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Table of Contents 
THERAPEUTIC ROUND
Year : 2013  |  Volume : 58  |  Issue : 2  |  Page : 117-123
Evaluation of efficacy, safety, and tolerability of fixed dose combination (FDC) of halometasone 0.05% and fusidic acid 2% w/w topical cream versus FDC of betamethasone valerate 0.12% and neomycin sulphate 0.5% w/w topical cream in the treatment of infected eczematous dermatosis in Indian subjects: A randomized open-label comparative phase III multi-centric trial


1 Department of Dermatology and Venerology, Osmania Medical College and Hospital, Hyderabad, Andhrapradesh, India
2 Department of Dermatology, Dr. SMCSI Medical College, Trivandrum, Kerala, India
3 Department of Dermatology, King George Hospital, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India
4 Department of Dermatology, LTM Medical College and LTM General Hospital, Sion, Mumbai, Maharashtra, India
5 Department of Skin and STD, Deccan College of Medical Sciences, Hyderabad, Andhrapradesh, India
6 Department of Dermatology KMC Hospital, Mangalore, Karnataka, India
7 Global Medical Affairs, Dr. Reddy's Laboratories, Hyderabad, India

Date of Web Publication5-Mar-2013

Correspondence Address:
Mariam Philip
Department of Dermatology, Dr. SMCSI Medical College, Trivandrum, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.108041

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   Abstract 

Aim: To evaluate the efficacy and safety of fixed drug combination (FDC) halometasone 0.05% and fusidic acid 2% (group A) vs FDC betamethasone 0.12% and neomycin sulfate 0.5% cream (group B) in acute or chronic infected eczematous dermatosis, through a randomized open-label, comparative, multicentric study. Materials and Methods: A total of 152 patients were randomized to either Group A or Group B. EASI (Eczema Area and Severity Index), IGA (Investigator's global assessment), scale for severity of eczema, pruritus, and safety parameters were assessed at baseline, Day 5/Day 10, Day 10/20, and Day 20/Day 30 for acute/chronic cases. Skin swabs were tested at screening, Day 10, and end of the study. Results: Staphylococcus aureus was the frequently encountered causative agent. There was a significant reduction within the study groups in EASI, IGA scales for severity of eczema, pruritus at various visits, compared to baseline. At the end of study, 83.87% in group A and 65.71% in group B were culture negative. Cure rate was 54.28% and 50% in group A and B, respectively. Five adverse events were reported in five patients, of which three patients withdrew from the study. Conclusion: Halometasone 0.05% and Fusidic acid 2% cream is effective, safe, well tolerated with comparable efficacy to the comparator in the treatment of acute and chronic infected eczematous dermatosis.


Keywords: Betamethasone 0.12% and neomycin sulfate 0.5% cream, eczema area and severity index, halometasone 0.05% and fusidic acid 2% cream, investigator′s global assessment scale for severity of eczema, pruritus


How to cite this article:
Pratap DV, Philip M, Rao NT, Jerajani HR, Kumar SA, Kuruvila M, Moodahadu LS, Dhawan S. Evaluation of efficacy, safety, and tolerability of fixed dose combination (FDC) of halometasone 0.05% and fusidic acid 2% w/w topical cream versus FDC of betamethasone valerate 0.12% and neomycin sulphate 0.5% w/w topical cream in the treatment of infected eczematous dermatosis in Indian subjects: A randomized open-label comparative phase III multi-centric trial. Indian J Dermatol 2013;58:117-23

How to cite this URL:
Pratap DV, Philip M, Rao NT, Jerajani HR, Kumar SA, Kuruvila M, Moodahadu LS, Dhawan S. Evaluation of efficacy, safety, and tolerability of fixed dose combination (FDC) of halometasone 0.05% and fusidic acid 2% w/w topical cream versus FDC of betamethasone valerate 0.12% and neomycin sulphate 0.5% w/w topical cream in the treatment of infected eczematous dermatosis in Indian subjects: A randomized open-label comparative phase III multi-centric trial. Indian J Dermatol [serial online] 2013 [cited 2019 Sep 22];58:117-23. Available from: http://www.e-ijd.org/text.asp?2013/58/2/117/108041

What was known? Use of steroids and antibacterial agents topically or systemically in the management of infected eczema is recommended in clinical practice. Various combinations of steroid and antibacterial agents as combination product are available in the market. Halometasone, fusidic acid, and betamethasone are frequently used by dermatologists in the management of eczema.



   Introduction Top


Eczema is a pruritic, papulovesicular skin condition, categorized to acute phase which is associated with erythema and oedema, and chronic phase in which lichenification and scaling are the main features. [1] It reflects morphological changes in the skin occurring due to a complex interaction between genetic and environmental factors, inducing immunological and biochemical changes, resulting in pruritic, inflammatory lesions. With damaged protective skin function and disturbance of quantity and quality of skin lipids, patients with eczema may develop secondary bacterial infections. [2] In 90% of patients, Staphylococcus aureus is the infecting organism. [3]

Changes in the environment are one of the leading causes resulting in an increase in the incidence of eczema in developing countries. [4] In developed countries, 15 to 20% of the population is affected by eczema. [5] Religious, [6] environmental factors, variation in structure and function of skin in different geographical regions, and personal hygiene can affect the clinical presentation and also determine the chance of secondary infection. Due to the increasing emergence of methicillin-resistant S. aureus, treatment of secondary infection of eczema is challenging. [5] Data on the disease impact of eczema on Indian population and health reforms are not available. Chougule and Thappa [7] have reported the frequency of eczema in lower leg and foot as 2.5 per 1000 out patients and infected eczema in 5% patients in their study population. Early recognition and treatment is crucial to prevent further complications. Topical corticosteroids, topical and systemic immunosuppressants, emollients, and antihistamines are used frequently in the management of eczema.

Halometasone 0.05% is a well-tolerated synthetic tri-halogenated corticosteroid with pronounced anti-inflammatory, anti-exudative, anti-epidermoplastic actions along with anti-allergic, and anti-pruritic properties which has been utilized in the management of various clinical conditions. It is often used in the symptomatic treatment of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. It is well tolerated and its good safety profile [8] allows long-term use. [9] Treatment with halometasone and antibacterial agent (triclosan) was found to be superior with higher success and cure rate along with good safety profile; an early cure (in less than 20 days) compared to other steroid and antibiotic combination. [10],[11],[12] Safety, efficacy, and tolerability of Halometasone in Indian patients with acute and chronic eczema have been documented. [13]

Fusidic acid is a potent antibacterial agent, either bacteriostatic or bactericidal depending on the size of inoculum and inhibits nearly all strains of S. aureus. Topical application of fusidic acid was safe and effective in bacterial skin infections. [14] Resistance to fusidic acid is low and short lived. Fusidic acid has been successfully used along with other corticosteroids (betamethasone 1% and hydrocortisone 1%) wherein the antibacterial effect of fusidic acid was not being affected even in the presence of steroids. It was also effective in infected eczema as it aims to treat both inflammation and infection. [15]

Halometasone 0.05% with fusidic acid 2% topical cream combines the anti-inflammatory and antipruritic effects of halometasone with the potent topical antibacterial action of fusidic acid. We selected halometasone with betamethasone as both are having comparable activity with a good safety profile. [10],[16]

We evaluated the efficacy and safety of fixed dose combination (FDC) of halometasone 0.05% and fusidic acid 2% vs FDC betamethasone 0.12% and neomycin sulfate 0.5% cream in adult Indians with acute and chronic infected eczematous dermatosis.


   Materials and Methods Top


Patients

One hundred and ninety two patients with acute or chronic eczema were screened and 152 eligible subjects were enrolled into the study which was conducted between March 2009 and August 2009.

Methodology

This study was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki (October 2000) and in compliance with Schedule Y. All necessary study documents were approved by the Drugs Controller General of India and the Institutional Ethics committees prior to study initiation. Written informed consent was obtained from each patient prior to screening. This study was registered with clinical trial registry of India (CTRI) on 06/Apr/2009 (Registration No: CTRI/2009/091/000039).

Adult patients aged >18 years, with infected eczematous dermatitis who met the selection criteria, were screened, enrolled, and randomized to either Group A (halometasone and fusidic acid cream) or Group B (betamethasone and neomycin cream) using a computer-generated randomization list. Patients were diagnosed to have either acute or chronic eczema based on history and clinical features. [17] Those with history of hypersensitivity to the drug or any of the stated excipients, uncontrolled diabetes mellitus, other concomitant diseases including other skin infections and unwilling to give written informed consent were not screened. Patient in need of any form of treatment which influences the healing of the lesion such as topical treatment other than trial preparation, topical radiation therapy, systemic medication with antibiotics, antimicrobials, antihistamines, cytostatics, corticosteroids or ACTH, pregnant and nursing women, and patients with clinically significant cardiovascular, hematological, pancreatic, metabolic, neurological, or clinically significant laboratory abnormalities which in the judgment of investigator, would interfere with patient participation in the study or evaluation of patient's response to therapy were excluded from screening.

Safety evaluations, including a physical examination, clinical laboratory tests including hematological, biochemical tests, urine examination (including urine pregnancy tests in females of child bearing potential), and cardiovascular evaluation were performed at screening and at the end of therapy. Skin swab test for bacterial culture and sensitivity was done at screening to confirm bacterial presence, on Day 10 and at the end of the study to assess the improvement. Severity of eczema was assessed based on IGA (Investigator's global assessment) scale (grades 0-3).

Enrolled patients with acute eczema were treated for 20 days and those with chronic eczema for 30 days. Medication was applied twice a day without any occlusive bandage to the eczematous skin, using enough to cover the entire affected area lightly. Patients with acute eczema were assessed on Day 5, Day 10, and Day 20, whereas those with chronic eczema on Day 10, Day 20, and Day 30 of treatment. Efficacy parameters like EASI (Eczema Area and Severity Index), IGA scale for severity of eczema, and pruritus severity grades (grades 0-3) and safety parameters were assessed and recorded at baseline, at subsequent visits, and at the end of therapy. Patients were observed for adverse events throughout the study.

The response to treatment was defined as Cure, Improvement, and Failure based on the IGA scores at the end of therapy.

If a patient was withdrawn/dropped out prematurely, the safety evaluations specified for the final visit were performed.

Statistics

Evaluation of study population was on an intention-to-treat* basis and LOCF (last observation carried forward) was considered for efficacy variables. Student's t test was used to compare demographic characteristics and baseline laboratory parameters of study groups.

Comparison of means of continuous variables was done using two-sided paired and unpaired t-test. Wilcoxon rank sum test and Chi-Square test were used for categorical variables.

EASI score was analyzed using unpaired t test with 95% CI (confidence interval). Results of skin swab test was analyzed using Chi-square test and presented as frequencies and percentages. Change in severity of eczema and pruritus were analyzed using Wilcoxon Rank sum test. Result of therapeutic response was analyzed in frequencies and percentages.

Adverse Events (Clinical) were coded using MedDRA version 10.0. Biochemical Parameters were assessed by paired t-test technique.

Concomitant Medication was categorized by generic name and summarized using frequency count.


   Results Top


Of 152 enrolled patients, 62 in group A and 65 in group B completed the study. Fifteen patients in group A and 10 in group B dropped out at different stages during treatment [Figure 1]. There was no statistical difference between the two groups demographically at baseline.
Figure 1: Study flow chart

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Thirty seven patients in group A and 29 patients in group B received prior treatment either with emollients or steroids. The most commonly used corticosteroid was betamethasone, used either alone or in FDCs.

Efficacy results

Primary efficacy analysis


Change in Eczema Area and Severity Index Score

There was a statistically significant reduction (P0 < 0.001) in EASI at visits 2, 3, and 4 compared to baseline within the study groups, but without any difference between the groups [Table 1].
Table 1: Dispersion of EASI in study population at different visits


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Two patients in group B and one patient in group A showed no change in EASI score at visit 4 compared to baseline.

/Cure of Infection

At baseline, 93.5% in group A and 81.3% in group B were positive for S. aureus. Other infecting organisms were Klebsiella, E. coli, Streptococcus, and skin commensals.

A statistically significant reduction (P < 0.05) in culture positivity was observed in the subsequent visits, with only 33 (25.39%) patients being culture positive at the end of study [Table 2].
Table 2: Bacterial culture report


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Secondary efficacy

Change in severity of eczema

There was a significant reduction (P0 < 0.001) in IGA scales for severity of eczema at visits 2, 3, and 4 compared to baseline within the study groups, but without any difference between the groups [Table 3].
Table 3: Dispersion of IGA eczema scales in study population during the study


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On day 10, improvement was seen in 53.85% of mild to moderately severe cases in group A compared to 46.15% patients in group B.

At the end of therapy, 52.75% patients with mild to moderately severe eczema in group A showed statistically significant ( P < 0.05) improvement compared to 47.25% in group B.

in severity of Pruritus

was a significant reduction ( P < 0.001) in pruritus severity score at visits 2, 3, and 4 compared to baseline within the study groups, but there was no difference between the groups [Figure 2].
Figure 2: Change in Mean pruritic severity score with treatment. There was no statistically significant difference in pruritus severity score at any of the visits between study drug and comparator

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Severity of pruritus was reduced in 72.35% patients in group A and 69.68% patients in group B at the end of therapy compared to baseline.

Thirty seven (48.05%) patients in group A and 34 (45.33%) patients in group B were relieved of itching at the end of treatment. At baseline, 89.61% in group A and 89.33% in Group B had pruritus of severity more than grade I; 31.42% and 35.71% of patients achieved grade 1 or mild pruritus at the end of therapy in group A and group B, respectively.

Treatment response

In mild to moderately severe eczema, an early symptomatic relief was seen in 53.85% patients in group A compared to 46.15% in group B on day 10. At the end of study, 54.28% patients were cured in group A compared to 50% in group B [Figure 3]. [Figure 4] and [Figure 5] show the clinical response before and after treatment.
Figure 3: Treatment response at the end of therapy

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Figure 4: Treatment response at the end of therapy (a) Pre treatment (b) Post treatment

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Figure 5: Treatment response at the end of therapy (a) Pre treatment (b) Post treatment

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Adverse events

Both topical preparations were well tolerated by the study population.

Five adverse events (AEs) in five patients [Table 4], three from group A and two from group B, were reported and none was a serious adverse event.

There was no statistically significant change in the laboratory parameters at the end of study when compared to baseline except in lymphocyte count in group A, which was clinically insignificant.
Table 4: Adverse events


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Two patients in group B and one patient in group A were withdrawn from the study due to AEs. One of these patients in group B developed auto-sensitization (diagnosed clinically) for which the study drug was stopped and patient was treated with systemic steroid and antihistamines. Another patient developed ulcer at the site and the study drug was stopped. One patient in group A developed dissemination on face and limbs leading to discontinuation of study medication.


   Discussion Top


Treatment of eczema is challenging due to many reasons like poor treatment compliance, misdiagnosis, infection, and development of contact dermatitis. Emollients and moisturizers along with preventive measures are the first choice of treatment and use of steroids being the next. [18] If left untreated, bacteria (S. aureus) colonize the affected area, leading to further complications. Topical corticosteroids have been successful in reducing the density of S. aureus in previous study. [19]

Halometasone with its rapid onset of action, very good efficacy, tolerability, and good safety profile is considered for the treatment of eczematous skin lesions. Earlier studies have shown that combination of halometasone and antibacterial agents/fusidic acid is safe and effective in the treatment of eczema. [11],[12] Studies have shown that combination of halometasone and fusidic acid is safe and effective [19] and our study confirms this in Indian population. This FDC was well tolerated among our patients, as only one AE was reported in the group A. Contact dermatitis is one of the reason for not using neomycin in this clinical condition, but it was not reported in our study. However, one patient developed auto-sensitization in group B, which could be attributable to neomycin component.

Literature mentions S. aureus as the most common infecting organism, [2],[3] and our study supports the same. Culture negativity was achieved better with halometasone and fusidic acid cream (83.87%) than betamethasone and neomycin cream (65.71%) which was statistically significant (P < 0.05). A statistically significant (P < 0.05) number of patients with mild to moderate eczema showed improvement with halometasone and fusidic acid cream (52.75%) than with comparator (47.25%). Treatment response (54.28%) observed in our study was comparable to a study by LI-Min et al. in which the cure and effective rate with halometasone and fusidic acid was 50.8% and 90.5%, respectively. [20]

In our study, early treatment response, as early as day 10 was seen in mild to moderately severe cases of eczema in patients treated with halometasone and fusidic acid (53.85%) compared to 46.15% in betamethasone plus neomycin group. Culture report on day 10 showed culture negativity in few patients in both groups, but clinically these patients continued to have symptoms of bacterial infection. Hence, the treatment was continued till the end of the study. Moreover, we did not see any development of resistance to the FDC in our study population.

Data on the combination product of halometasone and fusidic acid is limited, literature search yielding only one study by LI-Min et al. wherein both agents were used alternatively, and our study is the first to study the effects of this FDC on Indian population. This was an open-labeled study; hence, we recommend comparative, double blind studies with other routinely used agents in eczema. As resistance to fusidic acid has been exhibited by S. aureus, [21] judicial use of this preparation is advocated.


   Conclusion Top


Combination of halometasone 0.05% and fusidic acid 2% cream is effective and well tolerated in the treatment of both acute and chronic infected eczema with a comparable efficacy to betamethasone 0.12% and neomycin sulfate 0.5% cream. By virtue of its efficacy and safety coupled with early onset of relief, halometasone and fusidic acid would be a suitable therapeutic option in patients with infected eczematous dermatosis.


   Acknowledgements Top


This study was supported by Dr. Reddy's Laboratories Ltd, Hyderabad India.

We thank Dr. Paul A D, Dr. Binny Krishnankutty for their guidance, Mr. Gijo Thomas, Mr. Dennis Thomas, and Mr. Mohan for their support during the conduct of study. We thank Mr. Prabhakar Rao for supporting us in literature search.

 
   References Top

1.Thappa DM. Eczema. In: Thappa DM, editor. Textbook of dermatology, venereology and leprology 3 rd ed. India: Elsevier (Publishers); 2009. p. 131-45.  Back to cited text no. 1
    
2.Arslanagic N, Arslanagic R. Atopic dermatitis and staphylococcus aureus. Med Arh 2004;58:363-5.  Back to cited text no. 2
    
3.Gong JQ, Lin L, Lin T, Hao F, Zeng FQ, Bi ZG, et al. Skin colonization by staphylococcus aureus in patients with eczema and atopic dermatitis and relevant combined topical therapy: A double-blind multicentre randomized controlled trial. Br J Dermatol 2006;155:680-7.  Back to cited text no. 3
    
4.Schram ME, Tedja AM, Spijker R, Bos JD, Williams HC, Spuls PI. Is there a rural/urban gradient in the prevalence of eczema? A systematic review. Br J Dermatol 2010;162:964-73.  Back to cited text no. 4
    
5.Patricia AT. Eczema and infection. Pediatr Infect Dis J 2008;27:551-2.  Back to cited text no. 5
    
6.Ghosh SK, Bandyopadhyay D, Chatterjee G, Saha D. The 'holi'dermatoses: Annual spate of skin diseases following the spring festival in India. Indian J Dermatol 2009;54:240-2.  Back to cited text no. 6
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7.Chougule A, Thappa DM. Patterns of lower leg and foot eczema in south India. Indian J Dermatol Venereol Leprol 2008;74:458-61.  Back to cited text no. 7
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8.Yawalkar SJ, Macarol V, Montanari C. An overview of international clinical trials with halometasone ointment in chronic eczematous dermatoses. J Int Med Res 1983;11:13-20.  Back to cited text no. 8
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9.Weitgasser H, Yawalkar SJ. Clinical evaluation on the long-term use of halometasone ointment in chronic eczema and psoriasis. J Int Med Res 1983;11:34-7.  Back to cited text no. 9
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10.Weitgasser H, Schindléry C, Macarol V. A comparative multicentre trial of halometasone/triclosan cream and betamethasone dipropionate/gentamycin sulphate cream in the treatment of infected acute eczematous dermatitis. J Int Med Res 1983;11:43-7.  Back to cited text no. 10
    
11.Aliaga A, Castells A, Kriznik D, Laloseviæ J, Marrón J, Moragas J, et al . An overview of two comparative multicentre trials with halometasone/triclosan cream in acute superficial bacterial skin infections. J Int Med Res 1983;11:53-7.  Back to cited text no. 11
    
12.Abdel AH, Abdallah MA, Iskandar IO, Salama NR. Clinical experience with 0.05% halometasone/1% triclosan cream in the treatment of acute infected and infection-prone eczema in Egypt. J Int Med Res 1987;15:383-90.  Back to cited text no. 12
    
13.Jerajani HR, Kumar AS, Kuruvila M, Nataraja HV, Philip M, Pratap DV. Efficacy and safety of topical halometasone in eczematous dermatoses in Indian population: An open label, noncomparative study. Indian J Dermatol 2011;56:652-6.  Back to cited text no. 13
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14.Guo-xing Z, Wei L, Huai-qiu H, Chun L, Kang Z, Hao-qiang L. 2% Fusidic Acid Cream in the Treatment of Bacterial Infected Skin Diseases: A Multicenter Clinical Observation on Efficacy and Safety. Chin J Dermatovenereol 2007-05. Available from: http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZBFX200705013.htm. [Last cited on 2011 July 09].  Back to cited text no. 14
    
15.Schöfer H, Simonsen L. Fusidic acid in dermatology: An updated review. Eur J Dermatol 2010;20:6-15.  Back to cited text no. 15
    
16.Schuppli R, Dressler H, Yawalkar SJ, Weirich EG. Comparative clinical trial of a new trihalogenateddermatocorticoid (halometasone) versus betamethasone dipropionate. Z Hautkr 1983;58:230-7.  Back to cited text no. 16
    
17.James WD, Berger TG, Elston DR. Atopic dermatitis, eczema and noninfectious immunodeficiency disorders. In: James WD, Berger TG, Elston DR, editors. Andrews' diseases of the skin-Clinical dermatology, 10 th ed. Vol. 5. Canada: Elsevier; 2006. p. 69-91.  Back to cited text no. 17
    
18.Kurian A, Barankin B. Therapeutic moisturizers in eczema and xerosis management. Skin Ther Lett 2010;5:1-3.  Back to cited text no. 18
    
19.Nilsson EJ, Henning CG, Magnusson J. Topical corticosteroids and staphylococcus aureus in atopic dermatitis. J Am Acad Dermatol 1992;27:29-34.  Back to cited text no. 19
    
20.LI Min, FU Dan-dan, GUO Jin-mei, LIU Dong, LI Su-juan, TIAN Zhong-wei. Observation of clinical efficacy on subacute or chronic eczema treated with halometasone cream joint fusidic acid cream. J Pract Dermatol 2009-03. Available from: http://en.cnki.com.cn/Article_en/CJFDTOTAL-SYPF200903010.htm. [Last accessed on 2011 July 09].  Back to cited text no. 20
    
21.Shah M, Mohanraj M. High levels of fusidic acid-resistant Staphylococcus aureus in dermatology patients. Br J Dermatol 2003;148:1018-20.  Back to cited text no. 21
    

What is new? Though these two products are being used separately to treat eczema, this is the first time that this combination is formulated and used in India; this is the first study in India to evaluate this product in Indian population


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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