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Oral candidosis
oral medicine Editor: JAMES W. LITTLE, D.M.D., M.S.D. School of Dentist~ University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 55455 I
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Oral candidosis R e p o r t of a c a s e i m p l i c a t i n g
Candida parapsilosis
as a p a t h o g e n
Justin R. Kolnick, B.D.S., Johannesburg, South Africa This article deals with the etiology, pathogenesis,clinical manifestations,diagnosis, and treatment of oral candidosis. Emphasis is placed on drug therapy, and the literature reviewed indicates that although many drugs are available, amphotericin B (10 rag. lozenges) is favored as the drug of choice in the treatment of this condition. Attention is drawn to predisposing factors, particularly diabetes mellitus. A case in which the pathogen was identified as Candida parapsilosis is reported.
C
andidosis is a disease caused by infection with a yeastlike fungus belonging to the genus Candida. Although C. albicans is the species most commonly involved, there is experimental evidence of pathogenicity of other species for animals. In addition to affecting the oral cavity, candidal infections frequently involve the skin, vagina, gastrointestinal tract, urinary tract, and lungs. Oral candidosis is usually a localized disease, but it may extend to the pharynx or even to the lungs, often with a fatal outcome.
ETIOLOGY AND PATHOGENESIS Candida is classified as a true fungus belonging to the subfamily Cryptococoidiae. While C. albicans is the principal pathogenic member of the genus, there are other species known to be pathogenic. These include
C. tropicalis. C. stellatoidea, C. pseudotropicalis, C. viswanathii, C. parapsilosis, C. guilliermondii, and C. krusei. There are three morphologic forms of candida: yeast cell, hypha, and chlamydospore. It is widely believed, though by no means established, that the mycelium is the pathogenic form. Winner and Hurley ~ are of the opinion that the yeast phase is the penetrant ibrm, while the mycelial phase is involved in establishing the infective process and exciting the inflammatory reaction. Lehner" found the carder rate to be about 50 percent. However, Cayton and Noble (quoted by Drake and Maibach 3) isolated the fungus from the mouths of fewer 0030-4220/80/110411
+05500.50/0
~)
1980 The
C. V. Mosby
Co.
than 10 percent of healthy children and adults but from three times as many ill persons. Whether infection is endogenous or exogenous cannot be answered categorically, except with respect to oral thrush in infants, which has been shown by Woodruff and Hesseltine 4 to be transmitted from the mother's vagina and hence is exogenous. Candida albicans, as well as the other species mentioned, is of low pathogenicity and infection will not occur unless there are either local or systemic predisposing factors, such as endocrine disturbances, nutritional disorders, chronic debilitating diseases, antibiotic therapy, and extremes of age."
CLINICAL MANIFESTATIONS The oral manifestations are classified as follows2: Acute A. Pseudomembranous candidosis (thrush) B. Atrophic candidosis (antibiotic stomatitis) Chronic A. Atrophic candidosis (denture sore mouth) B. Hyperplastic candidosis (candidal leukoplakia) Endocrine candidosis syndrome Acute pseudomembranous candidosis is by far the most common form of candidosis, occurring in neonates and debilitated patients. White curdlike patches appear on the cheeks, lips, palate, and tongue. The surrounding mucosa is not inflamed, and the pseudomembranous patches can be removed with difficulty, leaving an erosion. The disease may spread to the phar-
411
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Kolnick
Oral Surg. November, 1980
Fig. I. White, plaquelike lesions resembling milk curds involving the right retromolar area and adjacent soft palate.
ynx and esophagus, causing feeding difficulties, regurgitation, and weight loss. DIAGNOSIS
Diagnosis of infection is difficult; the mere presence of the organism is insufficient. Serologic investigations are of limited value, although Lehner 2 has developed an immunofluorescent technique to quantitate serum and salivary antibodies. Demonstration of the organism within epithelium and of hyphae and chlamydospores in a scraping from the lesion, in addition to the clinical manifestations of the disease, substantiates the diagnosis. '3 TREATMENT
Several drugs have been used in the treatment of oral candidosis. Nystatin is still regarded as one of the safest and most effective antifungal antibiotics in the treatment of candidosis. It is nonirritant, nonstaining, and nonsensitizing. However, it has an unpleasant flavor and the oral suspension has a limited shelf-life, even when refrigerated.
In the treatment of oral thrush with nystatin oral suspension (100,000 1.U.), Lim s achieved a 38 percent clinical cure after 7 days and 78.5 percent cure after 14 days. However, only 65 percent of his patients were free of the infective agent within 20 days. Langslet and colleagues r obtained higher success rates with nystatin and amphotericin B than with gentian violet, but even these agents do not cure all cases of oral thrush, and it has been claimed that they have little effect when the patient's general immune responses are impaired, as in cases of acute leukemia. Treatment of chronic atrophic candidosis is entirely dependent on whether or not an oral candidosis is verified. Generalized inflammation is usually caused by infection. If candida can be isolated, the treatment of choice is antifungal therapy. One nystatin tablet (500,000 I.U.) dissolved slowly in the mouth three times a day for 10 to 14 days should be sufficient, but it may be necessary to continue this treatment for up to 4 weeks. Ideally, the dentures should be left out of the mouth until the condition clears up. Alternatively, the dentures should be disinfected during the night and while the patient is sucking the tablets, to avoid the risk
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413
Fig. 2. Candida smear from oral lesions. (Gram stain. Magnification, ×20.) of reinfection from the dentures, s A 1 percent cetrimide solution" or sodium hypochlorite 9 may be used as denture disinfectants. Denture cleansers based on a chelating agent with a mixture of enzymes were found to be effective, s Alternatively, the denture may be lined with a temporary liner containing nystatin 800,000 I.U. ~° Therapy must be successfully completed before a new set of dentures is made. Van Reenen ~1 implicated streptococci and pneumococci in chronic atrophic candidosis and found that nystatin inhibited the growth of these organisms, which may be the reason this drug is effective in the treatment of the disease. The success he obtained using penicillin in the treatment of denture sore mouth adds credence to this postulate. Amphotericin B has a greater antifungal spectrum than nystatin, but, like the latter, it has no antibacterial activity. When administered topically or orally, it is nontoxic and nonirritant and, like nystatin, it actively suppresses intestinal candida. It has no unpleasant flavor and, because of its greater aqueous stability, it can be prepared as a ready-mixed, nonstaining suspension without the sedimentation or loss of potency which occurs with nystatin.12 In a study by Ewing, 12 of eighty-one patients treated for oral candidosis with amphotericin B (10 mg. lozenges), 87 percent were clinically cured and 73 percent were free of the infective agent. Alban and Groel ~3 found that 86 percent of the patients treated with amphotericin B suspension (100 mg./ml.) had an excellent or good therapeutic re-
sponse, while 78 percent were free of the infective agent. The use of amphotericin B overcomes many of the drawbacks of gentian violet and nystatin and, with a success rate of 87 percent, 10 mg. lozenges of amphotericin B appear to offer an effective and pleasant form of therapy for children and adults suffering from oral candidosis?, ~z The results of a study of miconazole by Brincker ta compare very favorably with those of Ewing ~ and Lim. 6 Thirty-five episodes of clinically obvious oral candidosis were studied in twenty-four patients. Clinical cure was established in all episodes treated, while 97 percent were free of the infective agent. At one stage gentian violet in a 1 percent aqueous solution became the standard form of therapy for candidosis. Although not entirely ineffective, gentian violet is messy and unpopular from the patient's point of view because of staining of clothing and tissues. Sometimes the discoloration of the buccal mucosa is so intense as to obscure the lesion. Rarely, gentian violet may aggravate the condition as a result of superficial necrosis (the gentian violet burn), r' In a pilot trial on the therapeutic effects of chlorhexidine in oral candidosis, Langslet and associates 7 obtained a 100 percent clinical and mycologic cure. The results obtained in this limited trial are promising, and in oral fungal infections chlorhexidine deserves further attention as an alternative to such drugs as nystatin, amphotericin B, and gentian violet. Sharon and coworkers ~ found that, although chlorhexidine was
414
Kolnick
clearly fungicidal in vitro, no decrease in candida titer was obtained with the mouth rinse in a group of leukemic patients. K a y TM suggests that oral candidosis can be effectively treated by means of polynoxvlin (Anaflex) prepared as lozenges (30 mg). These have the advantage of a pleasant flavor. Phillips t7 concluded that the drug had little or no effect in the treatment of denture stomatitis. In a random double-blind trial, Cohen and associates TM found clotrimazole to be as effective as nystatin. In treating two patients with chronic mucocutaneous candidosis, Higgs and Wells '9 reported sustained clinical improvement in cutaneous lesions for more than 18 months following the use of topical clotrimazole.
Nutritional factors Higgs and Wells '~ believe that it is important to be aware of less obvious abnormalities, such as nutritional factors, which could play a significant role in the chronicity o f the disorder. In the treatment of two cases of mucocutaneous candidosis, almost complete remission of the oral lesions was observed when continuous iron therapy was given in addition to local treatment with nystatin suspension. The suspension was found to be of no value when used alone. It is suggested that the regeneration o f oral epithelium observed during the course o f iron therapy played an important role in achieving this effect. There is little documented evidence relating candidosis to vitamin deficiency, although it is well established that folate deficiency will produce widespread degenerative changes in the oral mucosa. Jenkins and co-authors 2° suggest that folic acid deficiency is at least as important as iron deficiency in the cause of chronic hyperplastic candidosis.
Immunologic aspects Kirkpatrick and colleagues 2' believe that reconstitution o f the immune system may be useful in treating certain patients with chronic mucocutaneous candidosis. Another currently available approach for reconstitution o f cellular immune function is the use of dialyzable transfer factor. 2z
CASE REPORT History A 51-year-old man complained of orofacial pain which had been present for about 1 week and was most severe on awakening. He had diabetes of adult onset, which was well controlled.
Examination lntraoral examination revealed small, numerous, white, plaquelike lesions resembling milk curds involving the buccal mucosa, palate, and gingiva (Fig. 1). Oral hygiene was poor,
Oral Surg. November, 1980 with evidence of extensive plaque and calculus formation as well as generalized periodontal disease. Removal of the plaque left an erosion.
Investigations Scrapings of the oral lesions were subjected to Gram stain and examined microscopically (Fig. 2). Scrapings of the surface of these lesions were plated onto Sabouraud's medium and incubated aerobically at 37 ° C for 24 hours. This procedure was repeated at each subsequent visit. The isolate was subjected to the germ tube test as well as sugar fermentation and assimilation tests. Growth on cornmeal agar revealed no evidence of chlamydospore formation. The patient's serum was subjected to indirect immunofluorescent antibody studies which revealed an antibody titer of 1/64, indicating a normal antibody response. The organism was found to be sensitive to nystatin in vitro. The results of these investigations confirmed a diagnosis of oral candidosis. The etiological organism was identified as Candida parapsilosis.
Treatment A vast improvement in oral hygiene was obtained by means of repeated scalings and oral hygiene instruction. Further treatment fell into three phases: Phase I. The patient was instructed to suck one nystatin suppository (100,000 I.U.) three times a day for the first week, followed by one tablet daily for l month, and to rinse with sodium bicarbonate and 0.2 percent chlorhexidine mouthwashes three times per day. The patient was reexamined 5 days after commencing therapy. A remarkable improvement in his oral condition was noted, indicating a clinical cure, but the organism was still isolated from the oral cavity. Phase 2. Re-examination 7 weeks after the start of therapy revealed that the oral condition had reappeared. A further course of nystatin oral tablets (500,000 I.U.) in decreasing doses was prescribed for 12 weeks, after confirmation that the diabetic state was still well under control. This failed to improve the patient's oral condition. Phase 3. Treatment was continued with amphotericin B lozenges ( 10 mg.), one lozenge to be sucked four times a day for 14 days, followed by one lozenge daily for a further 14 days. Both clinical and mycologic cures were recorded, and a follow-up examination 2 months later disclosed no reappearance of the condition,
DISCUSSION The literature reviewed indicates that, o f the several drugs available for the treatment of oral candidosis, amphotericin B and nystatin are the most efficient, although the former is now favored as the drug of choice. 23 Amphotericin B has a greater antifungal spectrum than nystatin '2 and has been shown to be more active in vitro against C. albicans. 24 Although nystatin is effective when applied topically in the oral cavity and on
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Volume 50 Number 5
perioral tissues, its widespread use for oral candidosis has been seriously curtailed by its unpleasant taste. 2~ Encouraging results have also been obtained with miconazole 14 and clotrimazole, ts Treatment of oral candidosis must be prolonged and should not be terminated immediately after clearing of the oral lesions. In addition, it is essential to diagnose and treat the underlying, predisposing condition in order to obtain successful results. Of these underlying conditions, diabetes mellitus is regarded as one of the most common. "In fact, when diagnosis of candidosis is made, other pathological conditions, especially diabetes, should be sought."2~ Drake and Maibach z found that in patients with diabetes mellitus or those taking corticosteroids, salivary glucose levels are greatly augmented. In addition, diabetic patients commonly complain of a dry mouth due to excessive fluid loss. These factors favor the establishment of a candidal infection in the mouth. Although diabetes mellitus has an insignificant disruptive effect on the immune system, it has been found to interfere with the inflammatory response in man by impeding neutrophil chemotaxis and phagocytosis. A case in which Candida parapsilosis was identified as the pathogen involved has been described. Neither the clinical manifestations nor the response to standard forms of treatment appeared to differ from cases in which Candida albicans was isolated as the pathogen. I wish to thank Professor J. Lemmer and the Department of Oral Medicine and Oral Microbiology of the University of Witwatersrand, South Africa, for their assistance in the preparation of this paper. REFERENCES 1, Winner, H. I., and Hurley, R.: Symposium on Candida Infections, ed. 2, Edinburgh, 1966, E. & S. Livingstone, Ltd. 2. Lehner, T.: Oral Candidosis, Dent. Practitioner 17: 209-216, 1967. 3. Drake, T. E., and Maibach, H. I.: Candida and Candidiasis. 1. Cultural Conditions, Epidaemiology and Pathogenesis, Postgrad. Med. 53: 83-87, 1973. 4. Woodruff, P. W., and Hesseltine, H. C.: Relationship of Oral Thrush to Vaginal Mycosis and the Incidence of Each, Am. J. Obstet. Gynecol. 36: 467, 1938. 5. Gayford, J. J., and Haskell, R.: Clinical Oral Medicine, ed. 1, London, 1971, Staples Press, pp. 80-86. 6. Lim, C. C.: Pediatric Clinical Studies With Formulation (Ready-Mix) of Mycostatin Oral Suspension; Report to the Squibb Institute for Medical Research, Feb. 22, 1972.
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7. Langslet, A., Olsen, I., Lie, S. O., and Lokken, P.: Chlorhexidine Treatment of Oral Candidiasis in Seriously Diseased Children, Acta Paediatr. Scand. 63:809-811, 1974. 8. Butz-Jorgensen, E.: Denture Stomatitis. II. The Effects of Antifungal and Prosthetic Treatment, Acta Odontol. Scand. 28: 283-304, 1970. 9. Cohen, L.: Oral Candidiasis--Its Diagnosis and Treatment, J. Oral Med. 27: 7-11, 1972. 10. Douglas, W. H., and Walker, D. M.: Nystatin in Denture Liners--An Alternative Treatment of Denture Stomatitis, Br. Dent. J. 135: 55-59, 1973. 11. van Reenen, J. F.: Microbiologic Studies of Denture Stomatitis, J. Prosthet. Dent. 30: 493-505, 1973. 12. Ewing, A.: Amphotericin B Lozenges in the Treatment of Oral Thrush, Practitioner 199: 62-67, 1967. 13. Alban, J., and Groel, J. T.: Amphotericin B Oral Suspension in the Treatment of Thrush, Curr. Ther. Res. 12" 479-484, 1970. 14. Brincker, H.: Treatment of Oral Candidosis in Debilitated Patients With Miconazole--A New Potent Anti-fungal Drug, Scand. J. Infect. Dis. 8: 117-120, 1976. 15. Sharon, A., Berdicevsky, I., Ben-Aryen, H., et al.: The Effect of Chlorhexidine Mouth Rinses on Oral Candida in a Group of Leukemic Patients, ORAL SURG. 44: 201-205, 1977. 16. Kay, L. W.: New Drugs, Br. J. Oral Surg. 5: 120-134, 1967. 17. Phillips, H. I. B.: The Treatment of Denture Stomatitis With Polynoxylin--A Double Blind Trial, Br. Dent. J. 128: 78-80, 1970. 18. Cohen, M., Harkness, R. A., Renz, M., and Farquhar, J. W.: Trials of the Use of Clotrimazole in the Treatment of Oral Candidiasis in Newborn Babies, Postgrad. Med. J. 50: Supp. I, 28-30, 1974. 19. Higgs, J. M.. and Wells, R. S.: Diffuse Chronic Mucocutaneous Candidiasis: Report of Two Patients Treated With Topical Clotrimazole and Replacement of Nutritional Deficiencies, Guys Hosp. Rep. 122" 135-153, 1973. 20. Jenkins, W. M. M., Macfarlane, T. W., Ferguson, M. M., and Mason, D. K.: Nutritional Deficiency in Oral Candidosis, Int. J. Oral Surg. 6: 204-210, 1977. 21. Kirkpatrick, C. H., Rich, R. R., Graw, R. G., Jr., Smith, T. K., Irad, Mickenberg, and Rogentine, G, N.: Treatment of Chronic Mucocutaneous Moniliasis by Immunological Reconstitution, Clin. Exp. Immunol. 9: 733-748, 1971. 22. Pabst, H. F., and Swanson; R.: Successful Treatment of Candidiasis With Transfer Factor, Br. Med. J. 2: 442-443, 1972. 23. Cartwright, R. Y.: Anti-fungal Agents, 3rd series, Part I, Med. S. Afr. pp. 109-115, June, 1978. 24. Stough, A. R,, Groel, J. T., and Kroeger, W. H: Amphotericin B - - a New Anti-fungal Agent for the Prophylaxis of AntibioticInduced Moniliasis, Antibiot. Med. Clin. Ther. 6: 653-661, 1959. 25. Cawson, R. A.: Thrush in Adult Out-Patients, Dent. Practitioner 15: 361-364, 1965. 26. Witten, H. V., and Katz, S. I.: Nystatin, Med. Clin. North Am. 54: 1329-1337, 1970. Reprint requests to: Dr. Justin R. Kolnick 50, Club Street Linksfield Johannesburg 2192, South Africa
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Oral candidosis R e p o r t of a c a s e i m p l i c a t i n g
Candida parapsilosis
as a p a t h o g e n
Justin R. Kolnick, B.D.S., Johannesburg, South Africa This article deals with the etiology, pathogenesis,clinical manifestations,diagnosis, and treatment of oral candidosis. Emphasis is placed on drug therapy, and the literature reviewed indicates that although many drugs are available, amphotericin B (10 rag. lozenges) is favored as the drug of choice in the treatment of this condition. Attention is drawn to predisposing factors, particularly diabetes mellitus. A case in which the pathogen was identified as Candida parapsilosis is reported.
C
andidosis is a disease caused by infection with a yeastlike fungus belonging to the genus Candida. Although C. albicans is the species most commonly involved, there is experimental evidence of pathogenicity of other species for animals. In addition to affecting the oral cavity, candidal infections frequently involve the skin, vagina, gastrointestinal tract, urinary tract, and lungs. Oral candidosis is usually a localized disease, but it may extend to the pharynx or even to the lungs, often with a fatal outcome.
ETIOLOGY AND PATHOGENESIS Candida is classified as a true fungus belonging to the subfamily Cryptococoidiae. While C. albicans is the principal pathogenic member of the genus, there are other species known to be pathogenic. These include
C. tropicalis. C. stellatoidea, C. pseudotropicalis, C. viswanathii, C. parapsilosis, C. guilliermondii, and C. krusei. There are three morphologic forms of candida: yeast cell, hypha, and chlamydospore. It is widely believed, though by no means established, that the mycelium is the pathogenic form. Winner and Hurley ~ are of the opinion that the yeast phase is the penetrant ibrm, while the mycelial phase is involved in establishing the infective process and exciting the inflammatory reaction. Lehner" found the carder rate to be about 50 percent. However, Cayton and Noble (quoted by Drake and Maibach 3) isolated the fungus from the mouths of fewer 0030-4220/80/110411
+05500.50/0
~)
1980 The
C. V. Mosby
Co.
than 10 percent of healthy children and adults but from three times as many ill persons. Whether infection is endogenous or exogenous cannot be answered categorically, except with respect to oral thrush in infants, which has been shown by Woodruff and Hesseltine 4 to be transmitted from the mother's vagina and hence is exogenous. Candida albicans, as well as the other species mentioned, is of low pathogenicity and infection will not occur unless there are either local or systemic predisposing factors, such as endocrine disturbances, nutritional disorders, chronic debilitating diseases, antibiotic therapy, and extremes of age."
CLINICAL MANIFESTATIONS The oral manifestations are classified as follows2: Acute A. Pseudomembranous candidosis (thrush) B. Atrophic candidosis (antibiotic stomatitis) Chronic A. Atrophic candidosis (denture sore mouth) B. Hyperplastic candidosis (candidal leukoplakia) Endocrine candidosis syndrome Acute pseudomembranous candidosis is by far the most common form of candidosis, occurring in neonates and debilitated patients. White curdlike patches appear on the cheeks, lips, palate, and tongue. The surrounding mucosa is not inflamed, and the pseudomembranous patches can be removed with difficulty, leaving an erosion. The disease may spread to the phar-
411
412
Kolnick
Oral Surg. November, 1980
Fig. I. White, plaquelike lesions resembling milk curds involving the right retromolar area and adjacent soft palate.
ynx and esophagus, causing feeding difficulties, regurgitation, and weight loss. DIAGNOSIS
Diagnosis of infection is difficult; the mere presence of the organism is insufficient. Serologic investigations are of limited value, although Lehner 2 has developed an immunofluorescent technique to quantitate serum and salivary antibodies. Demonstration of the organism within epithelium and of hyphae and chlamydospores in a scraping from the lesion, in addition to the clinical manifestations of the disease, substantiates the diagnosis. '3 TREATMENT
Several drugs have been used in the treatment of oral candidosis. Nystatin is still regarded as one of the safest and most effective antifungal antibiotics in the treatment of candidosis. It is nonirritant, nonstaining, and nonsensitizing. However, it has an unpleasant flavor and the oral suspension has a limited shelf-life, even when refrigerated.
In the treatment of oral thrush with nystatin oral suspension (100,000 1.U.), Lim s achieved a 38 percent clinical cure after 7 days and 78.5 percent cure after 14 days. However, only 65 percent of his patients were free of the infective agent within 20 days. Langslet and colleagues r obtained higher success rates with nystatin and amphotericin B than with gentian violet, but even these agents do not cure all cases of oral thrush, and it has been claimed that they have little effect when the patient's general immune responses are impaired, as in cases of acute leukemia. Treatment of chronic atrophic candidosis is entirely dependent on whether or not an oral candidosis is verified. Generalized inflammation is usually caused by infection. If candida can be isolated, the treatment of choice is antifungal therapy. One nystatin tablet (500,000 I.U.) dissolved slowly in the mouth three times a day for 10 to 14 days should be sufficient, but it may be necessary to continue this treatment for up to 4 weeks. Ideally, the dentures should be left out of the mouth until the condition clears up. Alternatively, the dentures should be disinfected during the night and while the patient is sucking the tablets, to avoid the risk
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413
Fig. 2. Candida smear from oral lesions. (Gram stain. Magnification, ×20.) of reinfection from the dentures, s A 1 percent cetrimide solution" or sodium hypochlorite 9 may be used as denture disinfectants. Denture cleansers based on a chelating agent with a mixture of enzymes were found to be effective, s Alternatively, the denture may be lined with a temporary liner containing nystatin 800,000 I.U. ~° Therapy must be successfully completed before a new set of dentures is made. Van Reenen ~1 implicated streptococci and pneumococci in chronic atrophic candidosis and found that nystatin inhibited the growth of these organisms, which may be the reason this drug is effective in the treatment of the disease. The success he obtained using penicillin in the treatment of denture sore mouth adds credence to this postulate. Amphotericin B has a greater antifungal spectrum than nystatin, but, like the latter, it has no antibacterial activity. When administered topically or orally, it is nontoxic and nonirritant and, like nystatin, it actively suppresses intestinal candida. It has no unpleasant flavor and, because of its greater aqueous stability, it can be prepared as a ready-mixed, nonstaining suspension without the sedimentation or loss of potency which occurs with nystatin.12 In a study by Ewing, 12 of eighty-one patients treated for oral candidosis with amphotericin B (10 mg. lozenges), 87 percent were clinically cured and 73 percent were free of the infective agent. Alban and Groel ~3 found that 86 percent of the patients treated with amphotericin B suspension (100 mg./ml.) had an excellent or good therapeutic re-
sponse, while 78 percent were free of the infective agent. The use of amphotericin B overcomes many of the drawbacks of gentian violet and nystatin and, with a success rate of 87 percent, 10 mg. lozenges of amphotericin B appear to offer an effective and pleasant form of therapy for children and adults suffering from oral candidosis?, ~z The results of a study of miconazole by Brincker ta compare very favorably with those of Ewing ~ and Lim. 6 Thirty-five episodes of clinically obvious oral candidosis were studied in twenty-four patients. Clinical cure was established in all episodes treated, while 97 percent were free of the infective agent. At one stage gentian violet in a 1 percent aqueous solution became the standard form of therapy for candidosis. Although not entirely ineffective, gentian violet is messy and unpopular from the patient's point of view because of staining of clothing and tissues. Sometimes the discoloration of the buccal mucosa is so intense as to obscure the lesion. Rarely, gentian violet may aggravate the condition as a result of superficial necrosis (the gentian violet burn), r' In a pilot trial on the therapeutic effects of chlorhexidine in oral candidosis, Langslet and associates 7 obtained a 100 percent clinical and mycologic cure. The results obtained in this limited trial are promising, and in oral fungal infections chlorhexidine deserves further attention as an alternative to such drugs as nystatin, amphotericin B, and gentian violet. Sharon and coworkers ~ found that, although chlorhexidine was
414
Kolnick
clearly fungicidal in vitro, no decrease in candida titer was obtained with the mouth rinse in a group of leukemic patients. K a y TM suggests that oral candidosis can be effectively treated by means of polynoxvlin (Anaflex) prepared as lozenges (30 mg). These have the advantage of a pleasant flavor. Phillips t7 concluded that the drug had little or no effect in the treatment of denture stomatitis. In a random double-blind trial, Cohen and associates TM found clotrimazole to be as effective as nystatin. In treating two patients with chronic mucocutaneous candidosis, Higgs and Wells '9 reported sustained clinical improvement in cutaneous lesions for more than 18 months following the use of topical clotrimazole.
Nutritional factors Higgs and Wells '~ believe that it is important to be aware of less obvious abnormalities, such as nutritional factors, which could play a significant role in the chronicity o f the disorder. In the treatment of two cases of mucocutaneous candidosis, almost complete remission of the oral lesions was observed when continuous iron therapy was given in addition to local treatment with nystatin suspension. The suspension was found to be of no value when used alone. It is suggested that the regeneration o f oral epithelium observed during the course o f iron therapy played an important role in achieving this effect. There is little documented evidence relating candidosis to vitamin deficiency, although it is well established that folate deficiency will produce widespread degenerative changes in the oral mucosa. Jenkins and co-authors 2° suggest that folic acid deficiency is at least as important as iron deficiency in the cause of chronic hyperplastic candidosis.
Immunologic aspects Kirkpatrick and colleagues 2' believe that reconstitution o f the immune system may be useful in treating certain patients with chronic mucocutaneous candidosis. Another currently available approach for reconstitution o f cellular immune function is the use of dialyzable transfer factor. 2z
CASE REPORT History A 51-year-old man complained of orofacial pain which had been present for about 1 week and was most severe on awakening. He had diabetes of adult onset, which was well controlled.
Examination lntraoral examination revealed small, numerous, white, plaquelike lesions resembling milk curds involving the buccal mucosa, palate, and gingiva (Fig. 1). Oral hygiene was poor,
Oral Surg. November, 1980 with evidence of extensive plaque and calculus formation as well as generalized periodontal disease. Removal of the plaque left an erosion.
Investigations Scrapings of the oral lesions were subjected to Gram stain and examined microscopically (Fig. 2). Scrapings of the surface of these lesions were plated onto Sabouraud's medium and incubated aerobically at 37 ° C for 24 hours. This procedure was repeated at each subsequent visit. The isolate was subjected to the germ tube test as well as sugar fermentation and assimilation tests. Growth on cornmeal agar revealed no evidence of chlamydospore formation. The patient's serum was subjected to indirect immunofluorescent antibody studies which revealed an antibody titer of 1/64, indicating a normal antibody response. The organism was found to be sensitive to nystatin in vitro. The results of these investigations confirmed a diagnosis of oral candidosis. The etiological organism was identified as Candida parapsilosis.
Treatment A vast improvement in oral hygiene was obtained by means of repeated scalings and oral hygiene instruction. Further treatment fell into three phases: Phase I. The patient was instructed to suck one nystatin suppository (100,000 I.U.) three times a day for the first week, followed by one tablet daily for l month, and to rinse with sodium bicarbonate and 0.2 percent chlorhexidine mouthwashes three times per day. The patient was reexamined 5 days after commencing therapy. A remarkable improvement in his oral condition was noted, indicating a clinical cure, but the organism was still isolated from the oral cavity. Phase 2. Re-examination 7 weeks after the start of therapy revealed that the oral condition had reappeared. A further course of nystatin oral tablets (500,000 I.U.) in decreasing doses was prescribed for 12 weeks, after confirmation that the diabetic state was still well under control. This failed to improve the patient's oral condition. Phase 3. Treatment was continued with amphotericin B lozenges ( 10 mg.), one lozenge to be sucked four times a day for 14 days, followed by one lozenge daily for a further 14 days. Both clinical and mycologic cures were recorded, and a follow-up examination 2 months later disclosed no reappearance of the condition,
DISCUSSION The literature reviewed indicates that, o f the several drugs available for the treatment of oral candidosis, amphotericin B and nystatin are the most efficient, although the former is now favored as the drug of choice. 23 Amphotericin B has a greater antifungal spectrum than nystatin '2 and has been shown to be more active in vitro against C. albicans. 24 Although nystatin is effective when applied topically in the oral cavity and on
Oral candidosis
Volume 50 Number 5
perioral tissues, its widespread use for oral candidosis has been seriously curtailed by its unpleasant taste. 2~ Encouraging results have also been obtained with miconazole 14 and clotrimazole, ts Treatment of oral candidosis must be prolonged and should not be terminated immediately after clearing of the oral lesions. In addition, it is essential to diagnose and treat the underlying, predisposing condition in order to obtain successful results. Of these underlying conditions, diabetes mellitus is regarded as one of the most common. "In fact, when diagnosis of candidosis is made, other pathological conditions, especially diabetes, should be sought."2~ Drake and Maibach z found that in patients with diabetes mellitus or those taking corticosteroids, salivary glucose levels are greatly augmented. In addition, diabetic patients commonly complain of a dry mouth due to excessive fluid loss. These factors favor the establishment of a candidal infection in the mouth. Although diabetes mellitus has an insignificant disruptive effect on the immune system, it has been found to interfere with the inflammatory response in man by impeding neutrophil chemotaxis and phagocytosis. A case in which Candida parapsilosis was identified as the pathogen involved has been described. Neither the clinical manifestations nor the response to standard forms of treatment appeared to differ from cases in which Candida albicans was isolated as the pathogen. I wish to thank Professor J. Lemmer and the Department of Oral Medicine and Oral Microbiology of the University of Witwatersrand, South Africa, for their assistance in the preparation of this paper. REFERENCES 1, Winner, H. I., and Hurley, R.: Symposium on Candida Infections, ed. 2, Edinburgh, 1966, E. & S. Livingstone, Ltd. 2. Lehner, T.: Oral Candidosis, Dent. Practitioner 17: 209-216, 1967. 3. Drake, T. E., and Maibach, H. I.: Candida and Candidiasis. 1. Cultural Conditions, Epidaemiology and Pathogenesis, Postgrad. Med. 53: 83-87, 1973. 4. Woodruff, P. W., and Hesseltine, H. C.: Relationship of Oral Thrush to Vaginal Mycosis and the Incidence of Each, Am. J. Obstet. Gynecol. 36: 467, 1938. 5. Gayford, J. J., and Haskell, R.: Clinical Oral Medicine, ed. 1, London, 1971, Staples Press, pp. 80-86. 6. Lim, C. C.: Pediatric Clinical Studies With Formulation (Ready-Mix) of Mycostatin Oral Suspension; Report to the Squibb Institute for Medical Research, Feb. 22, 1972.
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7. Langslet, A., Olsen, I., Lie, S. O., and Lokken, P.: Chlorhexidine Treatment of Oral Candidiasis in Seriously Diseased Children, Acta Paediatr. Scand. 63:809-811, 1974. 8. Butz-Jorgensen, E.: Denture Stomatitis. II. The Effects of Antifungal and Prosthetic Treatment, Acta Odontol. Scand. 28: 283-304, 1970. 9. Cohen, L.: Oral Candidiasis--Its Diagnosis and Treatment, J. Oral Med. 27: 7-11, 1972. 10. Douglas, W. H., and Walker, D. M.: Nystatin in Denture Liners--An Alternative Treatment of Denture Stomatitis, Br. Dent. J. 135: 55-59, 1973. 11. van Reenen, J. F.: Microbiologic Studies of Denture Stomatitis, J. Prosthet. Dent. 30: 493-505, 1973. 12. Ewing, A.: Amphotericin B Lozenges in the Treatment of Oral Thrush, Practitioner 199: 62-67, 1967. 13. Alban, J., and Groel, J. T.: Amphotericin B Oral Suspension in the Treatment of Thrush, Curr. Ther. Res. 12" 479-484, 1970. 14. Brincker, H.: Treatment of Oral Candidosis in Debilitated Patients With Miconazole--A New Potent Anti-fungal Drug, Scand. J. Infect. Dis. 8: 117-120, 1976. 15. Sharon, A., Berdicevsky, I., Ben-Aryen, H., et al.: The Effect of Chlorhexidine Mouth Rinses on Oral Candida in a Group of Leukemic Patients, ORAL SURG. 44: 201-205, 1977. 16. Kay, L. W.: New Drugs, Br. J. Oral Surg. 5: 120-134, 1967. 17. Phillips, H. I. B.: The Treatment of Denture Stomatitis With Polynoxylin--A Double Blind Trial, Br. Dent. J. 128: 78-80, 1970. 18. Cohen, M., Harkness, R. A., Renz, M., and Farquhar, J. W.: Trials of the Use of Clotrimazole in the Treatment of Oral Candidiasis in Newborn Babies, Postgrad. Med. J. 50: Supp. I, 28-30, 1974. 19. Higgs, J. M.. and Wells, R. S.: Diffuse Chronic Mucocutaneous Candidiasis: Report of Two Patients Treated With Topical Clotrimazole and Replacement of Nutritional Deficiencies, Guys Hosp. Rep. 122" 135-153, 1973. 20. Jenkins, W. M. M., Macfarlane, T. W., Ferguson, M. M., and Mason, D. K.: Nutritional Deficiency in Oral Candidosis, Int. J. Oral Surg. 6: 204-210, 1977. 21. Kirkpatrick, C. H., Rich, R. R., Graw, R. G., Jr., Smith, T. K., Irad, Mickenberg, and Rogentine, G, N.: Treatment of Chronic Mucocutaneous Moniliasis by Immunological Reconstitution, Clin. Exp. Immunol. 9: 733-748, 1971. 22. Pabst, H. F., and Swanson; R.: Successful Treatment of Candidiasis With Transfer Factor, Br. Med. J. 2: 442-443, 1972. 23. Cartwright, R. Y.: Anti-fungal Agents, 3rd series, Part I, Med. S. Afr. pp. 109-115, June, 1978. 24. Stough, A. R,, Groel, J. T., and Kroeger, W. H: Amphotericin B - - a New Anti-fungal Agent for the Prophylaxis of AntibioticInduced Moniliasis, Antibiot. Med. Clin. Ther. 6: 653-661, 1959. 25. Cawson, R. A.: Thrush in Adult Out-Patients, Dent. Practitioner 15: 361-364, 1965. 26. Witten, H. V., and Katz, S. I.: Nystatin, Med. Clin. North Am. 54: 1329-1337, 1970. Reprint requests to: Dr. Justin R. Kolnick 50, Club Street Linksfield Johannesburg 2192, South Africa