Study. Kunal J. Khobragade GlaxoSmithKline Pharmaceuticals Ltd., Mumbai, India

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1 Study Efficacy and safety of combination ointment fluticasone propionate 0.005% plus mupirocin 2.0% for the treatment of atopic dermatitis with clinical suspicion of secondary bacterial infection: An open label uncontrolled study Kunal J. Khobragade GlaxoSmithKline Pharmaceuticals Ltd., Mumbai, India Address for correspondence: Dr. Kunal J. Khobragade, Clinical Research and Medical Affairs, GlaxoSmithKline Pharmaceuticals Ltd. Dr. Annie Beasant Road, Worli, Mumbai , India. kunal.j.khobragade@gsk.com ABSTRACT Background: The skin of patients with atopic dermatitis is colonized with Staphylococcus aureus. Reduction of bacterial colonization has been reported to be effective in the treatment of atopic dermatitis. Aim: To assess the efficacy and safety of a combination of fluticasone propionate 0.005% and mupirocin 2.0% ointment twice daily for 2 weeks in patients with atopic dermatitis clinically suspected of secondary bacterial infection. Methods: An open-label, nonrandomized study of 122 patients (64 males and 58 females) from 20 centers was conducted. Atopic dermatitis was diagnosed by clinical assessment and scoring was done on the visual analogue scale (VAS). Clinical evaluation of the lesions was done on day 1 (baseline), day 8 and on day 15 of study visits. Results: At baseline, many patients had moderate itching (41.8%), moderate dryness (41.8%) and mild weeping lesions (49.2%). The baseline proportions of the clinicians global impressions (CGI) scale for mild, moderate and severe atopic dermatitis lesions were 19.7%, 55.7% and 12.2% respectively. At the end of the treatment period, 67.2% patients had mild disease, whereas only 9% and 0.8% patients had moderate and severe disease respectively. At baseline, only 33.65% patients were comfortable with the existing lesions when assessed on visual analog scale (VAS). However, after the treatment, this proportion increased to 51.77% and 78.60% patients on day 8 and on day 15 respectively. Conclusion: Twice daily topical application of a fluticasone propionate 0.005% and mupirocin 2.0% ointment is an effective and safe therapeutic regimen in atopic dermatitis. KEY WORDS: Superantigens, Staphylococcus aureus, Topical corticosteroid, Topical antibiotic INTRODUCTION Atopic dermatitis (AD) usually begins during childhood and can be a cause of significant emotional and financial impact on the families of the affected children. [1] Currently, there is no standard therapeutic regimen for the long-term management of moderate to severe atopic dermatitis but most regimens include a topical How to cite this article: Khobragade KJ. Efficacy and safety of combination ointment fluticasone propionate 0.005% plus mupirocin 2.0% for the treatment of atopic dermatitis (AD) with clinical suspicion of secondary bacterial infection: An open label uncontrolled study. Indian J Dermatol Venereol Leprol 2005;71:91-5. Received: July, Accepted: October, Source of Support: The study was initiated and supported by M/s GlaxoSmithKline Pharmaceuticals Ltd. Conflict of interest: The author works as a Senior Medical Advisor for GlaxoSmithKline Ltd. 91

2 steroid and an emollient. [2] The skin of % of patients with AD is colonized with Staphylococcus aureus. [3] Staphylococcus aureus is able to secrete exotoxins with superantigenic properties. Superantigens are high molecular weight proteins produced by different bacteria (staphylococci, streptococci, yersinia, mycoplasma) and viruses. They are involved in the pathogenesis of diseases including food poisoning, psoriasis and septic shock. [4] The staphylococcal enterotoxins A-D (SEA-D) and the toxic shock syndrome toxin-1 (TSST-1) are produced by Staphylococcus aureus spp. isolated from the skin of up to 65% of atopic dermatitis patients who are carriers of this microorganism. [5,6] Several studies have investigated the effect of antimicrobial treatment on the colonization with Staphylococcus aureus and the severity of inflammation, with conflicting results. In one study it was found that antibiotics with an inhibitory effect on protein synthesis could suppress the production of superantigens. [7] Mupirocin is a topical antibacterial agent, active against Staphylococcus aureus, including methicillin-resistant strains. After topical application, mupirocin is only very minimally absorbed systemically and whatever is absorbed is rapidly metabolized to an inactive metabolite, monic acid. Fluticasone propionate ointment 0.005% is a potent topical corticosteroid with a good safety profile. It has been shown to be effective and safe in the treatment of moderate to severe atopic dermatitis. [8] We conducted a multicentric trial in departments of dermatology across India to study the efficacy and safety of a combination ointment of fluticasone propionate 0.005% and mupirocin 2.0% in patients with atopic dermatitis clinically suspected of having secondary bacterial infection. METHODS This was an open-label and non-randomized study. Patients with atopic dermatitis who visited the departments of dermatology as out-patients were recruited for the study. Patients of all age groups (3 months to 76 years of age) with recurrent or newly diagnosed mild to severe atopic dermatitis were eligible. Atopic dermatitis was diagnosed by clinical assessment and scoring was done on the visual analogue scale (VAS) which included itch (pruritus), dryness, weeping lesion, typical morphology and distribution. Patients with any medical situation for which topical corticosteroids were contraindicated, those with concomitant skin conditions that may have prevented accurate assessment of atopic dermatitis, and those receiving any treatment that might have affected the study results were excluded. Written informed consent was taken from all parents, guardians or patients. Patients or the caregivers were instructed to apply fluticasone propionate 0.005% plus mupirocin 2% combination ointment twice daily for 2 weeks to the affected area over the body surface. No eyelid or panorbital areas were treated because of the potential risk of intra-ocular absorption leading to increased intraocular pressure. The efficacy parameters of all treated and affected areas were recorded at baseline and at all subsequent visits. The efficacy of treatment was evaluated using clinicians assessment of clinical response, clinicians global impression (CGI) and the patients assessment of clinical response on the visual analogue scale (VAS). The clinical response was judged by evaluating improvement in signs and symptoms, i.e. itch (pruritus), dryness and weeping lesions. At each visit, patients were questioned about adverse events, and these were recorded. Use of any concurrent medication was noted and signs of cutaneous atrophy and abnormal pigmentation changes were visually observed. The analyses were conducted on an intention-totreat basis (total number of patients enrolled 122) with the last observation carried forward, such that patients who worsened on treatment remained in the analyses as treatment failures. The change from baseline in the signs and symptoms severity score was calculated as the absolute value and percentage change. In line with the overall objective of the study, the primary end point for the study was the improvement in signs and symptoms of atopic dermatitis assessed by clinicians as well as by 92

3 patients. Data was analyzed using the Chi-square test to compare the observed readings at baseline with the readings obtained at visit 2 and visit 3. RESULTS In the study a total of 122 patients (64 males and 58 females) from 20 centers (between May 2002 and January 2003) were recruited. The mean age of the patients was 13.5 years with a range of 3 months to 76 years. Eight patients were lost to follow-up and 114 patients completed the 2-week treatment period (Table 1). At baseline, the majority of the patients had moderate itching (41.8%), moderate dryness (41.8%), and mild weeping lesions (49.2%) according to the clinicians assessment of clinical response (Table 2). The clinician s assessment of clinical response demonstrated an improvement with fluticasone propionate plus mupirocin treatment. On visit 2 (day 8), treatment success was seen for Table 1: Demographics and associated allergies Age in years - Range (mean) 3 months - 76 years (13.5 years) Male: 6 months - 73 years Female: 3 months - 76 years Sex Male 64 (52.45%) Female 58 (47.55%) No. of patients with history of Asthma - 27 (22.13%) Allergy - 44 (36.00%) Eczema - 52 (42.62%) Values indicate number of patients (%) moderate to severe signs and symptoms, i.e. itch, dryness and weeping lesions. On visit 3 (day 15), less than 2% of patients reported with severe signs and symptoms, and less than 10% patients reported with moderate signs and symptoms. Improvement in the severity of atopic dermatitis was measured by Clinicians Global Impression (CGI) scale (Table 3). At baseline the proportions of patients with mild, moderate and severe atopic dermatitis lesions were 19.7%, 55.7% and 12.2% respectively on the CGI scale; these declined to 67.2%, 9% and 0.8% respectively at the end of treatment (day 15). During all three visits, the patients assessed the clinical response on a visual analog scale (VAS) to analyze the relief from signs and symptoms. At baseline only 33.65% patients were comfortable with the existing lesions; this proportion increased to 51.77% and 78.60% patients on days 8 and 15 respectively (Table 4). No adverse events related to the study medication were observed. There were no local side effects, including irritation, stinging or skin atrophy, with use of fluticasone propionate plus mupirocin ointment during the 2-week treatment period. Using the Chi-square test baseline values were compared with visit 2 (day 8) and visit 3 (day 15) values. We have observed that all comparative parameters showed statistically significant difference (P < 0.05) at visit 2 and visit 3 (P < 0.05) when compared to baseline values. Table 2: Clinician s assessment of clinical response Signs and Visit 1 (Baseline) Visit 2 (Day 8)* Visit 3 (Day 15)* symptoms Mild Moderate Severe Mild Moderate Severe Mild Moderate Severe Itch 19 (15.5) 51 (41.8) 42 (34.4) 45 (36.9) 59 (48.4) 5 (4.1) 85 (69.7) 12 (9.8) 1 (0.8) Dryness 41 (33.6) 51 (41.8) 10 (8.2) 58 (47.5) 35 (28.6) 4 (3.3) 79 (64.8) 11 (9.0) 2 (1.6) Weeping lesion 60 (49.2) 37 (30.3) 8 (6.6) 65 (53.3) 23 (18.8) 1 (0.8) 54 (44.2) 4 (3.3) 1 (0.8) Values indicate number of patients (%).; *P < 0.05: All values indicate statistically significant improvement when compared to baseline. Table 3: Clinicians Global Impression (CGI) of severity of atopic dermatitis CGI Mild Moderate Severe Visit 1 (Baseline) 24 (19.7) 68 (55.7) 15 (12.2) Visit 2* (Day 8) 55 (45.1) 47 (38.5) 4 (3.3) Visit 3* (Day 15) 82 (67.2) 11 (9.0) 1 (0.8) Values indicate number of patients (%); *P < 0.05: All values indicate statistically significant difference when compared to baseline. Table 4: Patients assessment of clinical response on visual analog scale (VAS) Clinical response on VAS Relief from signs and symptoms (%) Visit 1 (Baseline) Visit 2 *(Day 8) Visit 3 *(Day 15) *P < 0.05: Values indicate statistically significant improvement when compared to baseline. 93

4 DISCUSSION Topical corticosteroids are the mainstay of treatment in AD. [9] But there is no specific treatment plan for longterm management of the disease and the inappropriate use of corticosteroids can negatively influence the treatment s success and safety. [10] In a systematic review, Hoare et al found that most practitioners use one of two approaches: either a potent topical corticosteroid followed by a lower potency preparation as the condition improves, or short-term use of a topical corticosteroid followed by a maintenance regimen of emollients. [2] The usual practice is to recommend a short burst (up to 2 weeks) of a topical corticosteroid for each acute episode of AD. Fluticasone propionate is a highly effective topical corticosteroid with a low potential for local and systemic side effects. In our study, we did not assess the function of the HPA axis. However, several previous studies in children (including as young as 3 months) and adults with extensive involvement have shown that fluticasone propionate exhibits no significant effect on the basal or stimulated plasma concentration of cortisol or the 24 h urinary concentration of cortisol during short or long-term treatment. [8,11] Atopic skin is susceptible to colonization with Staphylococcus aureus. Staphylococcal superantigens (SsAg) contribute to the pathogenesis of cutaneous inflammation in atopic dermatitis through various potential mechanisms, viz. direct stimulation of antigen presenting cells and keratinocytes, stimulation of T cell proliferation (by binding to T cell receptors), expansion of skin-homing cutaneous lymphocyte antigen positive T cells. [12] Superantigens also play a role as allergens and in reduction of apoptosis. The cell wall of Staphylococcus aureus exhibits receptors adhesins, for epidermal and dermal fibronectin and fibrinogen. As the skin of patients with AD may have breaches in the stratum corneum, dermal fibronectin might bind to Staphylococcus aureus. [13] Staphylococcus aureus penetrates into intracellular spaces of the epidermis and deteriorates the skin surface lipids in patients with AD. [14] Skin surface lipids such as free fatty acids and polar lipids are important because they exhibit antibacterial activity. [15] Staphylococcus aureus can be eliminated from the skin of patients with AD by topical treatment with potent corticosteroids or a combination of a corticosteroid and a topical antibiotic, which suggests the contribution of immunological factors that support colonization. [16] Bacterial superantigens were recently shown to induce corticosteroid insensitivity. [17] Hence the eradication of Staphylococcus aureus may lead to a steroid-saving effect. In double-blind placebocontrolled studies, the use of oral flucloxacillin or cefuroxime axetil significantly reduced Staphylococcus aureus colonization, but did not significantly improve AD. [18,19] However, in another study, antimicrobial therapy (including the use of mupirocin ointment) led to the complete eradication of Staphylococcus aureus and to an improvement in AD in 9 out of 10 cases. [20] Our study has demonstrated that patients with AD respond well to treatment with fluticasone propionate 0.005% plus mupirocin 2% combination ointment. More than 90% of patients were converted to the mild severity group from the moderate and severe groups in two weeks on the clinicians global impression (CGI) scale for the severity of AD. This suggests that such a combination is an effective, safe and practical therapeutic regimen in AD. Although we did not study quality of life indices, the reduction in signs and symptoms observed could be expected to significantly improve the quality of life of such patients. Topical antibacterial-corticosteroid combinations can be useful when treating small areas of AD for a limited period but their use is accompanied by the risk of sensitization and the emergence of resistant strains of bacteria. Use of a systemic antibacterial in combination with a topical corticosteroid is more appropriate when larger areas are involved. Systematic comparative studies are needed to document the impact of adjuvant topical antibacterial treatment in clinically infected and uninfected AD. ACKNOWLEDGEMENTS The author thanks the following investigators who recruited patients and took part in this study: Dr. Anil Abraham, Dr. K. 94

5 Aravamadu, Dr. N. Balasubramanium, Dr. J. O. Coladia, Dr. Sandipan Dhar, Dr. G. G. Dhir, Dr. Manisha Gupta, Dr. Sanjeev Handa, Dr. (Mrs.) V. R. Janaki, Dr. Suresh P. Joshipura, Dr. Hema Jerajani, Dr. K. Pavithran, Dr. Sudhir Pujara, Dr. S. S. Rajendran, Dr. Vineet Relhan, Dr. S. Sacchidanand, Dr. B. V. Selvan, Dr. V. K. Sood, Dr. Tagde, and Dr. R. L. Sah. Statistical Assistance: Dr. Murtuza Bughediwalla, Assistant Clinical Research Manager. Clinical Research and Medical Affairs, GlaxoSmithKline Pharmaceuticals Ltd., Worli, Mumbai , India. Clinical Trial Supplies (CTS): Flutibact is a brand of Fluticasone Propionate 0.005% plus Mupirocin 2.0%: ointment provided to the all investigators by Medical Department (Clinical Research and Medical Affairs), GlaxoSmithKline Pharmaceuticals Ltd., Worli, Mumbai , India REFERENCES 1. Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens RG. The family impact of childhood atopic dermatitis: The Dermatitis Family Impact Questionnaire. Br J Dermatol 1998;138: Hoare C, Li Wan Po A, Williams H. Systematic review of treatments of atopic eczema. Health Technol Assess 2000;4: Hauser C, Wuethrich B, Matter L, Wilhelm JA, Sonnabend W, Schopfer K. Staphylococcus aureus skin colonization in atopic dermatitis. Dermatologica 1985;170: Schlievert PM. Role of superantigens in human disease. J Infect Dis 1993;167: Akiyama H, Toi Y, Kanzaki H, Tada J, Arata J. Prevalence of producers of enterotoxins and the toxic shock syndrome toxin- 1 among staphylococcus aureus strains isolated from atopic dermatitis lesions. Arch Dermatol Res 1996;288: McFadden JP, Noble WC, Camp RD. Superantigenic exotoxinsecreting potential of staphylococci isolated from atopic eczematous skin. Br J Dermatol 1993;128: Adachi Y, Akamatsu H, Horia T. The effect of antibiotics on the production of superantigen from staphylococcus aureus isolated from atopic dermatitis. J Dermatol Sci 2002;28: Spencer CM, Wiseman LR. Topical Fluticasone Propionate: A review of its pharmacological properties and therapeutic use in the treatment of dermatologic disorders. Biodrugs 1997;4: Hoare C, Li Wan Po A, Williams H. Systemic review of treatments for atopic eczema. Health Technol Assess 2000;4: Hanifin JM, Tofte SJ. Update on therapy of atopic dermatitis. J Allergy Clin Immunol 1999;104:S Friedlander SF, Hebert A, Allen DB; Fluticasone Pediatrics Safety Study Group. Safety of fluticasone propionate 0.05% for the treatment of severe and extensive atopic dermatitis in children as young as 3 months. J Am Acad Dermatol 2002;46: Taskapan MO, Kumar P. Role of staphylococcal superantigens in atopic dermatitis: From colonisation to inflammation. Ann Allergy Asthma Immunol 2000;84: Cole GW, Silverberg NL. The adherence of staphylococcus aureus to human corneocytes. Arch Dermatol 1986;122: Morishita Y, Tada J, Sato A, Toi Y, Kanzaki H, Akiyama H, et al. Possible influences of staphylococcal aureus in atopic dermatitis the colonizing features and the effects of staphylococcal enterotoxins. Clin Exp Allergy 1999;29: Miller SJ, Aly R, Shinefeld HR, Elias PM. In vitro and in vivo antistaphylococcal activity of human stratum corneum lipids. Arch Dermatol 1988;124: Lever R, Hadley K, Downey D, Mackie R. Staphylococcal colonization in atopic dermatitis and the effect of topical mupirocin therapy. Br J Dermatol 1988;119: Hauk PJ, Hamid QA, Chrousos GP, Leung DY. Induction of corticosteroid insensitivity in human PBMCs by microbial superantigens. J Allergy Clin Immunol 2000;105: Boguniewicz M, Sampson H, Leung SB, Harbeck R, Leung DY. Effects of cefuroxime axetil on s. aureus colonization and superantigen production in atopic dermatitis. J Allergy Clin Immunol 2001;108: Ewing CI, Ashcroft C, Gibbs AC, Jones GA, Connor PJ, David TJ. Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 1998;138: Breuer K, Haussler S, Kapp A, Werfel T. Staphylococcus aureus: Colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis. Br J Dermatol 2002;147: