A COMPARATIVE STUDY OF EFFICACY OF CLOTRIMAZOLE AND FLUCONAZOLE EAR DROPS IN OTOMYCOSIS.
Otomycosis is a clinical term to describe fungal infection of the external auditory canal. It is a common condition faced by an ENT practitioner and accounts for nearly 10% of ENT outpatient cases . It is particularly common in hot, humid climates (Tropical and subtropical areas). Abuse of topical antibiotics in the ear is often a precipitating factor. Immunocompromised states predispose to the condition. Common clinical finding is a black, grey, green or white discharge with debris that is often said to resemble a wet newspaper. Sometimes fungal hyphae with spores can also be appreciated clinically.
Aspergillus accounts for 80-90% of cases and Candida being responsible for the remaining 10-20%. [1,2] Treatment of choice for fungal otitis externa includes thorough debridement followed by topical application of antifungal agents. Acidifying agents, topical antifungals and antiseptics have been used for otomycosis with variable degree of cure rates.
MATERIALS AND METHODS
We conducted a Randomised Prospective Comparative clinical study for a period of 1 year in the ENT Department in association with the Microbiology Laboratory, Chettinad Health centre and Research Institute, Kelambakkam. 120 patients with otomycosis were included in the study based on the following criteria.
Sample Size Determination
* Sample size calculation was done on the basis of efficacy of two drugs in treating otomycosis. With the help of previous literature findings, anticipated incidence of both the drugs was calculated.
* Anticipated incidence (Persistence of infection) at the end of 4 weeks treatment with clotrimazole = 20%
* Anticipated incidence (Persistence of infection) at the end of 4 weeks treatment with fluconazole = 4%
* Keeping 95% Confidence interval (5% alpha error) and 80% power of the study,
* Sample size for two independent group and categorical outcome was calculated with software clincalc,
* Sample size arrived was 64 per group.
In our Study, Sample Size of 60 were Recruited in each Group Study Participants Allocation
Study participants who fulfilled inclusion criteria were randomly allocated in to two groups with the help of random table numbers. The ratio of allocation was 1:1. Odd number lot were allocated to group A to receive 1% Clotrimazole ear drops and even number lot were allocated to Group B to receive 0.3% Fluconazole ear drops.
Data was analysed with Statistical Package for Social Sciences (SPSS IBM) version 21.0. The qualitative variables are described in the form of proportions and quantitative variables are described in the terms of mean and standard deviation. Baseline characteristics of the two group was checked for homogeneity. Data was checked for normality before applying appropriate tests of significance. Significance of difference in proportions (Qualitative variables) was calculated using chi square test. Significance of p value was taken as p<0.05
1. Age > 12 years.
2. Patients of either sex.
3. Culture positive fungal otitis externa.
4. Both immunocompetent and immunocompromised patients.
1. Culture negative cases.
2. Otomycosis associated with otitis media.
3. Prior usage of topical antifungals.
4. Patients not consenting for participation.
5. Noncompliance with medication/follow-up.
This study was conducted after the approval of the institutional ethical committee and obtaining an informed consent from each patient. 120 patients with otomycosis were selected based on the criteria mentioned above. They were equally divided into two cohorts--A and B. All the patients underwent a microscopic suction clearance and the material forwarded for fungal smear and culture. Patients in Group A were put on 1% Clotrimazole ear drops and those in Group B were put on 0.3% Fluconazole ear drops in the dosage of 3 drops thrice daily. Patients in both the groups used the ear drops for a period of 3 weeks. All the patients were educated on the importance of re-establishing a dry ear and about water precautions. All patients were reviewed weekly for 4 weeks for reduction in symptoms and signs.
A total of 120 study participants were recruited of which group 1 constituted 60 participants and group 2 constituted 60 study participants. Group 1 were given clotrimazole and group 2 were prescribed fluconazole. 47% and 45% were males in group 1 and group 2 respectively. Baseline characteristics of the study participants are comparable and there was no significant difference between the groups. (Table 1)
Among the study participants, pain was a presenting feature in 81.7% of group 1 and 85% of group 2. Itching of ear was seen in 26.7% and 31.7% of group 1 and group 2 respectively. Ear block was observed in 30% and 21.7% of group 1 and group 2 respectively. Ear discharge was seen in 11(18.3%) of group 1 and 7 (11.7%) of group 2 participants. Duration of the symptoms were ranging from 1-10 days in group 1 and 1-7 days in group 2. Predisposing factors were--history of use of ear buds for cleaning (72% and 68%), history of water entry into ear canal (18% and 14%), Diabetes mellitus (6% and 14%). Other factors were oil instillation (2% and 4%), syringing into ear canal (2% and 0%).
The species of fungal infection among the study participants are varied. Out of 120 patients, Aspergillus Niger was most common (36.7% and 63.3%), followed by aspergillus flavus (30% and 15%), aspergillus fumigatus (11.7% and 3.3%) and other organisms. (Figure 1) Fungal spores were found in 31.7% of group 1 and 40% of group 2 patients. (Table 2)
At the end of four weeks of treatment, debris was observed in 13(21.7%) of clotrimazole treated group and in 12(20%) of fluconazole treated group. Comparing the two groups, it was observed that the effectiveness of the drug in terms of fungal colonization, fluconazole was found to be better than clotrimazole at the end of 2nd week, 3rd week and 4th week. (p value = 0.000, 0.000, 0.000)
Otomycosis is fungal infection of the external auditory canal and its associated complications sometimes involving the middle ear.  It occurs because the protective lipid/acid balance of the ear is lost.  Most common fungi implicated in this infection are Aspergillus and Candida. In the studies conducted by Chander et al, Paulose et al, Mohanty et al, and Yassin et al, Aspergillus spp were the most common fungi isolated, and C albicans was the next most common. [4-7] Similarly in our study, Aspergillus Niger was most common, followed by aspergillus flavus, aspergillus fumigatus and C albicans and Non-Candida albicans.
Treatment of Otomycosis consists of debridement along with topical agents--acidifying agents, antifungal drugs and antiseptics. Topical preparations of Azole group of antifungals are widely used, the most common being 1% Clotrimazole ear drops. Bassiouny et al studied the effects of anti-fungal agents and found that clotrimazole and econazole were effective antifungal agents in the treatment of otomycosis . According to Stern et al and Jackman et al, clotrimazole is an effective antifungal agent against most yeasts and fungi, and nystatin has the widest spectrum of activity among the antifungals [9, 10]. In a study by Yadav et al, fluconazole was found to be an effective antifungal agent in the treatment of otomycosis . In a study conducted by Nagendran et al, in the first week, clotrimazole had a good response than miconazole and fluconazole and in the second week, there was a drastic response in patients instilling fluconazole ear drops compared to those using miconazole and clotrimazole. This better outcome did not show a statistical significance  since p value was 0.882.
In our study, it was observed that the clinical effectiveness of fluconazole was found to be better than clotrimazole at the end of 2nd week, 3rd week and 4th week, which was statistically significant.
Otomycosis is relatively a common clinical disorder in tropical climatic condition like ours. It usually affects one ear and bilateral involvement is more common in immunocompromised individuals. Use of ear buds, topical antibiotic drops and ear probing predispose to this infection. Most common pathogen involved is Aspergillus, followed by Candida sp. In a few immunocompromised patients, we have observed tympanic membrane perforations. In our study, we have observed that topical Fluconazole is more effective than Clotrimazole to treat otomycosis.
 Bojrab Dl, Bruderly T, Abdulrazzak Y. Otitis externa. Otolaryngologic Clinics of North America 1996;29(5):761-82.
 Carney AS. Otitis externa and otomycosis. In: Gleeson MJJ, Jones NS, Clarke R, et al. eds. Scott-Brown's otolaryngology, head and neck surgery. Vol. 3. 7th edn. London: Hodder Arnold Publishers 2008: p. 3351-7.
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 Chander J, Maini S, Subrahmanyan S, et al. Otomycosisa clinico-mycological study and efficacy of mercurochrome in its treatment. MycopathoIogia 1996;135(1):9-12.
 Mohanty JC, Mohanty SK, Sahoo RC, et al. Clinicomicrobial profile of otomycosis in Berhampur. Indian Journal of Otology 1999;5(2):81-3.
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 Bassiouny A, Kamel T, Moawad MK, et al. Broad spectrum antifungal agents in otomycosis. J Laryngol Otol 1986;00(8):867-73.
 Stern JC, Shah MK, Lucente FE. In vitro effectiveness of 13 agents in otomycosis and review of the literature. Laryngoscope 1988;98(11):1173-7.
 Jackman A, Ward R, Apri M, et al. Topical antibiotic induced otomycosis. Int J Pediatr Otorhinolaryngol 2005;69(6):857-60.
 Yadav SP, Gulia JS, Jagat S, et al. Role of ototopical fluconazole and clotrimazole in management of otomycosis. Indian Journal of Otology 2007;13:12-5.
 Navaneethan N, Yaadhavakrishnan RPD. Type of antifungals: Does it matter in empirical treatment of otomycosis? Indian Jouranal of Otolaryngology and Head and Neck Sugery 2015;67(1):64-7.
Preethi Prabhakaran (1), Namasivaya Navin (2), Rajasekaran Srinivasan (3), Thirunavukarasu Palanisamy (4), Priya Kanagamuthu (5), Prabakaran Somu (6), Venkata Kasyapi (7), Balaji Dhanasekaran (8)
(1) Assistant Professor, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(2) Postgraduate Student, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(3) HOD, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(4) Professor, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(5) Associate Professor, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(6) Senior Resident, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(7) Postgraduate Student, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
(8) Postgraduate Student, Department of ENT, Chettinad Hospital and Research Institute, Kelambakkam, Tamilnadu.
'Financial or Other Competing Interest': None.
Submission 12-03-2018, Peer Review 05-04-2018,
Acceptance 12-04-2018, Published 23-04-2018.
Dr. Preethi Prabhakaran, Flat No.1, Sharanya Apts., No. 11, 1st Street, Gopalapuram, Chennai-600086, Tamilnadu.
Table 1. Baseline characteristics of study participants. (N=120) Sl. Baseline Group 1 Group 2 P value No. Characteristics of N=60 N N=60 N Study Participants (%) (%) Sex 1. Male 28 (46.7) 27 (45) Female 32 (53.3) 33 (55) 0.855 Age group 0-18 years 10 (16.7) 10 (16.7) 19-60 years 49 (81.7) 47 (78.3) 0.594 >60 years 1 (1.7) 3 (5) Side of the ear affected 10 (16.7) 5 (8.3) 3. Both 21 (35) 29 (48.3) 0.211 Right 29 (48.3) 26 (43.3) Left Pain 4. Present 49 (81.7) 51 (85) Absent 11 (18.3) 9 (15) 0.624 Itching 5. Present 16 (26.7) 19 (31.7) Absent 44 (73.3) 41 (68.3) 0.547 Ear block 6. Yes 18 (30) 13 (21.7) 0.202 No 42 (70) 47 (78.3) Table 2. Presenting features and organisms in otomycosis. (N=120) Sl. No. Otomycosis Group 1 Group 2 Features N=60 N (%) N=60 N (%) Spores 1. Present 19 (31.7) 24 (40) Absent 41(68.3) 36 (60) Granulations 2. Present 6 (10) 4 (6.7) Absent 54 (90) 56 (93.3) 3. Otitis externa 19 (31.7) 17 (28.3) features 41 (68.3) 43 (71.7) Present Absent Fungal organism Asp. niger 22 (36.7) 38 (63.3) Asp. flavus 18 (30) 9 (15) 4. Asp. fumigatus 7 (11.7) 2 (3.3) Candida albicans 4 (6.7) 1 (1.7) Non albicans candida 3 (5) 3 (5) No growth 6 (10) 6 (10) Table 3. Comparison of study participants of two groups according to course of disease. (N=120) Sl. Disease course Week 1 P value Week 2 P value No. N (%) N (%) Clotrimazole (N=60) NAD 0 1 (1.7) 1. Minimal 1 (1.7) 4 (6.7) Debris 59 (98.3) 55 (91.7) 0.175 0.00 Fluconazole (N=60) NAD 0 5 (8.3) 2. Minimal 6 (10) 23 (38.3) Debris 54 (90) 32 (53.3) Sl. Disease course Week 3 P value Week 4 P value No. N (%) N (%) Clotrimazole (N=60) NAD 6 (10) 23 (38.3) 1. Minimal 14 (23.3) 24 (40) Debris 40 (66.7) 13 (21.7) 0.00 0.00 Fluconazole (N=60) NAD 27 (45) 46 (76.7) 2. Minimal 22 (36.7) 12 (20) Debris 11 (18.3) 2 (3.3) NAD--No abnormality detected, Chi square test applied p value <0.05 is significant. Figure 1. Bar diagram showing distribution of study participants according to fungal organism Fungal organisms isolated from the patients Group 1 Group 2 Aspergillus niger 36.70% 63.30% Aspergillus fumigatus 30% 15% Aspergillus flavus 11.70% 3.30% Candida albicans 6.70% 1.70% Non candida albicans 5% 5% No growth 10% 10% Note: Table made from bar graph. Figure 2. Bar diagram showing distribution of study participants according to findings of disease at the end of 1st and 4th week. (N=120) Findings at the end of 1st week of treatment Clotrimazole Fluconazole NAD 0% Minimal 10% Debris 98.30% 90% Findings at the end of 4th week of treatment Clotrimazole Fluconazole NAD 38.30% 76.7% Minimal 40% 20% Debris 21.70% 3.30% Note: Table made from bar graph.
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|Title Annotation:||Original Research Article|
|Author:||Prabhakaran, Preethi; Navin, Namasivaya; Srinivasan, Rajasekaran; Palanisamy, Thirunavukarasu; Kanag|
|Publication:||Journal of Evolution of Medical and Dental Sciences|
|Date:||Apr 23, 2018|
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