Study

Efficacy and safety of combination ointment “ propionate 0.005% plus 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 - 400 030, India. E-mail: [email protected]

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 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, non- randomized 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 , Topical

INTRODUCTION impact on the families of the affected children.[1] Currently, there is no standard therapeutic regimen for Atopic dermatitis (AD) usually begins during childhood the long-term management of moderate to severe and can be a cause of significant emotional and financial 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, 2004. Accepted: October, 2004. 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 Indian J Dermatol Venereol Leprol March-April 2005 Vol 71 Issue 2 Khobragade KJ: Efficacy and safety of combination ointment steroid and an emollient.[2] diagnosed mild to severe atopic dermatitis were eligible. Atopic dermatitis was diagnosed by clinical The skin of 80-100% of patients with AD is colonized assessment and scoring was done on the visual with Staphylococcus aureus.[3] Staphylococcus aureus is able analogue scale (VAS) which included itch (pruritus), to secrete exotoxins with superantigenic properties. dryness, weeping lesion, typical morphology and Superantigens are high molecular weight proteins distribution. Patients with any medical situation for produced by different bacteria (staphylococci, which topical were contraindicated, streptococci, yersinia, mycoplasma) and viruses. They are those with concomitant skin conditions that may have involved in the pathogenesis of diseases including food prevented accurate assessment of atopic dermatitis, poisoning, psoriasis and septic shock.[4] The and those receiving any treatment that might have staphylococcal enterotoxins A-D (SEA-D) and the toxic affected the study results were excluded. Written shock syndrome toxin-1 (TSST-1) are produced by informed consent was taken from all parents, guardians Staphylococcus aureus spp. isolated from the skin of up or patients. to 65% of atopic dermatitis patients who are carriers of this microorganism.[5,6] Patients or the caregivers were instructed to apply fluticasone propionate 0.005% plus mupirocin 2% Several studies have investigated the effect of combination ointment twice daily for 2 weeks to the antimicrobial treatment on the colonization with affected area over the body surface. No eyelid or pan- Staphylococcus aureus and the severity of inflammation, orbital areas were treated because of the potential risk with conflicting results. In one study it was found that of intra-ocular absorption leading to increased intra- with an inhibitory effect on protein synthesis ocular pressure. could suppress the production of superantigens.[7] Mupirocin is a topical antibacterial agent, active against The efficacy parameters of all treated and affected areas Staphylococcus aureus, including methicillin-resistant were recorded at baseline and at all subsequent visits. strains. After topical application, mupirocin is only very The efficacy of treatment was evaluated using clinicians’ minimally absorbed systemically and whatever is assessment of clinical response, clinicians’ global absorbed is rapidly metabolized to an inactive impression (CGI) and the patients’ assessment of clinical metabolite, monic acid. response on the visual analogue scale (VAS). The clinical response was judged by evaluating improvement in Fluticasone propionate ointment 0.005% is a potent signs and symptoms, i.e. itch (pruritus), dryness and topical corticosteroid with a good safety profile. It has weeping lesions. At each visit, patients were questioned been shown to be effective and safe in the treatment about adverse events, and these were recorded. Use of of moderate to severe atopic dermatitis.[8] We any concurrent medication was noted and signs of conducted a multicentric trial in departments of cutaneous atrophy and abnormal pigmentation changes dermatology across India to study the efficacy and were visually observed. safety of a combination ointment of fluticasone propionate 0.005% and mupirocin 2.0% in patients with The analyses were conducted on an intention-to- atopic dermatitis clinically suspected of having treat basis (total number of patients enrolled 122) secondary bacterial infection. with the last observation carried forward, such that patients who worsened on treatment remained in METHODS the analyses as treatment failures. The change from baseline in the signs and symptoms severity score This was an open-label and non-randomized study. was calculated as the absolute value and percentage Patients with atopic dermatitis who visited the change. In line with the overall objective of the study, departments of dermatology as out-patients were the primary end point for the study was the recruited for the study. Patients of all age groups (3 improvement in signs and symptoms of atopic months to 76 years of age) with recurrent or newly dermatitis assessed by clinicians as well as by

Indian J Dermatol Venereol Leprol March-April 2005 Vol 71 Issue 2 92 Khobragade KJ: Efficacy and safety of combination ointment patients. Data was analyzed using the Chi-square test moderate to severe signs and symptoms, i.e. itch, to compare the observed readings at baseline with dryness and weeping lesions. On visit 3 (day 15), less the readings obtained at visit 2 and visit 3. than 2% of patients reported with severe signs and symptoms, and less than 10% patients reported with RESULTS moderate signs and symptoms.

In the study a total of 122 patients (64 males and 58 Improvement in the severity of atopic dermatitis was females) from 20 centers (between May 2002 and measured by Clinicians’ Global Impression (CGI) scale January 2003) were recruited. The mean age of the (Table 3). At baseline the proportions of patients with patients was 13.5 years with a range of 3 months to 76 mild, moderate and severe atopic dermatitis lesions years. Eight patients were lost to follow-up and 114 were 19.7%, 55.7% and 12.2% respectively on the CGI patients completed the 2-week treatment period (Table scale; these declined to 67.2%, 9% and 0.8% respectively 1). at the end of treatment (day 15).

At baseline, the majority of the patients had moderate During all three visits, the patients assessed the clinical itching (41.8%), moderate dryness (41.8%), and mild response on a visual analog scale (VAS) to analyze the weeping lesions (49.2%) according to the clinicians’ relief from signs and symptoms. At baseline only 33.65% assessment of clinical response (Table 2). patients were comfortable with the existing lesions; this proportion increased to 51.77% and 78.60% patients The clinician’s assessment of clinical response on days 8 and 15 respectively (Table 4). demonstrated an improvement with fluticasone propionate plus mupirocin treatment. No adverse events related to the study medication were observed. There were no local side effects, including On visit 2 (day 8), treatment success was seen for irritation, stinging or skin atrophy, with use of fluticasone propionate plus mupirocin ointment during Table 1: Demographics and associated allergies the 2-week treatment period. Age in years - Range (mean) 3 months - 76 years (13.5 years) Male: 6 months - 73 years Female: 3 months - 76 years Using the Chi-square test baseline values were Sex compared with visit 2 (day 8) and visit 3 (day 15) values. • Male 64 (52.45%) • Female 58 (47.55%) We have observed that all comparative parameters No. of patients with history of Asthma - 27 (22.13%) showed statistically significant difference (P < 0.05) at Allergy - 44 (36.00%) Eczema - 52 (42.62%) visit 2 and visit 3 (P < 0.05) when compared to baseline Values indicate number of patients (%) 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 Table 4: Patients’ assessment of clinical response on visual atopic dermatitis analog scale (VAS) CGI Mild Moderate Severe Clinical response on VAS Relief from signs and symptoms (%) Visit 1 (Baseline) 24 (19.7) 68 (55.7) 15 (12.2) Visit 1 (Baseline) 33.65 Visit 2* (Day 8) 55 (45.1) 47 (38.5) 4 (3.3) Visit 2 *(Day 8) 51.77 Visit 3* (Day 15) 82 (67.2) 11 (9.0) 1 (0.8) Visit 3 *(Day 15) 78.60 Values indicate number of patients (%); *P < 0.05: All values indicate *P < 0.05: Values indicate statistically significant improvement when statistically significant difference when compared to baseline. compared to baseline.

93 Indian J Dermatol Venereol Leprol March-April 2005 Vol 71 Issue 2 Khobragade KJ: Efficacy and safety of combination ointment

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

Indian J Dermatol Venereol Leprol March-April 2005 Vol 71 Issue 2 94 Khobragade KJ: Efficacy and safety of combination ointment

Aravamadu, Dr. N. Balasubramanium, Dr. J. O. Coladia, Dr. Sandipan 8. Spencer CM, Wiseman LR. Topical Fluticasone Propionate: A Dhar, Dr. G. G. Dhir, Dr. Manisha Gupta, Dr. Sanjeev Handa, Dr. review of its pharmacological properties and therapeutic use (Mrs.) V. R. Janaki, Dr. Suresh P. Joshipura, Dr. Hema Jerajani, Dr. K. in the treatment of dermatologic disorders. Biodrugs Pavithran, Dr. Sudhir Pujara, Dr. S. S. Rajendran, Dr. Vineet Relhan, 1997;4:318-34. Dr. S. Sacchidanand, Dr. B. V. Selvan, Dr. V. K. Sood, Dr. Tagde, and 9. Hoare C, Li Wan Po A, Williams H. Systemic review of Dr. R. L. Sah. treatments for atopic eczema. Health Technol Assess 2000;4: 1-191. Statistical Assistance: Dr. Murtuza Bughediwalla, Assistant Clinical 10. Hanifin JM, Tofte SJ. Update on therapy of atopic dermatitis. J Research Manager. Clinical Research and Medical Affairs, Allergy Clin Immunol 1999;104:S123-5. GlaxoSmithKline Pharmaceuticals Ltd., Worli, Mumbai - 400 030, 11. Friedlander SF, Hebert A, Allen DB; Fluticasone Pediatrics Safety India. Study Group. Safety of fluticasone propionate 0.05% for the treatment of severe and extensive atopic dermatitis in children Supplies (CTS): Flutibact® is a brand of “Fluticasone as young as 3 months. J Am Acad Dermatol 2002;46:387-93. Propionate 0.005% plus Mupirocin 2.0%: ointment provided to the 12. Taskapan MO, Kumar P. Role of staphylococcal superantigens all investigators by Medical Department (Clinical Research and in atopic dermatitis: From colonisation to inflammation. Ann Medical Affairs), GlaxoSmithKline Pharmaceuticals Ltd., Worli, Allergy Asthma Immunol 2000;84:3-12. Mumbai - 400 030, India 13. Cole GW, Silverberg NL. The adherence of staphylococcus aureus to human corneocytes. Arch Dermatol 1986;122: 166-9. REFERENCES 14. Morishita Y, Tada J, Sato A, Toi Y, Kanzaki H, Akiyama H, et al. Possible influences of staphylococcal aureus in atopic dermatitis 1. Lawson V, Lewis-Jones MS, Finlay AY, Reid P, Owens RG. The – the colonizing features and the effects of staphylococcal family impact of childhood atopic dermatitis: The Dermatitis enterotoxins. Clin Exp Allergy 1999;29:1110-7. Family Impact Questionnaire. Br J Dermatol 1998;138:107-13. 15. Miller SJ, Aly R, Shinefeld HR, Elias PM. In vitro and in vivo 2. Hoare C, Li Wan Po A, Williams H. Systematic review of antistaphylococcal activity of human stratum corneum lipids. treatments of atopic eczema. Health Technol Assess 2000;4: Arch Dermatol 1988;124:209-15. 1-191. 16. Lever R, Hadley K, Downey D, Mackie R. Staphylococcal 3. Hauser C, Wuethrich B, Matter L, Wilhelm JA, Sonnabend W, colonization in atopic dermatitis and the effect of topical Schopfer K. Staphylococcus aureus skin colonization in atopic mupirocin therapy. Br J Dermatol 1988;119:189-98. dermatitis. Dermatologica 1985;170:35-9. 17. Hauk PJ, Hamid QA, Chrousos GP, Leung DY. Induction of 4. Schlievert PM. Role of superantigens in human disease. J Infect corticosteroid insensitivity in human PBMCs by microbial Dis 1993;167:997-1002. superantigens. J Allergy Clin Immunol 2000;105:782-7. 5. Akiyama H, Toi Y, Kanzaki H, Tada J, Arata J. Prevalence of 18. Boguniewicz M, Sampson H, Leung SB, Harbeck R, Leung DY. producers of enterotoxins and the toxic shock syndrome toxin- Effects of cefuroxime axetil on s. aureus colonization and 1 among staphylococcus aureus strains isolated from atopic superantigen production in atopic dermatitis. J Allergy Clin dermatitis lesions. Arch Dermatol Res 1996;288:418-20. Immunol 2001;108:651-2. 6. McFadden JP, Noble WC, Camp RD. Superantigenic exotoxin- 19. Ewing CI, Ashcroft C, Gibbs AC, Jones GA, Connor PJ, David secreting potential of staphylococci isolated from atopic TJ. Flucloxacillin in the treatment of atopic dermatitis. Br J eczematous skin. Br J Dermatol 1993;128:631-2. Dermatol 1998;138:1022-9. 7. Adachi Y, Akamatsu H, Horia T. The effect of antibiotics on the 20. Breuer K, Haussler S, Kapp A, Werfel T. Staphylococcus aureus: production of superantigen from staphylococcus aureus Colonizing features and influence of an antibacterial treatment isolated from atopic dermatitis. J Dermatol Sci 2002;28: in adults with atopic dermatitis. Br J Dermatol 2002;147: 76-83. 55-61.

95 Indian J Dermatol Venereol Leprol March-April 2005 Vol 71 Issue 2