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Clotrimazole treatment of oral candidiasis in patients with neoplastic disease
Clotrimazole Treatment of Oral Candidiasis in Patients with Neoplastic Disease
LEE B. SHECHTMAN, M.D. LAURA FUNARO, R.N., B.A. THOMAS ROBIN, M.S. EDWARD J. BOTTONE, Ph.D JANET CUTTNER, M.D. New York, New York
A double-blind controlled study was performed to evaluate the effectiveness of clotrimazole in the treatment of oral candidiasis in patients with neoplastic disease. Six of seven patients who received clotrimazole had resolution of symptoms and signs of oral candidiasis. In five of six patients who received placebo, clinical progression of signs and symptoms occurred, esophagitis developed, and amphoterlcin B therapy had to be given. No toxicity was observed that could be attributed to clotrimazole. The results were statistically significant (p = 0.025 by Fisher’s exact test). Clotrimazole is effective therapy for oral candidiasis in patients with neoplastlc disease, and may prevent the development of esophagltis. Oral candidiasis is a troublesome complication of therapy in patients with neoplastic disease. Although local infection is non-life-threatening, it may discourage adequate nutrition, and may progress to monilial esophagitis with potential for fungemia. Clotrimazole is a synthetic tritylimidazole bisphenyl-(2-chlorphenyl)-1-imidazolyl-methane that has shown clinical effectiveness in the treatment of patients with chronic superficial mycoses [l-4]. Use of the oral tablet for long-term therapy has been limited by gastrointestinal intolerance, by the development of hematologic and biochemical abnormalities, and by the induction of the hepatic microsomal enzyme system that accelerates catabolism of the drug. This report describes the results of a controlled double-blind clinical trial of clotrimazole troches in patients with oral candidiasis and neoplastic disease, with respect to efficacy and toxicity of the troche form of the drug. PATIENTS AND METHODS
From the Polly Annenberg Levee Division of Hematology (Department of Medicine) and the Department of Microbiology, Mount Sinai Medical Center, New York, New York. This work was supported in part by Miles Pharmaceuticals and the Alice Rosenzweig Memorial Fund. Requests for reprints should be addressed to Dr. Janet Cuttner, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Manuscript accepted July 7, 1983. NOTE: Clotrimazole troches have recently become available and are marketed under the name Mycelex troches.
Sixteen patients were admitted to the study. Three patients subsequently had to be excluded from the study because of clinical deterioration in their condition, lack of adequate time to assess a therapeutic response, or inability to properly assess a therapeutic response, leaving a total of 13 patients in the study. All had oral candidiasis as documented by the presence of blastospores and pseudohyphae in 10 percent potassium hydroxide preparation of buccal mucosa scrapings. Prior to scraping, the buccal cavity was examined for the presence of white plaques. If found, these areas were scraped with a tongue blade and inoculated directly onto Sabouraud’sdextrose agar containing gentamicin. The area was scraped again and the scrapings placed onto a slide, after which a drop of 10 percent potassium hydroxide was added and a cover slip applied. Upon return to the laboratory, the slides were gently heated and examined for the presence of blastospores and/or pseudohyphae through phase microscopy. In the absence of visible plaques, the buccal mucosa on either cheek was randomly scraped and processed as just described.
January 1984
The American Journal of Medicine
Volume 76
91
CLOTRIMAZOLE
TABLE I Patient Numlmr’
TREATMENT OF CANDIDIASIS-SHECHTMAN
ET AL
Clotrimazole versus Placebo Therapy for Oral Candidiasis
Predisposing Contlltiur~
Clotrimazole Therapy 1 Acute leukemia, neutropenia, broad-spectrum antibiotics
ClinicalResponseto Therapy
Clinical esophagitis developed requiring treatment with amphotericin B within 48 hours Oral symptoms and visible plaques resolved
2
Lymphoma. steroids, chemotherapy
7
Lymphoma, steroids
Oral symptoms and visible plaques decreased in number and size
Acute leukemia, neutropenia, steroids, chemotherapy, broadspectrum antibiotics
Visible plaques resolved, but pain and dysphagia persisted
12
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
Visible plaques and oral symptoms resolved
13
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
14
Acute leukemia, neutropenia. chemotherapy, steroids
Oral symptoms persisted, and clinical esophagitis developed on Day 10 of therapy, requiring treatment with amphotericin B Dysphagia resolved
10
16
Acute leukemia, chemotherapy, broad-spectrum antibiotics
Pain, ulceration, dysphagia, and visible plaques resolved
and giutamic oxaiacetic
transaminase.
Each patient was advised that the design of the study included
a placebo control, and informed consent was obtained. Design of the study was approved by the Research Advisory Committee at the Mount Sinai Hospital. Eight patients were assigned by random allocation to treatment with cfotrimazofe and eight were assigned to receive placebo. Neither the patient, microbiologist, physicians, or nurse knew whether the patients were receiving placebo or cfotrimazole. A troche containing 10 mg of cfotrimazoie or a placebo was taken by each patient five times daily for a period of time
92
January 1984
+/-t
The American Journal of Medicine
Comments
Inadequate duration of therapy to assess response; dropped from study
+/+ t/t -/-/+/-I-It -1-k Not done/i-/t +/t
+/-t -/-I-
All cultures were incubated at 30% in a humid atmosphere and examined daily for a period of 10 days, before being discarded as negative. Yeast-like colonies, when present, were isolated and the species identified by assessing assimilation reactions through the use of the API-20C system (Anafytab Products, Inc., Plainview, New York). Cultures of the scrapings yielded pure growth of Candida aibicans in 14 patients; one scraping grew both Candida albicans and Torulopsis glabrata and another scraping grew Candff albicans and Saccharomyces cerevisiae. Each patient had a complete blood count, urinalysis, and measurements of blood glucose, urea nitrogen, calcium, phosphate, uric acid, albumin, total protein, cholesterol, afkafine phosphatase,
MycologicResponse to Therapy7
t/t -/-I-/t -1-k +/+ t/t -/-I-
Methotrexate-induced mucositis was responsible for persistence of oral pain and dysphagia. Patient took only 50 percent of prescribed therapy
Clotrirnazole discontinued
-I-t -/-l-/+/+ t/t -I+ -/-
ranging from 48 hours to four weeks. The cfotrimazofe troches and placebos were supplied in identical bottles by Miles Pharmaceuticals, West Haven, Connecticut. The two preparations were identical in appearance, taste, and consistency. The troches were to be retained in the mouth and allowed to dissolve over 15 to 30 minutes; saliva was swaflowed. Clinical responses were assessed at varying intervals, and included assessment of symptoms such as dysphagia, burning or pain of oral mucosa, itching, and objective evafuation of glossftis, petechiae, mucosai patches, fissures, and ulcerations. Repeat scrapings and cultures were obtained on three occasions within four weeks from the start of therapy by a microbiologist who came to the patient’s bedside. Therapy with the troche (placebo or clotrimazofe) was continued unless clinical symptoms developed, warranting the use of amphotericin B, at which point administration of the troche (placebo or clotrimazole) was discontinued. RESULTS The patients who received clotrfmazole or placebo were similar with respect to initial symptoms of oral candidiasis and with respect to factors predisposing to development of symptomatic oral candidiasis: all were
Volume 76
CLOTRIMAZOLE
TABLE I Patient Number’
Predisposing Comlilion
4
Multiple myeioma, neutropenia, chemotherapy
6
Breast cancer (metastatic to brain), steroids, broad-spectrum antibiotics
9
ET AL
(Cont’d) Clotrimazole versus Placebo Therapy for Oral Candidiasis
Placebo Therapy Acute leukemia, neutropenia, 3 chemotherapy
a
TREATMENT OF CANOIDIASIS-SHECHTMAN
Hodgkin’s disease Acute leukemia, neutropenia. chemotherapy, broad-spectrum antibiotics
11
Lymphoma, steroids
15
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
17
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
Mycologic Response to Therapy’
Clinical Response to Therapy
Clinical esophagitis developed requiring treatment with amphotericin B Oral symptoms and visible plaques resolved
Subjective symptoms not evaiuabie because patient had a seizure after a second smear and culture obtained Not evaluabie Oral signs and symptoms progressed, and clinical esophagitis developed, requiring treatment with amphotericin B Marked worsening of oral symptoms and of visible ulcerations requiring treatment with amphotericin B Dysphagia and ulceration worsened, and clinical esophagitis developed requiring treatment with amphotericin B Dysphagia and visible plaques worsened, and clinical esophagitis developed requiring treatment with amphotericin B
+/+
Comments
Placebo discontinued
+I+ +/+ +/+ -/+ -I+/+
+I+ +I+ +/+ +/-I+/+ +/+
+/+ -I-/+
Resolution of oral candidiasis corresponded to recovery from neutropenia Inability to assess subjective symptoms: dropped from study
Patient died on first day of study Placebo discontinued
Placebo discontinued
Placebo discontinued
-/+ -I-i-
Placebo discontinued
* Seventeen oatients were consecutively admitted to the study if both smear and culture demonstrated positive findings. Patient 5 never received therepy due to a medication err& and is not listed in the table. t Evaluated every five to seven days by smear/culture. The designation on the left of the slant mark indicates a positive (+) or negative (-) finding on smear, and the designation on the right side of the slant mark indicates a postive (+) or negative (-) finding on culture. Results of successive evaluations noted also, where applicable.
exposed to chemotherapy, most were neutropenic, and
most were receiving broad-spectrum antibiotics (Table 1). In the group of six patients receiving placebo, one had visible Candida plaques, which persisted until neutropenia resolved; in five, clinical progression of oral candidiasis developed, warranting discontinuation of the troche and administration of intravenous amphotericin B. In the group of patients receiving clotrimazole, esophagitis developed in one after 10 days of clotrimazole therapy, and amphotericin B was given. The remaining six patients all had marked clinical improvement in their condition, usually within five days,
and received maintenance clotrimazole therapy until the predisposing clinical condition had resolved. Thus, in only one patient could clotrimazole clearly be called a therapeutic failure. It should be noted that in these groups of patients, a smear that failed to show pseudohyphae did not correlate well with negative findings on a culture. Indeed,
clinical improvement in the condition of patients in the clotrimazole group was not regularly accompanied by negative results of a smear or culture. In the clotrimazole-treated group of seven patients, only one required therapy with amphotericin B, whereas five of six patients who received placebo ultimately required amphotericin B for treatment of progressive oral candidiasis with or without esophagitis (p = 0.025). These results are summarized in Table II. No toxicity related to clotrimazole was noted. COMMENTS Oral candidiasis is the symptomatic development of localized Candida infection. In contrast, many patients have asymptomatic colonization with Candida, and symptoms develop only when predisposing conditions exist. Fungal infections are an important cause of mortality in acute leukemia [ 51. We have examined 67 additional patients with malignant disease on admission to the hospital and found that 11 patients had both smears and cultures with positive findings for Candida
January 1984
The American Journalof Medicine
Volume 76
93
CLOTRIMAZOLE
TREATMENT OF CANDIDIASIS-SHECHTMAN
TABLE II
Efficacy of Oral Clotrimazole Troche Therapy in Patients with Neoplastic Disease and Oral Candidiasis
Therapy
ET AL
Numberof Clinical Patients ImproveMycologic AmphoIncluded for ment ImprovementNoledt tericin Noted Culture Therapy Final Smear Evaluation’ (p = 0.025) (p = 0.078) (p = 0.12) Required
Clotrimazole Placebo
7 6
86 % 17%
72% 17%
43 % 0%
14% 83%
Patients were excluded from final evaluation if there was an inability to assess a therapeutic response due to clinical deterioration in their condition or due to inadequate duration of therapy. t Mycologic improvement was defined as the absence of pseudohyphae on smear and negative findings on culture. l
and that an additional 26 patients had only positive findings on cultures for Candida. This would indicate that more than half of the patients (55 percent) with malig nant disease have colonization with Candida at the time of admission, and presumably are at high risk for the development of symptomatic oral candidiasis, particularly if neutropenia develops, if steroids are given, or if broad-spectrum antibiotic therapy is instituted. Our study indicates that clotrimazole is a good therapeutic agent for the treatment of oral candidiasis in patients with malignant disease, and that symptomatic relief is to be expected with or without mycologic cure. A disparity between clinical resolution of disease and mycologic cure was also noted by Montes et al [6], who reported successful therapy for oral candidiasis using
94
January
1984
The American
Journal of Medicine
10 mg to 50 mg clotrimazole troches 10 times daily in an uncontrolled trial. The present study would appear to justify the use of oral clotrimazole troche therapy in patients in whom asymptomatic colonization is demonstrated and who are felt to be at risk for development of oral candidiasis. Clotrimazole offers an attractive alternative to the use of amphotericin B or ketoconazole, both of which have potential adverse systemic effects. ACKNOWLEDGMENT
We wish to thank Miles Pharmaceuticals for providing the coded placebo/troche preparations, and Susan Mauch, Margaret Gibbons, and Natalie Flynn for aiding in the preparation of the manuscript.
REFERENCES 1.
2.
3. 4.
5. 6.
Volume 78
Kirkpatrick CH, Ailing DW: Treatment of chronic oral candidiasis with clotrimazole troches. N Engl J Med 1978; 299: 1201-1203. Frederiksson T: Topical treatment with Bay b 5097. a new broad spectrum antimycotic agent. Br J Dermatol 1972; 86: 628-670. Bennett JE: Chemotherapy of systemic mycoses. N Engl J Med 1974; 290: 30-32. Kirkpatrick CH, Smith TK: Chronic mucocutaneous candidiasis: immunologic and antibiotic therapy. Ann Intern Med 1974; 80: 310-320. Mirsky H, Cuttner J: Fungal infection in acute leukemia. Cancer 1972; 30: 348-352. Montes LF, Soto TG, Parker JM, et al: Clotrimazole troches: a new therapeutic approach to oral candidiasis. Cutis 1976; 17: 277-280.
LEE B. SHECHTMAN, M.D. LAURA FUNARO, R.N., B.A. THOMAS ROBIN, M.S. EDWARD J. BOTTONE, Ph.D JANET CUTTNER, M.D. New York, New York
A double-blind controlled study was performed to evaluate the effectiveness of clotrimazole in the treatment of oral candidiasis in patients with neoplastic disease. Six of seven patients who received clotrimazole had resolution of symptoms and signs of oral candidiasis. In five of six patients who received placebo, clinical progression of signs and symptoms occurred, esophagitis developed, and amphoterlcin B therapy had to be given. No toxicity was observed that could be attributed to clotrimazole. The results were statistically significant (p = 0.025 by Fisher’s exact test). Clotrimazole is effective therapy for oral candidiasis in patients with neoplastlc disease, and may prevent the development of esophagltis. Oral candidiasis is a troublesome complication of therapy in patients with neoplastic disease. Although local infection is non-life-threatening, it may discourage adequate nutrition, and may progress to monilial esophagitis with potential for fungemia. Clotrimazole is a synthetic tritylimidazole bisphenyl-(2-chlorphenyl)-1-imidazolyl-methane that has shown clinical effectiveness in the treatment of patients with chronic superficial mycoses [l-4]. Use of the oral tablet for long-term therapy has been limited by gastrointestinal intolerance, by the development of hematologic and biochemical abnormalities, and by the induction of the hepatic microsomal enzyme system that accelerates catabolism of the drug. This report describes the results of a controlled double-blind clinical trial of clotrimazole troches in patients with oral candidiasis and neoplastic disease, with respect to efficacy and toxicity of the troche form of the drug. PATIENTS AND METHODS
From the Polly Annenberg Levee Division of Hematology (Department of Medicine) and the Department of Microbiology, Mount Sinai Medical Center, New York, New York. This work was supported in part by Miles Pharmaceuticals and the Alice Rosenzweig Memorial Fund. Requests for reprints should be addressed to Dr. Janet Cuttner, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, New York 10029. Manuscript accepted July 7, 1983. NOTE: Clotrimazole troches have recently become available and are marketed under the name Mycelex troches.
Sixteen patients were admitted to the study. Three patients subsequently had to be excluded from the study because of clinical deterioration in their condition, lack of adequate time to assess a therapeutic response, or inability to properly assess a therapeutic response, leaving a total of 13 patients in the study. All had oral candidiasis as documented by the presence of blastospores and pseudohyphae in 10 percent potassium hydroxide preparation of buccal mucosa scrapings. Prior to scraping, the buccal cavity was examined for the presence of white plaques. If found, these areas were scraped with a tongue blade and inoculated directly onto Sabouraud’sdextrose agar containing gentamicin. The area was scraped again and the scrapings placed onto a slide, after which a drop of 10 percent potassium hydroxide was added and a cover slip applied. Upon return to the laboratory, the slides were gently heated and examined for the presence of blastospores and/or pseudohyphae through phase microscopy. In the absence of visible plaques, the buccal mucosa on either cheek was randomly scraped and processed as just described.
January 1984
The American Journal of Medicine
Volume 76
91
CLOTRIMAZOLE
TABLE I Patient Numlmr’
TREATMENT OF CANDIDIASIS-SHECHTMAN
ET AL
Clotrimazole versus Placebo Therapy for Oral Candidiasis
Predisposing Contlltiur~
Clotrimazole Therapy 1 Acute leukemia, neutropenia, broad-spectrum antibiotics
ClinicalResponseto Therapy
Clinical esophagitis developed requiring treatment with amphotericin B within 48 hours Oral symptoms and visible plaques resolved
2
Lymphoma. steroids, chemotherapy
7
Lymphoma, steroids
Oral symptoms and visible plaques decreased in number and size
Acute leukemia, neutropenia, steroids, chemotherapy, broadspectrum antibiotics
Visible plaques resolved, but pain and dysphagia persisted
12
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
Visible plaques and oral symptoms resolved
13
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
14
Acute leukemia, neutropenia. chemotherapy, steroids
Oral symptoms persisted, and clinical esophagitis developed on Day 10 of therapy, requiring treatment with amphotericin B Dysphagia resolved
10
16
Acute leukemia, chemotherapy, broad-spectrum antibiotics
Pain, ulceration, dysphagia, and visible plaques resolved
and giutamic oxaiacetic
transaminase.
Each patient was advised that the design of the study included
a placebo control, and informed consent was obtained. Design of the study was approved by the Research Advisory Committee at the Mount Sinai Hospital. Eight patients were assigned by random allocation to treatment with cfotrimazofe and eight were assigned to receive placebo. Neither the patient, microbiologist, physicians, or nurse knew whether the patients were receiving placebo or cfotrimazole. A troche containing 10 mg of cfotrimazoie or a placebo was taken by each patient five times daily for a period of time
92
January 1984
+/-t
The American Journal of Medicine
Comments
Inadequate duration of therapy to assess response; dropped from study
+/+ t/t -/-/+/-I-It -1-k Not done/i-/t +/t
+/-t -/-I-
All cultures were incubated at 30% in a humid atmosphere and examined daily for a period of 10 days, before being discarded as negative. Yeast-like colonies, when present, were isolated and the species identified by assessing assimilation reactions through the use of the API-20C system (Anafytab Products, Inc., Plainview, New York). Cultures of the scrapings yielded pure growth of Candida aibicans in 14 patients; one scraping grew both Candida albicans and Torulopsis glabrata and another scraping grew Candff albicans and Saccharomyces cerevisiae. Each patient had a complete blood count, urinalysis, and measurements of blood glucose, urea nitrogen, calcium, phosphate, uric acid, albumin, total protein, cholesterol, afkafine phosphatase,
MycologicResponse to Therapy7
t/t -/-I-/t -1-k +/+ t/t -/-I-
Methotrexate-induced mucositis was responsible for persistence of oral pain and dysphagia. Patient took only 50 percent of prescribed therapy
Clotrirnazole discontinued
-I-t -/-l-/+/+ t/t -I+ -/-
ranging from 48 hours to four weeks. The cfotrimazofe troches and placebos were supplied in identical bottles by Miles Pharmaceuticals, West Haven, Connecticut. The two preparations were identical in appearance, taste, and consistency. The troches were to be retained in the mouth and allowed to dissolve over 15 to 30 minutes; saliva was swaflowed. Clinical responses were assessed at varying intervals, and included assessment of symptoms such as dysphagia, burning or pain of oral mucosa, itching, and objective evafuation of glossftis, petechiae, mucosai patches, fissures, and ulcerations. Repeat scrapings and cultures were obtained on three occasions within four weeks from the start of therapy by a microbiologist who came to the patient’s bedside. Therapy with the troche (placebo or clotrimazofe) was continued unless clinical symptoms developed, warranting the use of amphotericin B, at which point administration of the troche (placebo or clotrimazole) was discontinued. RESULTS The patients who received clotrfmazole or placebo were similar with respect to initial symptoms of oral candidiasis and with respect to factors predisposing to development of symptomatic oral candidiasis: all were
Volume 76
CLOTRIMAZOLE
TABLE I Patient Number’
Predisposing Comlilion
4
Multiple myeioma, neutropenia, chemotherapy
6
Breast cancer (metastatic to brain), steroids, broad-spectrum antibiotics
9
ET AL
(Cont’d) Clotrimazole versus Placebo Therapy for Oral Candidiasis
Placebo Therapy Acute leukemia, neutropenia, 3 chemotherapy
a
TREATMENT OF CANOIDIASIS-SHECHTMAN
Hodgkin’s disease Acute leukemia, neutropenia. chemotherapy, broad-spectrum antibiotics
11
Lymphoma, steroids
15
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
17
Acute leukemia, neutropenia, chemotherapy, broad-spectrum antibiotics
Mycologic Response to Therapy’
Clinical Response to Therapy
Clinical esophagitis developed requiring treatment with amphotericin B Oral symptoms and visible plaques resolved
Subjective symptoms not evaiuabie because patient had a seizure after a second smear and culture obtained Not evaluabie Oral signs and symptoms progressed, and clinical esophagitis developed, requiring treatment with amphotericin B Marked worsening of oral symptoms and of visible ulcerations requiring treatment with amphotericin B Dysphagia and ulceration worsened, and clinical esophagitis developed requiring treatment with amphotericin B Dysphagia and visible plaques worsened, and clinical esophagitis developed requiring treatment with amphotericin B
+/+
Comments
Placebo discontinued
+I+ +/+ +/+ -/+ -I+/+
+I+ +I+ +/+ +/-I+/+ +/+
+/+ -I-/+
Resolution of oral candidiasis corresponded to recovery from neutropenia Inability to assess subjective symptoms: dropped from study
Patient died on first day of study Placebo discontinued
Placebo discontinued
Placebo discontinued
-/+ -I-i-
Placebo discontinued
* Seventeen oatients were consecutively admitted to the study if both smear and culture demonstrated positive findings. Patient 5 never received therepy due to a medication err& and is not listed in the table. t Evaluated every five to seven days by smear/culture. The designation on the left of the slant mark indicates a positive (+) or negative (-) finding on smear, and the designation on the right side of the slant mark indicates a postive (+) or negative (-) finding on culture. Results of successive evaluations noted also, where applicable.
exposed to chemotherapy, most were neutropenic, and
most were receiving broad-spectrum antibiotics (Table 1). In the group of six patients receiving placebo, one had visible Candida plaques, which persisted until neutropenia resolved; in five, clinical progression of oral candidiasis developed, warranting discontinuation of the troche and administration of intravenous amphotericin B. In the group of patients receiving clotrimazole, esophagitis developed in one after 10 days of clotrimazole therapy, and amphotericin B was given. The remaining six patients all had marked clinical improvement in their condition, usually within five days,
and received maintenance clotrimazole therapy until the predisposing clinical condition had resolved. Thus, in only one patient could clotrimazole clearly be called a therapeutic failure. It should be noted that in these groups of patients, a smear that failed to show pseudohyphae did not correlate well with negative findings on a culture. Indeed,
clinical improvement in the condition of patients in the clotrimazole group was not regularly accompanied by negative results of a smear or culture. In the clotrimazole-treated group of seven patients, only one required therapy with amphotericin B, whereas five of six patients who received placebo ultimately required amphotericin B for treatment of progressive oral candidiasis with or without esophagitis (p = 0.025). These results are summarized in Table II. No toxicity related to clotrimazole was noted. COMMENTS Oral candidiasis is the symptomatic development of localized Candida infection. In contrast, many patients have asymptomatic colonization with Candida, and symptoms develop only when predisposing conditions exist. Fungal infections are an important cause of mortality in acute leukemia [ 51. We have examined 67 additional patients with malignant disease on admission to the hospital and found that 11 patients had both smears and cultures with positive findings for Candida
January 1984
The American Journalof Medicine
Volume 76
93
CLOTRIMAZOLE
TREATMENT OF CANDIDIASIS-SHECHTMAN
TABLE II
Efficacy of Oral Clotrimazole Troche Therapy in Patients with Neoplastic Disease and Oral Candidiasis
Therapy
ET AL
Numberof Clinical Patients ImproveMycologic AmphoIncluded for ment ImprovementNoledt tericin Noted Culture Therapy Final Smear Evaluation’ (p = 0.025) (p = 0.078) (p = 0.12) Required
Clotrimazole Placebo
7 6
86 % 17%
72% 17%
43 % 0%
14% 83%
Patients were excluded from final evaluation if there was an inability to assess a therapeutic response due to clinical deterioration in their condition or due to inadequate duration of therapy. t Mycologic improvement was defined as the absence of pseudohyphae on smear and negative findings on culture. l
and that an additional 26 patients had only positive findings on cultures for Candida. This would indicate that more than half of the patients (55 percent) with malig nant disease have colonization with Candida at the time of admission, and presumably are at high risk for the development of symptomatic oral candidiasis, particularly if neutropenia develops, if steroids are given, or if broad-spectrum antibiotic therapy is instituted. Our study indicates that clotrimazole is a good therapeutic agent for the treatment of oral candidiasis in patients with malignant disease, and that symptomatic relief is to be expected with or without mycologic cure. A disparity between clinical resolution of disease and mycologic cure was also noted by Montes et al [6], who reported successful therapy for oral candidiasis using
94
January
1984
The American
Journal of Medicine
10 mg to 50 mg clotrimazole troches 10 times daily in an uncontrolled trial. The present study would appear to justify the use of oral clotrimazole troche therapy in patients in whom asymptomatic colonization is demonstrated and who are felt to be at risk for development of oral candidiasis. Clotrimazole offers an attractive alternative to the use of amphotericin B or ketoconazole, both of which have potential adverse systemic effects. ACKNOWLEDGMENT
We wish to thank Miles Pharmaceuticals for providing the coded placebo/troche preparations, and Susan Mauch, Margaret Gibbons, and Natalie Flynn for aiding in the preparation of the manuscript.
REFERENCES 1.
2.
3. 4.
5. 6.
Volume 78
Kirkpatrick CH, Ailing DW: Treatment of chronic oral candidiasis with clotrimazole troches. N Engl J Med 1978; 299: 1201-1203. Frederiksson T: Topical treatment with Bay b 5097. a new broad spectrum antimycotic agent. Br J Dermatol 1972; 86: 628-670. Bennett JE: Chemotherapy of systemic mycoses. N Engl J Med 1974; 290: 30-32. Kirkpatrick CH, Smith TK: Chronic mucocutaneous candidiasis: immunologic and antibiotic therapy. Ann Intern Med 1974; 80: 310-320. Mirsky H, Cuttner J: Fungal infection in acute leukemia. Cancer 1972; 30: 348-352. Montes LF, Soto TG, Parker JM, et al: Clotrimazole troches: a new therapeutic approach to oral candidiasis. Cutis 1976; 17: 277-280.