SCIENTIFIC ARTICLE

Australian Dental Journal 2009; 54: 341346 doi: 10.1111/j.1834-7819.2009.01160.x

Comparison of efcacy of uconazole mouthrinse and clotrimazole mouthpaint in the treatment of oral candidiasis
AA Sholapurkar,* KM Pai,* S Rao
*Department of Oral Medicine and Radiology, Manipal College of Dental Sciences, Manipal, Karnataka, India. Department of Microbiology, Kasturba Medical College, Manipal, Karnataka, India.

ABSTRACT
Candidiasis is by far the most common oral fungal infection in humans and has a variety of clinical features. It is considered to be an opportunistic infection, affecting individuals who are debilitated by another disease. Fluconazole, one of the newer azoles available for systemic use and clotrimazole as a topical ointment are both shown to be effective in the treatment of oral candidiasis and are considered to be well tolerated and useful medications. No study has evaluated the comparison of clinical and mycological response of oral candidiasis to uconazole mouthrinse and clotrimazole mouthpaint. The aim of this study was to evaluate the efcacy of uconazole mouthrinse and compare it with clotrimazole mouthpaint in the treatment of oral candidiasis.
Keywords: Oral candidiasis, opportunistic infection, fluconazole mouthrinse, clotrimazole mouthpaint, clinical and mycological response. Abbreviations and acronyms: ALL = acute lymphoblastic leukaemia; MRG = median rhomboid glossitis; PPH = palatal papillary hyperplasia. (Accepted for publication 19 March 2009.)

INTRODUCTION Fungi are eukaryotic micro-organisms. The most relevant of these to dentistry belong to the genus Candida.1 Many types of fungal infections occur in the mouth although the most common is the candidiasis caused by Candida albicans.2 Candida albicans is the most common part of the normal flora of the mouth and is found in more than 40 per cent of the symptom-free population. An ageing population and the use of antibiotics have contributed to the increasing prevalence of oral candidiasis. Oral candidiasis is associated with local factors such as dry mouth, denture and tobacco use, and with systemic risk factors including immuno-suppressive conditions caused by illness or medications. Early recognition of the potential risk and prophylactic treatment of oral candidiasis may prevent serious morbidity and fatal consequences in high-risk patients. Oral candidiasis affects 6593 per cent of elderly patients wearing dentures.3 Localized oral candidiasis should be managed initially with local treatment conned to the site of involvement before systemic antifungal drugs are used. Polyene antibiotics have been
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the initial choice of antifungal for almost half a century. The azoles have been developed more recently with ketoconazole, itraconazole and uconazole being used to treat patients with systemic fungal infections. Fluconazole and clotrimazole are both known to be effective in the treatment of oral candidiasis. The aim of this study was to compare the efcacy of uconazole mouthrinse and clotrimazole mouthpaint in the treatment of oral candidiasis. Comparisons were made between the two test groups in terms of age, gender, severity of lesions prior to treatment; the clinical efcacy of the two drugs; and the mycological cure achieved by the two drugs. Side-effects associated with the two drugs were also determined. SUBJECTS AND METHODS Eighty-nine subjects (47 men and 42 women) with the clinical signs and symptoms of oral candidiasis seen between September 2006 and August 2007 were enrolled in the study. Patients completed institutionapproved consent forms. Medical histories were obtained and all the patients underwent a physical examination before initiation of the therapy. Previous
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AA Sholapurkar et al. episodes of oral candidiasis and recent use of antifungal drug therapy were noted. Information about medical status was obtained from their hospital records. Patients were excluded from the study if they: were pregnant or lactating; had used any other antifungal agent during the past 10 days; were taking barbiturates or anticoagulants; had a known sensitivity to polyenes or the azole group of antimycotics; had a history of alcoholism, drug abuse, psychiatric disorder, or any other problem that might invalidate informal consent. The rst 43 patients were treated with uconazole mouthrinse (Group A) and the other 46 patients were treated with clotrimazole mouthpaint (Group B). The clinical diagnosis of oral candidiasis was based on symptoms such as burning sensation, altered taste and signs such as mucosal erythema and adherent plaques. The patient was asked to grade oral discomfort as mild (+), moderate (++) or severe (+++). The clinical signs were also categorized into mild (+), moderate (++) and severe (+++) based on the extent of the lesion in the oral cavity. It was considered as mild if it involved one or two localized areas, moderate if it involved more than two localized areas and severe if there was a generalized involvement. The diagnosis was supported by microbiological cultures. The mucosa of the patients was swabbed. Swabbing was done from the palate, the tting surface of the denture, the tongue, the oor of mouth, and the angles of mouth. The swab was dipped thoroughly in 1 ml of saline sample and transported immediately to the laboratory where they were cultured with the use of standard techniques. Candida colony counts were obtained using Sabourauds dextrose agar. Inoculation, incubation and colony collection Each specimen was inoculated on Sabourauds dextrose agar. The plates were then incubated for 24 and 48 hours at 37C and 25C. After 48 hours, the plates were examined and yeast colonies were counted. Seventeen patients in Group A and 18 patients in Group B who were medically compromised (Table 1B), had a history of diabetes mellitus, HIV, acute lymphoblastic leukaemia (ALL), were undergoing radiotherapy of head and neck region, were on treatment with antibiotics or steroids. Group A used a suspension of 2 mg ml of uconazole in distilled water (with no sweetness and avour) which was prepared by a hospital pharmacist, stored in brown bottles and kept refrigerated. Each patient in this group was instructed to rinse 5 ml of the treatment solution for 23 minutes and then swallow. Mouthrinse was used three times daily for two weeks. Patients were instructed to avoid consuming water and food for at least two hours after rinsing, and to maintain their oral hygiene. Group B patients were treated with clotrimazole mouthpaint (1%). Patients were
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prescribed the commercially available mouthpaint (Candid Mouthpaint 1%, with propylene glycol and glycerine base, 15 ml; Glenmark Pharmaceuticals, Mumbai, India) which was dispensed in small ambercoloured bottles. Patients were advised to apply the mouthpaint to affected areas with the index nger thrice daily for two weeks. Other instructions were similar to those given to Group A. Patients were recalled after two weeks, checked for clinical signs and symptoms, and mycological assessment was carried out by repeating the oral swabs from the same site of the lesion. Side-effects associated with both the mouthrinse and the mouthpaint were noted. Statistical methods Data were entered into the computer and frequency tables were generated using SPSS Software Version 13. Students t-test was used for a comparison of age between the two groups. The distributions of all the variables were compared between the treatment groups using the chi-square test. Wilcoxons signed rank sum test was used for the comparison of mycological cure between the two groups. The test was considered signicant if the p value was 0.05; highly signicant if the p value was 0.01; and very highly signicant if the p value was 0.001. RESULTS Patients of all age groups with a clinical and microbiological diagnosis of oral candidiasis were eligible to enrol in the study. The study group included 89 patients with a clinical diagnosis of oral candidiasis and were assigned to one of the two treatment groups (Group A and Group B). Group A included those patients who were treated with uconazole (n = 43) and Group B included those who were treated with clotrimazole (n = 46). Of 43 patients in Group A, 11 did not return for follow-up, 2 were withdrawn from the study as they did not follow the instructions properly, and in 3 patients the cultures were contaminated. Hence, the study sample was reduced to 27. On the other hand, of 46 patients in Group B, 12 did not return for follow up, 2 were withdrawn from the study as they did not follow the instructions properly and in 4 patients the cultures were contaminated. Hence, the study sample was reduced to 28 in Group B. The mean age for Group A and Group B was 48.37 and 52.14, respectively. There was no statistically signicant difference between two groups (Table 1A). Group A consisted of 27 patients of which 18 (66.7 per cent) were males and 9 (33.3 per cent) were females. Similarly, Group B consisted of 28 patients of which 17 (60.7 per cent) were males and 11 (39.3 per cent) were females. There was no signicant difference between
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Fluconazole mouthrinse and clotrimazole mouthpaint Table 1A. Comparison of age between two groups using Students t-test
Group N Fluconazole Clotrimazole 27 28 Mean 48.3704 52.1429 Age Std. deviation 13.01522 11.57812 t 1.13700 p = 261 ns Gender Male Female Medically compromised patients Description of lesions DS EC Kissing lesion MRG PC Palatal papillary hyperplasia Clinical signs before treatment + (mild) ++ (moderate) +++ (severe) Clinical signs after treatment + (mild) ) (no signs)

Table 2. Comparison of the two groups using Chi-square test

Group A Group B (n = 27) (n = 28) 18 9 17 8 2 2 5 8 1 5 19 3 1 26 17 11 18 14 1 1 6 6 0 12 15 1 6 22 0.21 3.6 0.646 ns 0.825 ns X2 p

Table 1B. Distribution of medically compromised patients among both the groups
Medically compromised state Diabetes mellitus Antibiotic therapy Steroid therapy Radiotherapy HIV ALL Patients under Group A (17) 8 1 3 4 0 1 Patients under Group B (18) 11 1 2 3 1 0

4.663 0.588 ns

4.336 0.114 ns 3.888 0.049 sig

the two groups when numbers of patients were compared (Table 2). Seventeen patients in Group A and 18 patients in Group B who were medically compromised (Table 1B), had a history of diabetes mellitus, HIV, ALL, were undergoing radiotherapy of the head and neck region, were on treatment with antibiotics or steroids. Patients in our study most commonly presented with erythema. Others presented with soreness and white plaques. Patients in both groups presented with denture stomatitis, erythematous candidiasi, pseudomembranous candidiasis, palatal papillary hyperplasia (PPH), kissing lesions and median rhomboid glossitis (MRG). In Group A, pseudomembranous candidiasis and denture stomatitis accounted for 29.6 per cent of cases. In Group B, denture stomatitis accounted for 50 per cent, whereas pseudomembranous candidiasis and MRG accounted for 21.4 per cent of the total cases. Of the 8 (29.6 per cent) patients with pseudomembranous candidiasis in Group A, 3 occurred on the buccal mucosa and palate, and 2 occurred on the tongue. On the other hand, all 6 (21.4 per cent) patients in Group B had pseudomembranous candidiasis of the buccal mucosa. Table 2 shows the descriptions of lesions in both groups. The mucosa of the patients was swabbed and dipped thoroughly in 1 ml of saline sample and transported immediately to the laboratory where they were cultured with the use of standard techniques. Although Group A seemed to have more severe signs and symptoms as compared to Group B (Table 2), there was no statistically signicant difference between the two groups before treatment. The clinical signs and symptoms after treatment were evaluated. Of the 27 patients in Group A, only 1 patient had a persistence of clinical signs and symptoms evidenced by burning
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sensation to a mild extent, and presence of pseudomembranous plaque. However, of the 28 patients in Group B, a total of 6 patients had persistent clinical signs and symptoms. These patients also presented with mild burning sensation and presence of localized pseudomembranous plaque, erythematous area and persistence of MRG. Fluconazole-treated patients were more likely to remain disease-free during the 15 days follow-up than those treated with clotrimazole. The clinical resolution rates in Group A and Group B were 96.29 per cent and 78.57 per cent, respectively. The mean candidal colony counts before and after treatment in Groups A and Group B were 1221.48 and 980.00, respectively. There was no statistically signicant difference between the two groups when mean candidal colony counts before treatment were calculated (Table 3). The mean candida colony counts after treatment in both the groups were 7.4074 and 20.00, respectively. However, there was no statistically signicant difference between the two groups when mean candida colony counts were calculated after treatment (Table 3). The mycological eradication for Groups A and Group B was 88.8 per cent (24 out of 27 patients) and 85.71 per cent (24 out of 28 patients), respectively. However, intergroup comparison (Tables 4A and 4B) between the two groups considering the mycological eradication showed that there was no statistically signicant difference. Both treatment regimens were well tolerated. Only one patient in Group A reported mild GI discomfort three days after ingesting the rinse. The discomfort resolved spontaneously and did not require any medical intervention.
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AA Sholapurkar et al. Table 3. Comparison between the two groups considering the Candida colony counts before and after treatment using Wilcoxon signed rank sum test
Group statistics Group Colony counts before Colony counts after Fluconazole Clotrimazole Fluconazole Clotrimazole N 27 28 27 28 Mean 1221.4815 980.0000 7.4074 20.0000 Std. deviation 3069.36062 2001.36435 24.89865 57.08992 Z 0.48000 p = 0.631 ns 0.45100 p = 0.652 ns

Table 4. Intergroup comparison (group statistics) considering the colony counts before and after treatment using Wilcoxon signed rank sum test
A Paired samples statistics Group Fluconazole Clotrimazole Colony Colony Colony Colony counts counts counts counts before after before after N 27 27 28 28 Mean 1221.4815 7.4074 980.0000 20.0000 Std. deviation 3069.36062 24.89865 2001.36435 57.08992 Std. error mean 590.69873 4.79175 378.22231 10.78898

B Paired samples test Group

a

Paired differences Mean Std. deviation 3068.99415 2009.42409

Fluconazole Clotrimazole

Colony Colony Colony Colony

counts counts counts counts

before after before after

1214.0741 960.0000

4.542 4.542

0.001 vhsig 0.001 vhsig

Z = Wilcoxon signed rank sum test.

DISCUSSION Candida is a common and harmless dimorphic yeast that lives without producing disease in the oral cavities of up to 68 per cent of normal individuals. McCarthy called candidiasis a disease of the diseased.4 This micro-organism is typically opportunistic and lacks the pathogenic features necessary to produce a fungal infection. Thus, local or general predisposing factors are necessary for Candida to establish an infection. Accordingly, management of Candida infections should be directed towards eradicating these predisposing factors, but when this is not possible to achieve, antifungal agents are warranted. Topical therapy is generally effective in controlling low grade uncomplicated mucosal candidiasis. In cases of severe oral candidiasis, topical therapy in conjunction with systemic therapy may ensure a lower systemic dose and shorten the duration of high-dose systemic antifungal therapy. In our study, Group A patients were given uconazole mouthrinse in the dose of 2 mg ml where the patient was advised to swish 5 ml of the solution for 23 minutes and swallow. This was used
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three times daily accounting for a total daily dose of 30 mg day. Group B patients were treated with clotrimazole mouthpaint (1%) and were advised to apply it to the affected areas with the index nger thrice daily for two weeks. A total of 89 patients were originally enrolled in the study and assigned to one of the two treatment groups (uconazole 43, clotrimazole 46), but only 27 and 28 patients were nally evaluated for uconazole and clotrimazole treatment, respectively. It can be hypothesized that the high rate of loss of follow-up in both groups was due to the fact that patients, satised with their therapeutic outcome, chose not to return. If a patient was dissatised with the response to therapy, he or she would be more likely to seek additional therapy. Also, the fact that oral candidiasis is not a serious infection means compliance with follow-up visit schedules may decrease. In Group A, both pseudomembranous candidiasis and denture stomatitis accounted for 29.6 per cent of cases. In group B, denture stomatitis accounted for 50 per cent, whereas pseudomembranous candidiasis and MRG accounted for 21.4 per cent of the total cases. Of the 8 (29.6 per cent) patients with pseudomembranous
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Fluconazole mouthrinse and clotrimazole mouthpaint candidiasis in Group A, 3 occurred on the buccal mucosa and palate, and 2 occurred on the tongue. On the other hand, all 6 (21.4 per cent) patients in Group B had pseudomembranous candidiasis of the buccal mucosa. The classic form of candidiasis is the pseudomembranous form, followed by denture stomatitis and acute erythematous candidiasis. This nding was consistent with the ndings of other studies.4,5 Erythematous candidiasis was found in both groups. The common anatomic location was the tongue and this is in agreement with other studies. Clinical resolution rates in the uconazole and clotrimazole group were found to be 96.29 and 78.57 per cent, respectively. In the preliminary investigation of 39 adult patients with HIV infection and oral candidiasis, Koletar6 reported a clinical resolution rate of 100 and 65 per cent for the uconazole and clotrimazole group, respectively. However, the drug dosage used in their study was higher (uconazole capsule 100 mg daily for 2 weeks and clotrimazole 10 mg troches ve times daily for 2 weeks) than that used in our study. This might be the reason for the 100 per cent clinical cure rates for the uconazole group. Mycological eradication was 88.8 and 85.71 per cent in the uconazole and clotrimazole group, respectively. However, in the study by Koletar, mycological eradication was 75 and 20 per cent, respectively. Side-effects were noted in only one patient in Group A which resolved spontaneously and did not require any medical intervention. Gussenhover et al.7 reported a case of Stevens-Johnson syndrome which occurred as a result of adverse effect to uconazole. Wells and Lever8 also reported liver toxicity in an HIV patient which on biopsy showed a central lobular cholestasis which was consistent with uconazole toxicity. However, we are not aware of any cases reported in the literature of adverse side-effects to clotrimazole mouthpaint. The advantages of mouthrinses over other type of applications are as follows: First, in patients with dry mouth, tablets given to dissolve in the mouth may be poorly soluble. Epstein5 reported that uconazole is detected in saliva two hours after systemic administration. On the other hand, uconazole mouthrinse enhances the drug exposure of the oral mucosa immediately, and lasts for four hours,5 compared with the same dose administered by systemic route. Because the pathogenic micro-organisms in oral candidiasis are usually in the supercial layers of the oral mucosa, the effectiveness of this mouthrinse may be attributed to the temporary higher concentration at the required site, resulting in improved efcacy. Secondly, this mouthrinse lacks the risk of systemic adverse effects and drug interactions.
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Similarly, the same advantages apply to mouthpaint. Martins et al.9 reported two HIV-positive cases with oropharyngeal candidiasis which were non-responsive to uconazole tablets but were responsive to the suspension form. However, mouthrinse and mouthpaint may not be effective in the treatment of widespread severe oral candidiasis in immunocompromised patients. This could be one of its disadvantages when compared to systemic drug therapy. However, one disadvantage of mouthrinse over mouthpaint is that it may not be effective at the corner of the mouth (in the case of angular cheilitis). Conversely, the disadvantage of the mouthpaint form of the antifungal drug (clotrimazole) when compared to mouthrinse is that it may be difcult to apply for hard-to-reach areas like the tonsils, the soft palate, etc. There were certain limitations in this study. It was not double-blinded which could have led to some bias among patients clinician. Secondly, patients were not followed-up after two weeks for any possibility of recurrence. Thirdly, patients were only asked about side-effects but were not assessed objectively for any liver damage. However, although the number of patients in the present study was small, the outcome was promising, more so because the dose of uconazole used per day was only 30 mg, which is less than one-third of the standard dose of uconazole. CONCLUSIONS The study was conducted to compare the efcacy of uconazole mouthrinse and clotrimazole mouthpaint in the treatment of oral candidiasis. The results of this study can be used as a basis for further studies with a larger sample of patients with oral candidiasis to compare the efcacy of uconazole aqueous mouthrinse with clotrimazole mouthpaint. REFERENCES
1. McCullough MJ, Savage NW. Oral candidosis and the therapeutic use of antifungal agents in dentistry. Aust Dent J 2005;50 Suppl 2:S36S39. 2. Patton LL, Bonito AJ, Shugars DA, Chapel Hill NC. A systematic review of the effectiveness of antifungal drugs for the prevention and treatment of oropharyngeal candidiasis in HIV-positive patients Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:170179. 3. Chandra J, Mukherjee PK, Leidich SD, et al. Antifungal resistance of candidal biolms formed on denture acrylic in vitro. J Dent Res 2001;80:903908. 4. Zegarelli DJ. Fungal infections of the oral cavity. Otolaryn Cl North Am 1993;26:10691089. 5. Epstein JB, Gorsky M, Caldwell J. Fluconazole mouthrinses for oral candidiasis in post irradiation, transplant and other patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:671 675.
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6. Koletar SL, Russell JA, Fass RJ, Plouffe JF. Comparison of oral uconazole and clotrimazole troches as treatment for oral candidiasis in patients infected with human immunodeciency virus. Antimicrob Agents Chemother 1990;34:22672268. 7. Gussenhover MS, Haak A, Peereboom-Wynia JD, vant Wout JW. Stevens-Johnson syndrome after Fluconazole. Lancet 1991;338: 120. 8. Wells C, Lever AM. Dose-dependent uconazole hepatotoxicity proven on biopsy and rechallenge. J Infect 1992;24:111112. 9. Martins MD, Rex JH. Fluconazole suspension for oropharyngeal candidiasis unresponsive to tablets. Ann Intern Med 1997;126: 332333.

Address for correspondence: Dr Amar A. Sholapurkar Assistant Professor Department of Oral Medicine and Radiology Manipal College of Dental Sciences Manipal, Karnataka 576104 India Email: dr.amar1979@yahoo.co.in

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