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 » Introduction
 »  Materials and Me...
 » Results
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RESEARCH ARTICLE
Year : 2019  |  Volume : 51  |  Issue : 5  |  Page : 316-322
 

Randomized controlled trial of topical mupirocin versus mupirocin with sucralfate combination in chronic skin ulcers


1 Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
2 Department of Dermatology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India

Date of Submission05-Apr-2017
Date of Decision16-Oct-2019
Date of Acceptance21-Oct-2019
Date of Web Publication26-Nov-2019

Correspondence Address:
Prof. Avijit Hazra
Department of Pharmacology, Institute of Postgraduate Medical Education and Research, 244B Acharya J. C. Bose Road, Kolkata - 700 020, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_237_17

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 » Abstract 


OBJECTIVES: The objective of this study was to carry out a head-to-head comparison of topical sucralfate combined with mupirocin versus mupirocin alone in the treatment of chronic skin ulcers with respect to both effectiveness and safety.
MATERIALS AND METHODS: A parallel-group, open-label, randomized, controlled trial (CTRI/2015/12/006443) was carried out with patients suffering from skin ulcers of Wagner grading 1 or 2 persisting for over 4 weeks. Ninety-six patients were recruited in total, and the modified intention-to-treat analysis dataset included 44 participants treated with mupirocin 2% and 46 treated with combined mupirocin 2% and sucralfate 7% ointment. Both medications were applied topically thrice daily for 6 weeks. Ulcer area assessed using millimeter graph paper and wound infection score assessed on a three-point scale were effectiveness measures. Treatment-emergent adverse reactions that were reported by patients or observed by the investigators were recorded.
RESULTS: The median ulcer area was significantly reduced in the combined treatment group at the end of treatment. Clinically, 41.3% of the participants in the combined group showed complete ulcer healing at 6 weeks compared to 18.18% in the mupirocin alone group (P = 0.022). The wound infection score declined significantly from baseline by the end of 3 weeks of treatment in both the groups. The frequency of qualitative wound attributes, namely pain, discharge, and erythema, remained comparable between the groups except for discharge which disappeared completely from all remaining ulcers in the combined group but was still present in 11.36% of the participants treated with mupirocin alone (P = 0.025) at 6 weeks. Adverse events were few, all local, mild, and tolerable.
CONCLUSIONS: The wound healing effect of topical sucralfate adds to the antimicrobial effect of mupirocin toward the overall improvement of chronic skin ulcers. The effect of combined topical treatment needs comparison with other topical medications and wound healing strategies.


Keywords: Chronic skin ulcer, mupirocin, randomized controlled trial, sucralfate


How to cite this article:
Chatterjee S, Sen S, Hazra A, Das AK. Randomized controlled trial of topical mupirocin versus mupirocin with sucralfate combination in chronic skin ulcers. Indian J Pharmacol 2019;51:316-22

How to cite this URL:
Chatterjee S, Sen S, Hazra A, Das AK. Randomized controlled trial of topical mupirocin versus mupirocin with sucralfate combination in chronic skin ulcers. Indian J Pharmacol [serial online] 2019 [cited 2023 Jun 3];51:316-22. Available from: https://www.ijp-online.com/text.asp?2019/51/5/316/271634





 » Introduction Top


Chronic skin ulceration refers to loss of skin cover over an area persistent for more than 4 weeks without healing tendency or as a frequently recurrent lesion.[1] These ulcers affect the quality of life of patients and impose a major burden on the health-care system. Diabetes mellitus, venous or arterial insufficiency, trauma, malignancy, smoking, and superadded infections are the major predisposing factors behind chronic skin ulcers. The lower limb is most commonly affected. Moist skin ulcers provide a conducive environment for bacterial proliferation, and different microorganisms may be isolated from these lesions upon culture.[2] Microbiological exploration indicates that 80%–100% of leg ulcers may be colonized by bacteria.[2] The most common isolates are Staphylococcus aureus and Pseudomonas aeruginosa.[2]

Traditionally, various methods of treatment of chronic skin ulcers are in vogue. These include topical and systemic antibiotics, surgical debridement, skin grafting, compression stockings, and various types of dressings. Recent advances in management include modalities such as biological skin equivalents and other biological dressings, platelet-rich plasma, keratinocytes, and collagen products. Yet, chronic skin ulcer remains a challenge, particularly in the context of coexisting morbidities and lack of patient adherence or caregiver support.[3]

Topical antibiotics such as mupirocin, fusidic acid, neomycin, gentamicin, bacitracin and polymyxin B combination, and metronidazole are widely used for superficial skin ulceration with inflammation.[4] Faced with increasing bacterial resistance to antimicrobials, prescribing guidelines now indicate that antibacterial formulations should not be used for bacterial colonization alone but only in cases of clinically evident infection.

Sucralfate, chemically, is a basic aluminum complex of sucrose octasulfate. It has a stimulating effect on the expression of epidermal growth factor (EGF) and other cytokines involved in tissue repair processes.[5],[6] Experimental evidence exists to suggest that sucralfate may promote wound healing for instance in burn wounds.[7] Sucralfate also has antibacterial activity[8],[9] and has been successfully studied in decreasing pain and improving healing after hemorrhoidectomy, in ulceration and erosion of the perineal area, in ulceration of the vagina, in peristomal and perineal dermatoses, in moist desquamation during radiotherapy, in epidermolysis bullosa, and in burns of the second and third degrees.[10],[11],[12],[13],[14],[15],[16],[17] In a pilot study, it has shown benefit in full-thickness, venous stasis ulcers not healing after 8 weeks of conventional therapy.[5]

Mupirocin is also widely used in skin ulcers although its role is not firmly established.[2] The combination of topical sucralfate with topical mupirocin has been introduced in the Indian market and is being promoted for all types of lesions involving breach of the cutaneous barrier. In this background, our objective was to conduct a randomized controlled trial to assess if sucralfate–mupirocin combination is better than mupirocin alone in facilitating healing of chronic skin ulceration.


 » Materials and Methods Top


We conducted an open-label, parallel-group, randomized controlled trial in a single center, duly registered with the Indian Clinical Trials Registry (CTRI/2015/12/006443). The Institutional Ethics Committee permission was obtained beforehand, and written informed consent was provided by every participant at the time of recruitment.

Adult male and female patients, with skin ulcers, visiting the dermatology outpatient department (OPD) of a teaching hospital in eastern India between June 2014 and July 2015, were screened. Those with a single Grade 1 or Grade 2 ulcer according to Wagner grading system [Table 1] were included in the trial if ulcer duration was more than 4 weeks. Thorough clinical history was taken and clinical examination was done to exclude patients with vital organ disease, history of psychiatric illness, or substance abuse or on concomitant drugs that may affect ulcer healing. Those with immunocompromising disorders such as HIV/AIDS and uncontrolled diabetes were also excluded. Other exclusion criteria were ulcer duration over 6 months, decubitus ulcer, ulceration due to malignancy, ischemic ulcers, and hypersensitivity to formulations containing mupirocin or sucralfate.
Table 1: Wagner grading system for skin ulcers

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The test drug, topical mupirocin 2% with sucralfate 7% w/w in water-soluble ointment base, was donated, on request, by the manufacturer M/s Strassenburg Pharmaceuticals Ltd., Kolkata. The control drug was topical mupirocin 2% w/w in water-soluble ointment base, marketed by M/s Wallace Pharmaceuticals Ltd., Mumbai, and purchased from a local stockist. Both topical formulations were to be applied three times daily, in a quantity sufficient to cover the whole ulcer and up to 1 cm beyond the ulcer edge. Both ointments were dispensed in their original collapsible tube packs. The administration was open label, and participants were instructed to use the medication at home as advised. Local toileting of the wound was permitted, as deemed necessary by the supervising dermatologist. Local toileting and ointment application were demonstrated initially in the OPD, but subsequent application was unsupervised.

Ulcer area was assessed using millimeter graph paper and marker. The area was expressed in cm2. A wound infection score was ascertained by grading the following parameters on a 3-point (1 = absent, 2 = mild, and 3 = moderate to severe) scale – purulent discharge, nonpurulent discharge, erythema, tenderness, and local warmth – and then summing up the individual components. Three qualitative ulcer attributes – pain, discharge, and erythema – were also rated as present and absent. These outcome measures were recorded at baseline, at the end of 3 weeks, and finally, at the end of 6 weeks of treatment. Although the strategy of confirming wound infection through microbiological testing was considered at the planning stage, this was not done in the actual study for two reasons. A participating clinician felt that this is not a usual practice in a real-world setting where decision to start antimicrobial treatment is based on clinical judgment of the presence of infection. Second, chronic skin ulcers are colonized in the great majority of cases, so that microbiological swab cultures would be mostly positive anyway.

Adherence to treatment was assessed as “excellent” if not more than 10% of scheduled applications were missed, “good” if not more than 20% were missed, “fair” if not more than 30% were missed, and “poor” for any situation worse than fair. Patients were given a medication adherence sheet to fill up after application of each dose and to hand it over to the investigator at each follow-up visit for compliance assessment.

Participants in both the groups were permitted to receive systemic treatment for concomitant diseases provided these were not antimicrobials. Participants in whom potentially interfering medications, such as corticosteroids, were being used were not included. Furthermore, no other topical wound treatment was allowed, except for saline irrigation.

For sample size calculation, the proportion of participants showing at least 50% reduction in ulcer area by the end of 6 weeks of treatment was considered as the principal outcome. It was estimated that 38 participants would be required per group in order to detect a difference of 30% in the proportion of participants who attain this endpoint (assuming response rate would be 50% in the control arm) with power 80% and Type 1 error probability 5%. Assuming a drop-out rate of 15%, we proposed to recruit 45 participants in each group. nMaster 2.0 (Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India; 2011) software was utilized for sample size calculation. Randomization was in fixed blocks of 16, using a computer-derived random number list, to either mupirocin arm or sucralfate and mupirocin combination arm in 1:1 allocation ratio.

The analysis dataset comprised of the modified intention-to-treat (mITT) population, defined as all the participants randomized who completed at least one postbaseline follow-up. Data summary is by mean and standard deviation for numerical variables with Gaussian distribution, median, and interquartile range for numerical variables that are skewed and counts and percentages for categorical variables. Fisher's exact test or Pearson's Chi-square test has been utilized for intergroup comparison of categorical variables. Numerical variables were compared between the groups by Student's independent-samples t-test, if parametric, or by Mann–Whitney U-test, if of nonnormal distribution. Ulcer area and wound infection score changes have been compared within a group by Friedman's analysis of variance followed by post hoc comparison between any two time points when needed using Dunn's test. The resolution of qualitative wound attributes was compared between baseline and end of treatment by McNemar's Chi-square test. Analysis has been two-tailed, and the cutoff for statistical significance was P < 0.05 for all comparisons. GraphPad Prism 5 (San Diego, California: GraphPad Software Inc., 2007) and Statistica 6 (Tulsa, Oklahoma: StatSoft Inc., 2001) software were used for analysis.


 » Results Top


Totally 96 patients were recruited, and 44 patients in the mupirocin alone group and 46 in the mupirocin with sucralfate group were eligible for mITT analysis. The patient flow is depicted in a Consolidated Standards of Reporting Trials style flow diagram in [Figure 1].
Figure 1: Flow of participants in the study

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The baseline clinical characteristics and demographics of the study participants in the two arms are shown in [Table 2]. Evidently, the participants were well matched in baseline characteristics. The wound infection score was, however, higher by a small but statistically significant degree (P = 0.020) in the combined group.
Table 2: Comparison of baseline demographic features of the two study groups

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All the participants recruited had a single nonhealing ulcer. The foot was the predominant site of involvement as is evident from [Table 3]. The foot versus nonfoot distribution was not statistically significant by Fisher's exact test.
Table 3: Distribution of lesions according to their location in the two study groups

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The sequential change in ulcer characteristics is depicted in [Table 4]. The ulcer size decreased significantly in both arms from baseline to study end (P< 0.001). Though comparable between the groups at baseline and end of week 3, the median ulcer area was significantly reduced in the combined treatment group following 6 weeks of treatment. Clinically, complete ulcer healing by the end of 6 weeks was noted in 41.30% of the participants in the combination group against 18.18% in the mupirocin alone group (P = 0.022).
Table 4: Change in ulcer characteristics with time compared between study groups

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Within respective groups, the wound infection score declined significantly from baseline by the end of 3 weeks of treatment (P< 0.001). Further reduction at the end of 6-week treatment was not statistically significant. This indicates that with both regimens, the medication acted relatively rapidly in bringing about wound improvement by 3 weeks. The frequency of the qualitative wound attributes of pain, discharge, and erythema also improved significantly in both the groups (P< 0.001) from baseline to study end. They remained comparable between the groups [Table 4] except for discharge which disappeared completely from all remaining ulcers in the combined group but was still present in 11.36% of the participants treated with mupirocin alone (P = 0.025).

Both treatments were tolerated well. Only a few local adverse events were reported as is summarized in [Table 5]. None were severe and none required discontinuation of treatment. Adverse event counts did not differ significantly between the groups. Medication adherence was good to excellent in over 60% of the participants in the mupirocin alone group (poor 9.09%, fair 29.55%, good 22.73%, and excellent 38.64%) as well as in the combined treatment (poor 2.17%, fair 34.78%, good 30.43%, and excellent 32.61%) group. This difference too was not significant statistically. Presumably, the thrice-daily application precluded higher figures for good to excellent compliance in both the groups.
Table 5: Profile of adverse events in the two study groups

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 » Discussion Top


Many a times, skin ulcers refuse to heal despite cleansing and treatment even without obvious comorbid conditions to impede healing. Histological and biochemical modifications of the local milieu may contribute to this tendency of the ulcer to persist.[18]

As shown in recent studies, bacteria persist in many chronic wounds in adhesive, polymeric biofilms and induce chronic inflammation. This delays healing and makes the wounds more resistant to antibacterial treatment.[19] Therefore, it has been suggested that if wounds are seemingly properly treated but still fail to heal, then physicians need to consider prolonged use of topical antimicrobials.[19] The role of mupirocin ointment is established in case of wound colonization by Gram-positive bacteria, particularly against methicillin-resistant S. aureus.[20] However, a major issue with the use of topical antimicrobial agents is the risk of development of antimicrobial resistance and the consequent negative impact on ulcer healing. Furthermore, for wounds having some inflammatory process in its pathophysiology, the sole use of topical antibiotics may not be justified.

Many factors affect wound repair, including angiogenesis, immune response activation locally, and availability of growth factors, including EGF, basic fibroblast growth factor (bFGF), and transforming growth factors, in the local environment.[6] Local infiltration of granulocyte-macrophage colony-stimulating factor has been shown to facilitate the repair of chronic venous leg ulcers by cellular mechanisms such as inflammatory cell recruitment, epithelial cell migration, and keratinocyte proliferation.[6] Sucralfate, which is a complex salt of aluminum hydroxide and sucrose octasulfate, was introduced as a mucoprotective drug, effective by mouth, for acid peptic disease management. Sucralfate behaves as a cytoprotective drug in peptic ulcer disease. It has structural resemblance to heparin and binds with bFGF to stabilize it in a manner akin to heparin.[17] Sucralfate due to its anti-inflammatory properties can protect the skin against acute radiation reactions, such as those inherent in electron beam therapy.[21]

Thus, we hypothesized that sucralfate, with its wound healing property, may add to the effects of a topical antimicrobial preparation to accelerate the ulcer healing process as well as to reduce the time of exposure to topical antimicrobials. The results of this study indicate that the combination is better in terms of reduction of ulcer size at 6 weeks. However, the absence of significant difference in wound infection score suggests that sucralfate, while promoting wound healing, may not be adding further to whatever antimicrobial effect is provided by mupirocin. We did not find analogous studies with which to compare these results. Not all studies with sucralfate have been positive. A recently published placebo-controlled study of 14-day topical sucralfate treatment of pressure ulcers in hospitalized patients did not show any benefit.[22] However, we excluded such ulcers from the purview of our study, and this is to be borne in mind.

Our study has its share of limitations. Very severe ulcers were excluded. We undertook antimicrobial treatment without any microbiological investigations, although we ensured that the wounds showed clinically evident infection. Local toileting was not standardized, but cleansing with normal saline irrigation before the application of study medication was advised to all the participants. Termination of treatment at 6 weeks meant we were not in a position to judge median wound healing time.

Notwithstanding these limitations, we can say that this relatively short-term study justifies the combination of sucralfate and mupirocin as a topical treatment for chronic skin ulcers. The wound healing effect of topical sucralfate appears to add to the antimicrobial effect of mupirocin toward overall ulcer healing. Therefore, this combination can be advocated as an accompaniment to adequate local care in the management of nonhealing skin ulcers. It remains to be seen whether the combination has a differential effect with respect to ulcers at various locations. Furthermore, the effect of combined topical treatment needs comparison with other topical medications and wound healing strategies.

Acknowledgment

We are grateful to the Department of Science and Technology (DST), Government of India, for providing financial support to the Department of Pharmacology, IPGME and R, Kolkata, under its Fund for Improvement of S and T Infrastructure in Universities and Higher Educational Institutions (FIST) program. Departmental resources procured through this funding were utilized in the conduct of this study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Beheshti A, Shafigh Y, Zangivand AA, Samiee-Rad F, Hassanzadeh G, Shafigh N. Comparison of topical sucralfate and silver sulfadiazine cream in second degree burns in rats. Adv Clin Exp Med 2013;22:481-7.  Back to cited text no. 7
    
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Gupta PJ, Heda PS, Kalaskar S, Tamaskar VP. Topical sucralfate decreases pain after hemorrhoidectomy and improves healing: A randomized, blinded, controlled study. Dis Colon Rectum 2008;51:231-4.  Back to cited text no. 10
    
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Godhi AS, Ram P, Powar R. Efficacy of topical sucralfate versus silver sulfadiazine in the management of burns: A 1-year randomized controlled trial. J West Afr Coll Surg 2017;7:57-70.  Back to cited text no. 11
    
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Lyon CC, Stapleton M, Smith AJ, Griffiths CE, Beck MH. Topical sucralfate in the management of peristomal skin disease: An open study. Clin Exp Dermatol 2000;25:584-8.  Back to cited text no. 12
    
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Delaney G, Fisher R, Hook C, Barton M. Sucralfate cream in the management of moist desquamation during radiotherapy. Australas Radiol 1997;41:270-5.  Back to cited text no. 13
    
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Markham T, Kennedy F, Collins P. Topical sucralfate for erosive irritant diaper dermatitis. Arch Dermatol 2000;136:1199-200.  Back to cited text no. 14
    
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Lentz SS, Barrett RJ, Homesley HD. Topical sucralfate in the treatment of vaginal ulceration. Obstet Gynecol 1993;81:869-71.  Back to cited text no. 15
    
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Marini I, Vecchiet F. Sucralfate: A help during oral management in patients with epidermolysis bullosa. J Periodontol 2001;72:691-5.  Back to cited text no. 16
    
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Gravante G, Sorge R, Giordan N, Georgescu SR, Morariu SH, Stoicescu I, et al. Multicenter clinical trial on the performance and tolerability of the hyaluronic acid-collagenase ointment for the treatment of chronic venous ulcers: A preliminary pilot study. Eur Rev Med Pharmacol Sci 2013;17:2721-7.  Back to cited text no. 18
    
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]

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