Topical agents Rinses Creams Oral tablets Vaginal tablets Systemic medications Oral Intravenous

infection and in those who become acutely suppressed during treatment for conditions such as leukemia and treatments such as organ transplant and bone marrow transplantation. In these patients, oral and pharyngeal colonization and infection may be the principle source of systemic infection. Early recognition and management of oral candidiasis are essential in preventing morbidity and mortality.37 TREATMENT

OF CANDIDIASIS

Management of candidiasis can be accomplished with topical applications, and when it is not controlled with topical agents only, treatment should include systemic medications (Table II). Advantage can be gained by use of topical medications inasmuch as the potential side effects of any systemic medication will not occur. Similarly, in patients with persistent infection, advantage can be gained by continuing topical agents, in addition to systemic medications. This may allow a lower dose or reduced duration of use of systemic medications. It is important that dentists be familiar with oral candidiasis and be familiar with topical and systemic

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antifungal medications. If the practitioner is not familiar with these agents and their potential side effects, referral to practitioners familiar with management of oral conditions is recomended. Medical practitioners may not be familiar with the advantage of use and the choices of topical antifungals. Systemic agents carry the risk of toxicity because fungal cell metabolism is similar to that of mammalian cells. Topical

antifungal

agents

Topical agents are available as oral rinses, oral tablets, vaginal tablets, and creams. In general, oral rinses provide a short contact time for the drug and are therefore of less efficacy. They are best used in patients who have dry mouth who may have difficulty in dissolving the tablet forms of these drugs. The tablets may be the most effective form of the medications because they can be dissolved slowly in the mouth and provide an increased contact of the drug with the oral environment, and the pharynx, on swallowing. The vaginal suppositories generally last longer than the oral tablets when dissolved in the mouth. Also, some of the oral products are sweetened with sugar, thus resulting in an increased risk of dental caries in dentate patients. Most patients tolerate the taste of the vaginal tablets. However, in patients with dry mouth, the tablets may dissolve very slowly and may become rough, irritating the mucosa. In these patients with friable mucosa and a dry mouth, tablet forms of the medication may not be the best choice. The cream forms of these topical antifungal agents can be applied to the corners of the mouth or placed in dentures for prolonged contact with the palatal mucosa, resulting in continuing release into the mouth. Combination of medications with different modes of action may allow an increased topical effect of the drugs. Systemic

agents

Systemic agents are required when the topical agents are not effective in controlling the infection. However, continuing the use of topical agents may result in more rapid clearing of the infection, and allow a lower dose, or shorter course of the systemic agent. The oral systemic drugs are used for outpatient care, but for systemic candidiasis in immunosuppressed patients, intravenous medications are frequently required. Prophylaxis of systemic candidiasis in patients with severe immunosuppression has been attempted among those with leukemia and those who have undergone bone marrow transplantation. Prevention of oral colonization and infection is the goal because the oropharyngeal region may be the primary source of

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initial colonization and allow subsequent spread of the infection. In HIV infection, topical agents will often control the infection until increasing immunosuppression results in the need for systemic agents. Polyene

antibiotics

These antibiotics are derived from Streptomyces species. They include nystatin and amphotericin B. These agents were introduced in the 1950s. Both agents bind to membrane sterols present in fungal cell membranes, resulting in membrane disruption, leading to leakage of cellular contents, and resulting in cell death.38 These agents have a preferential binding to ergosterol in the fungal cell membrane, which is not a component of mammalian cells. Their toxicity is due to the binding of cholesterol that is present in membranes of human cells. Nystatin is a useful medication for topical therapy in oral and pharyngeal candidiasis. Nystatin products are the agents most commonly used initially in treatment. The medication is available in a rinse form, oral and vaginal tablet, and as topical creams. The medications should be applied four times daily for therapeutic effect. In some cases, the tablets may be useful in patients who have chronic or recurring infection as prophylactic agents, being prescribed once or twice daily. In noncompromised patients, therapy must continue for at least 2 weeks so that a shift in the microbial flora can occur; otherwise, the infection will recur. In many cases, the therapy should continue for 2 to 3 weeks after resolution of signs and symptoms. Nystatin is poorly absorbed when used orally, and most is passed unchanged through the gastrointestinal tract.39 Topical oral use may occasionally lead to gastrointestinal side effects such as nausea, vomiting, and diarrhea. This is particularly important in patients who receive cancer chemotherapy and bone marrow transplantation inasmuch as they may not be able to tolerate the oral rinse because of nausea and vomiting. Amphotericin B is used in North America primarily as a systemic agent. It remains the drug of choice for intravenous treatment. Amphotericin B carries considerable risk of toxicity. Toxicity may manifest as fever, vomiting, renal toxicity, bone marrow toxicity, cardiovascular toxicity, and neurologic toxicity. 40-42For disseminated candidiasis and other fungi, this agent may be given concomitantly with oral flucytosine for possible synergistic effect and may reduce the risk of development of resistant organisms. 43Amphotericin B has been reported to be effective as a wpic;di kig;r;& h*
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the agent is not stable and must be used in 12 to 24 hours. Topical amphotericin B has shown encouraging results, and in cases in which it was ineffective, limited compliance with its use was reported.3 Flucytosine

(5-fluorocytosine)

Flucytosine is a fluorinated pyrimidine that may be useful as oral therapy for fungal infections that include Candida and aspergillus.40 Flucytosine is a fluorouracil analogue that becomes incorporated into fungal RNA, resulting in defective protein synthesis, and by inhibition of thymidylate synthetase impairs fungal DNA synthesis. M However, when used as a single agent resistance is a problem, and this drug has been used in combination with amphotericin B.43*45Toxicity due to metabolic effects on marrow cells, nausea, vomiting, and hepatic dysfunction may occur.40*43 Flucytosine is not nephrotoxic but is secreted by the kidneys. Caution must be taken with patients with impaired renal function, and when used in combination with amphotericin B, because this drug is nephrotoxic.40*42*43’46 The usual dose of flucytosine is 50 to 150 mg/kg/day in divided doses four times a day. Griseofulvin

Griseofulvin is derived from Penicillium griseofulvum. The agent is a systemic drug useful in treatment of superficial fungal infections and has been used in management of mucocutaneous candidiasis. Griseofulvin is not used in other forms of candidal infection. Absorption occurs in the gastrointestinal tract and is enhanced when the drug is taken with meals. The drug is plasma protein bound. It is metabolized in the liver by demethylation and is excreted by the kidneys.47*48 The drug is fungistatic, affecting growing, metabolically active fungi by affecting fungal cell wall synthesis, DNA synthesis, and mitosis.47 Side effects include gastrointestinal upset, headaches, drug reactions, and, rarely, marrow toxicity.49 Drug interactions include reduction in the effects of warfarin anticoagulants. Griseofulvin microsize daily dose is 500 to 1000 mg per day, the ultramicrosize, 350 to 750 mg. Azole compounds

These synthetic antifungals are the first broadspectrum agents active against a number of yeast and fungi. These agents are fungistatic through their property of changing membrane permeability, resulting in leakage of cellular contents. This membrane effect may be due to effects on the synthesis of ergosterol. The azole compounds bind more strongly

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to fungal enzymes than mammalian enzymes, resulting in a differential therapeutic effect.50*5’ The currently available imidazoles are clotrimazole, miconazole, econazole, and ketoconazole. Clotrimazole may be the most potent topical agent in this class of antifungals. It is used as a topical agent only because of its gastrointestinal and neurologic toxicity.51-53 Clotrimazole troches have become a commonly used form of topical antifungal. The troches are dissolved in the mouth five times daily for treatment of candidiasis. Miconazole can be used topically and systemically; however, because of a high rate of relapse with systemic use, the agent is used primarily as a topical agent.5’*52 Econazole is useful in topical application. It may also be effective systemically, although a systemic form of the medication is presently not available.54 The imidazoles may be applied twice daily for 2 to 4 weeks with continuation for at least 1 week after signs and symptoms have resolved. In more severe infection, or more compromised persons, application four or five times daily is recommended. Ketoconazole is the first oral systemic agent with broad antifungal activity. Ketoconazole is effective in treatment of candidal infections. It has become the drug of choice for mucocutaneous candidiasis and is the drug of choice for outpatient systemic therapy and Candidd esophagitis.@v 55*56 In HIV infection, ketoconazole is frequently prescribed, and maintenance therapy may be needed. Ketoconazole has been used for prophylaxis of yeast infections in patients with neutropenia. 57The usual dose for Candida infections is 200 mg once or twice per day. Ketoconazole is dependent on gastric acidity for absorption. Poor absorption may occur in persons with gastrointestinal disorders and limited intake of food. If the patient requires antacids, histamine-2 blockers, or other medications that affect the gastric secretion, these should be taken 2 hours after ketoconazole. The majority of ketoconazole is metabolized, and little active drug is excreted. Therefore dosage does not need to be altered in patients with renal failure. The drug does not appear to accumulate in hepatic disease. The metabolites are excreted primarily in the bile.58+59 The most frequent side effects of ketoconazole include nausea, vomiting, abdominal pain, and itching. Rarely, diarrhea, headache, tiredness, dizziness, rashes, leukopenia, hemolytic anemia, impotence, and gynecomastia may occur.6o Allergy appears very rare.61 The side effects of greatest concern are those that involve the liver. Asymptomatic reactions, such as elevation in liver enzymes, may occur. Symptomatic hepatitis with jaundice and associated symptoms

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of fatigue, weakness, malaise, and anorexia have been estimated to occur in I in 12,000 to 15,000 patients.62 These symptomatic reactions usually occur in the first few weeks of therapy. A few cases of fatal hepatitis have been linked to ketoconazo1e.62s63Patients who are taking high doses of ketoconazole (greater than 400 mg per day) should be monitored for signs and symptoms of hypoadrenalism and hypoandrogenism.64-66 Because of these effects, investigation of these agents in endocrinologic disorders is being carried out. Imidazoles in general may interfere with hepatic microsomal activity. Ketoconazole may potentiate the anticoagulant effect of warfarin.67 Drugs that potentiate the function of the hepatic microsome can decrease serum levels of ketoconazole.68,69 Ketoconazole is now available as a 2% topical cream and may prove to be useful in once or twice daily application. Other

topical

antifungals

Chlorhexidine. Chlorhexidine has antibacterial and antifungal properties. ‘O Chlorhexidine has been shown to reduce plaque formation and disperse preformed plaque, thus reducing the microbial load in the oral cavity.‘O Chlorhexidine is rapidly absorbed onto surfaces of microorganisms and results in increased permeability of cell membranes, leading to precipitation of cytoplasmic contents.70,7’ Chlorhexidine is not absorbed from the gastrointestinal tract, and systemic toxicity has not been reported.7’-73 The primary local side effects are a brown staining of dental surfaces and a bitter taste. The rinse is bound to salivary pellicle and hard tissue in the mouth, which leads to prolonged saliva titers after rinsing for up to 12 hours.‘O Chlorhexidine rinse was shown to be effective in treatment of oral candidiasis in children with serious diseases, including leukemia.74 In patients on chemotherapy, compliance with use is good because there is little problem with taste of the solution, when bitter sensation is altered. Gentian violet. Gentian violet has been used in treatment of vulvuovaginal candidiasis and other fungal infections. The mechanism of action is unknown. The disadvantages of this agent in the mouth are the blue-purple color and the fact that the liquid is an alcohol-based product that is dehydrating to the mucosa. Gentian violet is less effective than other available agents. The discoloration makes follow-up difficult as any further tissue change cannot be adeauatelv viwalind Thiq sEmt shnuld be avoided since better agents are available. Ciclopirox olamine. Ciclopirox olamine demonstrates a broad spectrum of activity that includes

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yeast, fungi, and various gram-positive and gramnegative bacteria.7s The mechanism of action appears to be via alteration of membrane transport and loss of membrane integrity. Newer

antifungals

under

study

These drugs are currently undergoing clinical trials and are not yet available for clinical use. The current studies include trials of new imidazoles. Bifonazole has a broad spectrum of activity against yeast and fungi.76 Tioconazole has anti-Candida activity and may result in more rapid resolution of infection than other imidazoles. Once daily application has been reported effective.” Systemic agents that may have greater efficacy than ketoconazole in candidiasis, aspergillosis, and infection with other fungi are being investigated.‘* Another class of antifungal agents consists of the triazole antifungals. Terconazole is a topical agent that demonstrates high anti-Candida activity.79 A systemic triazole, itraconazole has a wide spectrum of activity against yeast and fungi. This agent may represent an advance in antifungal therapy because of its relative lack of toxicity.78 Allylamines are a new class of fungicidal agents currently under investigation. These drugs interfere with synthesis of lanosterol and thus ergosterol and cholesterol, which are essential components of the cell membrane.51 Terbinafine is an agent that may have both topical and systemic applications.80 The drug has few side effects, and rapid response to treatment has been reported. PREVENTION OF INFECTION IN IMMUNOCOMPROMlSED PATIENTS

Because of the potential morbidity and mortality of Candida in immunocompromised hosts, prevention of colonization and infection is of considerable interest. Topical agents may be useful in the prevention of colonization and subsequent infection. Nystatin rinse has not shown effectiveness in preventing local infection nor in preventing systemic candidiasis in patients with leukemia.37 Despite nystatin rinse prophylaxis, clinically diagnosed oropharyngeal candidiasis developed in 30% of patients with leukemia.31 81,82 However, other topical antifungal agents alone or in combination may have greater potency and may reduce or prevent colonization or may reduce the development of disease or dissemination.82 Topical antiseptic rinses with chlorhexidine have shown encouraging results in studies with patients who have cancer.70*83-87Shepherd,85 in a study of patients with leukemia, found 0.2% chlorhexidine to

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reduce the total number of oral microorganisms by 98%. Rinsing with chlorhexidine every 2 to 3 hours may result in elimination of bacteria and yeast in patients with acute leukemia during neutropenia.84 During this protocol of intensive topical chlorhexidine rinsing and systemic preventive therapy, systemic infection’ developed in no patients during intensive chemotherapy. 85 McGaw and BelchE6 studied the prophylactic use of chlorhexidine 0.1% rinse twice daily in 16 patients and found a statistically significant improvement in gingival health, plaque scores, and mucositis in the chlorhexidine group. They also found that clinical candidiasis developed in half of the placebo group and that it developed in none of the chlorhexidine group. Ferretti and coworkers*’ found that prophylactic rinsing with chlorhexidine resulted in statistically significant reduction in mucositis and numbers of Candida organisms and no cases of clinical candidiasis, but in the control group clinical infection developed in two thirds and two died with systemic candidiasis. These studies suggest that prophylactic rinses of chlorhexidine reduce the colonization and infection by Candida species, as well as other oral complications in severely compromised patients. Further studies may confirm the effective use of prophylactic rinsing with chlorhexidine suspension. REFERENCES 1. Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol 1983;12:791-811. 2. Dreizen S, McCredie KB, Bodey GP, Keating MJ. Quantitative analysis of the oral complications of antileukemia chemotherapy. ORAL SURG ORAL MED ORAL PATHOL 1986;62: 650-3. 3. Barrett AP. A long-term prospective clinical study of oral complications during conventional chemotherapy for acute leukemia. ORAL SURC ORAL MED ORAL PATHOL 1987;63: 313-6.

4. Bodey GP. Fungal infections complicating acute leukemia. J Chronic Dis 1966;1:667-87. 5. Aisner J, Murillo J, Schimpff SC, Steere AC. Invasive aspergillosis in acute leukemia: correlation with nose cultures and antibiotic usage. Ann Intern Med 1979;90:4-9. 6. Epstein JB, Truelove EL., lzutzu KT. Oral candidiasis: pathogenesis and host defense. Rev Infect Dis 1984;6:96106. 7. Kodsi BE, Wickremesinghe PC, Kozinn PJ, et al. Candida esophagitis: a prospective study of 27 cases. Gastroenterology 1976;7 1:7 15-9. 8. Masson PL, Heremans JF, Dive C. An iron-binding protein common to many external secretions. Clin Chem Acta 1966;14:735-9. 9. MacKay BJ, Denepitiya L, Iacono VJ, Krost SB, Pollock JJ. Growth-inhibitory and bactericidal effects of human parotid salivary histidine-rich polypeptides on Streptococcus muians. Infect Immun 1984;44:695-701. 10. Polloek JJ, Denepitiya L, MacKay BJ, Iacono VJ. Fungistatic and fungicidal activity of human parotid salivary histidinerich polypeptides on Cundida albicans. Infect Immun 1984;44:702. 1 I. Williams RC, Gibbons RJ. Inhibition of streptococcal attach-

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ment to receptors on human buccal epithelial cells by antigenically similar salivary glycoproteins. Infect Immun 1975; 11:711-8. Rogers TJ, Balish E. Immunity to Candida albicans. Microbiol Rev 1980;44:660-82. Epstein JB, Pearsall NN, Truelove EL. Oral candidiasis: effects of antifungal therapy upon clinical signs and symptoms, salivary antibody and mucosal adherence of Candidu albicans. ORAL SURG ORAL MED ORAL PATHOL 1981;51: 32-6. Williams RC, Gibbons RJ. Inhibition of bacterial adherence by secretory immunoglobulin A: a mechanism of antigen disposal. Science 1972;177:697-9. Gibbons RJ, Van Houte J. Bacterial adherence in oral microbial ecology. Annu Rev Microbial 1975;29:19-44. Epstein JB, Kimura LH, Menard TW, Truelove EL, Pearsail NN. Effects of specific antibodies on the interaction between the fungus Can&da albicans and human oral mucosa. Arch Oral Biol 1982;27:469-74. Dreizen S, McCredie KB, Keating MJ, Bodey GP. Oral infections associated with chemotherapy in adults with acute leukemia. Postgrad Med 1982;71:133-46. Epstein JB, Gangbar SJ. Oral mucosal lesions in patients undergoing treatment for leukemia. J Oral Med 1987;42: 132-7. Valenti WM, Trudell RG, Bentley DW. Factors predisposing to oropharyngeal colonization with gram-negative bacilli in the aged. N Engl J Med 1978;298:1108-11. Brown LR, Driezen S, Handler S, Johnston DA. Effect of radiation-induced xerostomia on human oral microflora. J Dent Res 1975;54:740-50. Johnson WG, Pierce AK, Sanford JP. Changing pharyngeal bacterial flora of hospitalized patients: emergence of gramnegative bacilli. N Engl J Med 1969;281:1137-40. Rossie KM, Taylor J, Beck MF, Hodgson SE, Blozis GG. Influence of radiation therapy on oral Candidu albicans colonization: a quantitative assessment. ORAL SURG ORAL MED

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23. Weichselbaum RR, Epstein J, Little JB. In vitro radiosensitivity of human diploid fibroblasts derived from patients with unusual clinical responses to radiation. Radiology 1976;121: 479-82. 24. Silverman Jr S. Radiation effects. In: Oral Cancer. 2nd ed. New York: The American Cancer Society, 1985:70-8. 25. Lockhart PB, Sonis ST. Alterations in the oral mucosa caused by chemotherapeutic agents. J Dermatol Surg Oncol 1981;7:1019-25. 26. Dreizen S, Bodey GP, Valdivieso M. Chemotherapy-associated oral infections in adults with solid tumors. ORAL SURF ORAL

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27. Sickles EA. Greene WH, Wiernik PH. Clinical presentation in granulocytopenic patients. Arch Intern Med 1975;135: 7 15-9. 2x. Schimpf SC. Therapy of infection in patients with granulocytopenia. Med Clin North Am 1977:61:1101-18. >/:,. European Organization for Research of the Treatment of C‘anccr International Antimicrobial Therapy Project Group. Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer. J infect Dis 1978; 137: 14-29. 30. Courts FJ. Meuller WA. Suppression of salivary IgA secretion by methotrexate. J Dent Res 1983;62:181(ab& 102). 31. Main BE, Calman KC, Fereuson MM et al. The effects of cytotoxic therapy on saliva and oral flora. ORAL SURG ORAL MED

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32. Schimpff S, Young V, Greene W, Vermeulen G, Moody M, Wiernick P. Origin of infection in acute nonlymphocytic leukemia: significance of hospital acquisition of potential pathogens. Ann Intern Med 1972;77:707-14. 33. Silverman Jr S, Migliorati CA, Lozada-Nur F, et al. Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. J Am Dent Assoc 1986:l 12:187-92.

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group of leukemic patients. ORAL SURG ORAL MED ORAL PATHOL 1977;44:201-5.

Spiers AS, Dias SF, Lopez JA. Infection prevention in patients with cancer: microbiological evaluation of laminar air flow isolation, topical chlorhexidine and nonabsorbable antibiotics. J Hyg Can 1980;84:457-65. 85. Shepherd JP. The management of the oral complication of leukemia. ORAL SURG ORAL MED ORAL PATHOL 1978;45: 84.

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87. Ferretti GA, Ash RC, Brown AT, Largent BM, Kaplan A, Lillich TT. Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving bone marrow transplants. J Am Dent Assoc 1987;114:461-7. Reprint

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