968 Rajathilagam T. et al. / International Journal of Biological & Pharmaceutical Research. 2012; 3(8): 968-973.

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A STUDY OF PRESCRIBING PATTERN OF ANTIFUNGAL DRUGS IN DERMATOLOGY OUTPATIENT (OPD) OF A TERTIARY CARE HOSPITAL T. Rajathilagam*1, Tasneem Sandozi2, V. Rajagopalan3, R. Jamuna Rani1 1

Department of Pharmacology, SRM Medical College Hospital & Research Center, SRM University, Tamilnadu, India. 2 Department of Pharmacology, Dr.V.R.K. Women's Medical College, Hyderabad, Andhra Pradesh, India. 3 Department of Dermatology, SRM Medical College Hospital & Research Center, SRM University, Tamilnadu, India.

ABSTRACT A prospective cross-sectional study was done for 5 months (June - October 2011) in the dermatology outpatient department of SRM Medical College Hospital & Research Center, SRM university, Tamil Nadu to evaluate the drug utilization pattern of antifungal drugs. The prescription data of 100 patients with fungal infections of the skin was analyzed in this study. 72% of the patients presented with a single fungal lesion and 28% with fungal infections in multiple regions. The patients were predominantly (85%) treated with a combination of an oral along with a topical antifungal drug at an average of 2.32 drugs per patient. Imidazoles were the most commonly prescribed group of antifungal drugs (78%) followed by triazoles (63%), allylamines (40%) and antibiotics (4%). Fluconazole was noted to be the predominantly prescribed oral antifungal agent in the treatment of superficial fungal infections. In the topical agents eberconazole (45%) and clotrimazole (31%) were the primarily prescribed drugs. There were no reports of any severe adverse drug reactions or drug interactions during the study. Key Words: Fungal infection, Antifungal drugs, Imidazoles, Fluconazole, Eberconazole. INTRODUCTION The last two decades has seen an increase in incidence of invasive fungal infections. The major factors which predispose patients to invasive fungal disease include chemotherapy induced prolonged neutropenia, immunodeficiency and immunosuppression associated with organ transplantation, HIV infection and prolonged corticosteroid therapy. Amphotericin B was the only effective antifungal drug available for systemic use for a number of years. Despite being highly effective in many serious infections it is also a very toxic drug (Don Sheppard & Harry W. Lampiris, 2009). Currently, as the use of standard Corresponding Author T. Rajathilagam Email: [email protected]

antifungal therapies is limited because of toxicity, low efficacy rates and drug resistance new formulations are being prepared to improve absorption and efficacy of some of these standard therapies. Various new antifungal drugs – azoles with three new additional drugs and echinocandins have also demonstrated therapeutic potential (John E. Bennett, 2011). This study was planned to evaluate the utilization of these various new antifungal drugs that may provide additional options for the treatment of superficial fungal infections and help to overcome the limitations of current treatments. The aim of the study was to evaluate the prescribing pattern of antifungal drugs in the Dermatology outpatient department of a tertiary care hospital, Chennai, India. MATERIALS & METHODS

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Study design Prospective, observational, cross sectional study. The study was done in the Dermatology outpatient department of SRM Medical College Hospital and Research Centre. A prospective cross-sectional study was done for 5 months (June –October 2011) after getting approval from the Institutional ethical committee. The drugs prescribed for patients with fungal infections of the skin who attended this outpatient department were noted down after taking verbal consent from them.

RESULTS The prescription data of 100 patients was analyzed. 61% of the patients were men and 39% were women (Table 1 & Figure 1). The men to women ratio was 1.56.The average age of all patients was 31.96 years.Average ages of men and women were 29.03 and 36.54 years respectively.72% of the patients presented with a single fungal lesion and 28% with fungal infections in multiple regions. The single lesion fungal infections were mainly (dermatophytosis) like tinea corporis, tinea versicolor, tinea cruris, tinea faciei and tinea pedis. (Table 2 & Figure 2). Fungal infections at multiple sites included tinea cruris and glutealis, tinea cruris and corporis, tinea corporis and glutealis and tinea cruris, corporis and glutealis. (Table 2 & Figure 3). It has been observed in this study that an average of 2.32 drugs was prescribed per patient. Majority of the patients (85) were prescribed a combination of a topical with an oral antifungal drug followed by solely topical or oral antifungal drugs in 13 and 2 patients respectively. (Table 3 & Figure 4). Imidazoles were the most commonly prescribed group of antifungal drugs (78%) followed by triazoles (63%), allylamines (40%) and antibiotics (4%). (Table 4 & Figure 5). Among the topical antifungals, eberconazole (45%) and clotrimazole (31%) were most frequently prescribed in this study. The other topical antifungals prescribed were terbinafine (18%), ketoconazole (3%), fluconazole (2%) and miconazole (1%). (Table 5 & Figure 6). In the topical + oral antifungal combination therapy, Eberconazole + Fluconazole was prescribed to 31% and Clotrimazole + Fluconazole to 24% of the patients. The other antifungal drugs which were prescribed in combination were terbinafine, griseofulvin and miconazole (Table 6 & Figure 7). Along with antifungal drugs, antihistamines, antifungal shampoos and soaps, dusting powder and antibiotics were also prescribed. (Table 7 & Figure 8).

Inclusion criteria All adult patients with fungal infections of the skin attending the Dermatology outpatient department were included in this study. Exclusion criteria Inpatients, patients with deep seated and systemic fungal infections and children were excluded from this study. The collected data was analyzed to estimate the prescribing indicators and patient indicators. Prescribing indicators include: a) Average number of drugs prescribed per patient b) % of utilization of the different classes of antifungal drugs c) % of encounters (prescription) with an antihistaminic prescribed d) % of encounters (prescription) with a topical antifungal prescribed e) % of encounters (prescription) with a topical antibiotic prescribed Patient indicators include: a) Average age of men b) Average age of women c) Average age in years of all patients d) Men to women ratio Type of fungal infection (diagnosis)

Table 1. Sex Distribution N=100 Men Women

61 39

Table 2. Types of fungal infection Types of fungal infection (n= 100) Fungal infection (Single lesion ) Fungal infection (multiple regions) (n= 72) (n= 28) Tinea corporis 35% (25 patients) Tinea cruris & glutealis 32% (9 patients) Tinea versicolor 29% (21 patients) Tinea cruris & corporis 29% (8 patients) Tinea cruris 26% (19 patients) Tinea corporis & glutealis 25% (7 patients) Tinea faciei 6% (4 patients) Tinea cruris, corporis & glutealis 14% (4 patients) Tinea pedis 4% (3 patients)

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Table 3. Antifungal Therapy n=100 Drug therapy Topical + oral antifungal Topical antifungal only Oral antifungal only Other co administered drugs

Number of patients 85 13 2 50

Table 4. Commonly prescribed antifungal drugs Drug group Imidazoles a) Eberconazole b) Clotrimazole c) Ketoconazole d) Miconazole Triazoles -Fluconazole Allylamines -Terbinafine Antibiotics -Griseofulvin

Percentage (%) 78 % (78 patients) 44% (44 patients) 30% (30 patients) 3% (3 patients) 1% (1 patient) 63% (63 patients) 40% (40 patients) 4% (4 patients)

Table 5. Topical antifungal therapy n=98 Drug Eberconazole Clotrimazole Terbinafine Ketoconazole Fluconazole Miconazole

Percentage (% ) 45% (45 patients) 31% (30 patients) 18% (17 patients) 3% (3 patients) 2% (2 patients) 1% (1 patient)

Table 6. Topical + Oral antifungal therapy (n=85) Percentage (% ) 31% (26 patients) 24% (20 patients) 16% (14 patients) 15% (13 patients) 7% (5 patients) 2% (2 patients) 2% (2 patients) 2% (2 patients) 1% (1 patient)

Drugs Eberconazole + Fluconazole Clotrimazole + Fluconazole Terbinafine + Fluconazole Eberconazole + Terbinafine Terbinafine + Terbinafine Clotrimazole + Griseofulvin Clotrimazole + Terbinafine Fluconazole + Terbinafine Miconazole + Fluconazole Table 7. Other co administered drugs n= 50 Drug group Antihistamines Antifungal shampoo Dusting powder Antifungal soap Antibiotics

Percentage (%) 40 patients (80%) 3 patients (6%) 3 patients (6%) 3 patients (6%) 1 patient (2%)

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Figure 1. Sex Distribution

Figure 2. Fungal infection (Single Lesion)

Figure 3. Fungal infection (Multiple Regions)

Figure 4. Antifungal Therapy

Figure 5. Commonly prescribed antifungal drugs

Figure 6. Topical antifungal therapy

Figure 7. Topical + Oral antifungal therapy

Figure 8. Other co administered drugs

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DISCUSSION This study has shown that fungal infections were more common in men (61%) compared to women (39%). The patients mainly (72%) presented with single lesion fungal infections (tinea corporis, tinea versicolor or tinea cruris). Mixed multiple sites fungal infections (tinea cruris and glutealis) were seen only in about 28% of the patients. The patients were predominantly (85%) treated with a combination of an oral along with a topical antifungal drug at an average of 2.32 drugs per patient. Solely topical or oral antifungal drugs were prescribed in 13 and 2% of the patients respectively. Antifungal agents can be discussed under two main headings – systemic and topical. The antifungal agents like azoles and allylamines can either be used topically or systemically. Many superficial mycoses may be treated systemically or topically. The azoles are synthetic compounds which can be further subdivided into imidazoles and triazoles depending on the number of nitrogen atoms in their five ringed structure (Daniel J. Sheehan et al., 1999). The imidazoles include clotrimazole, ketoconazole, miconazole and eberconazole and the triazoles include fluconazole, itraconazole, voriconazole and posaconazole. Terbinafine is the antifungal drug belonging to the allylamines. This study demonstrated azoles (imidazoles-78% and triazoles- 63%) as the predominantly prescribed topical as well as systemic antifungal agent. Indications for topical antifungal use are superficial fungal infections – dermatophytoses (ringworm), tinea versicolor and mucocutaneous candidiasis. Resistance to imidazoles and triazoles is very rare among fungi that cause ringworm. Selection of one of these agents for topical use is based on cost and availability of the drug as in vitro testing of fungal susceptibility to these drugs does not predict clinical responses (John E. Bennett, 2011). Systemic triazoles compared to imidazoles are metabolized more slowly and have less effect on human sterol synthesis. On account of these advantages new congeners under development are mostly triazoles (John E. Bennett, 2011). Fluconazole belonging to the triazoles is the agent most commonly used for the treatment of mucocutaneous candidiasis. This study has also established fluconazole (63%) as the primarily prescribed oral antifungal drug. Its other advantages include fewer drug interactions and better gastrointestinal tolerance. Hence, it has the widest therapeutic index of the azoles permitting more aggressive dosing in a variety of fungal infections [Don Sheppard & Harry W. Lampiris 2009]. Despite being an inhibitor of CYP 3A4 and CYP2C9, drug interactions are seen only in azotemic patients with high fluconazole levels or patients who receive more than 400 mg daily (John E. Bennett, 2011). Ketoconazole belonging to the imidazoles was the first azole to be discovered. It is distinguished from

triazoles by being less selective and having greater propensity to inhibit mammalian cytochrome P450 enzymes. As it has fallen out of clinical use currently being available only for topical use as cream, foam, gel or shampoo it was prescribed topically to a very small number of patients. Terbinafine was the second commonly prescribed antifungal drug. It is well tolerated orally. It does not seem to affect microsomal enzyme system and has not exhibited any significant drug interactions till date (Don Sheppard & Harry W. Lampiris, 2009). This drug accumulates in the skin, nails and fat. It is effective in tinea capitis but more effective for onychomycoses (Sharon CA Chen and Tania C Sorrell, 2007). Topically it is more effective in tinea corporis, cruris and pedis. It is less effective against candida species but the cream can also be used in cutaneous candidiasis and tinea versicolor. Topical antifungal treatment is useful in many superficial fungal infections, those confined to the stratum corneum, squamous mucosa or cornea. Such diseases include dermatophytoses (ringworm), candidiasis and tinea versicolor. Topical administration of antifungal agents is usually not successful for mycoses of the nails (onychomycoses) and hair (tinea capitis). The efficacy of the topical agents in the treatment of superficial mycoses depends on the type of lesion and also the formulation of the drug (John E. Bennett, 2011). Topical imidazoles including clotrimazole, ketoconazaole, eberconazole and miconazole have a wide range of activity against dermatophytes and yeasts (candidiasis). When applied once or twice daily to the affected area it generally results in clearing of the dermatological infection in 2-3 weeks although medication has to be continued until complete eradication of the organism is confirmed (Don Sheppard & Harry W. Lampiris, 2009). The two most commonly used topical antifungal agents are clotrimazole and miconazole. In this study eberconazole (45%) and clotrimazole (31%) followed by terbinafine (18%) were noted to be the frequently prescribed topical antifungal drugs. Miconazole was prescribed only to one patient. Eberconazole has been shown to have broad antimicrobial spectrum of activity in vitro. It was found to be effective in dermatophytosis, candidiasis, infection by other yeasts such as Malassezzia furfur and causative agents of pityriasis versicolor in in vitro and animal studies. Its effectiveness against most triazole resistant yeasts (Candida krusei and Candida glabrata) and also fluconazole resistant Candida albicans has also been demonstrated in vitro. In addition it has also been shown to be effective against Gram-positive bacteria. Eberconazole is also distinct from other imidazoles in having anti-inflammatory activity which also favors its use in the management of inflamed dermatophytic infections (Latha Subramanya MoodahaduBangera et al., 2012).

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Irritable itching, blisters and oozing raised patches are few of the predominant symptoms of superficial fungal infections especially dermatophytoses. Hence in addition to the relevant antifungal therapy 50% of the patients were prescribed adjuvant drugs. Antihistaminics constituted the bulk (80%) of these concurrently prescribed drugs along with a small number of patients being prescribed antifungal shampoo, dusting powder and antifungal soap (6% each). Antibiotics were prescribed as adjuvant drugs only in 2% of the patients. There were no reports of any severe adverse drug reactions or drug interactions during the study although all azoles are prone to drug interaction as they affect cytochrome P450 system of enzymes to some extent. As none of the patients sought advice subsequently it was assumed that all the patients were cured of their topical

fungal infection. CONCLUSION Fluconazole was noted to be the predominantly prescribed oral antifungal agent in the treatment of superficial fungal infections. In the topical agents eberconazole and clotrimazole were the primarily prescribed drugs. Terbinafine was the next choice of antifungal agent prescribed in this study. ACKNOWLEDGEMENT We thank Dr. James Pandian, Dean, SRM Medical College Hospital and Research Center for permitting us to conduct this study. We are also grateful to the staff and faculty of Dermatology for extending all their help to us during this study.

REFERENCES Daniel J. Sheehan, Christopher A. Hitchcock and Carol M. Sibley. Current and Emerging Azole Antifungal Agents. Clinical microbiology reviews. 1999; 12 (1): 40- 79. Don Sheppard & Harry W. Lampiris. Antifungal agents. In: Bertram G.Katzung, Basic & clinical pharmacology, 11 thedition, Tata McGraw Hill, New Delhi, 2009: 835-842. John E. Bennett. Antifungal agents. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition, McGraw-Hill, New York, 2011: 1571-89. Latha Subramanya Moodahadu-Bangera, Jacintha Martis, Rajan Mittal, Binny Krishnakutty, Naveen Kumar, Shantala Bellary, Sunoj Varughese and Parinitha K Rao. Eberconazole - Pharmacological and clinical review. Indian Journal of Dermatology, Venereology and Leprology. 2012; 78 (2): 217-222. Sharon CA Chen and Tania C Sorrell. Antifungal agents. Medical Journal of Australia. 2007; 187 (7): 404-409.