Clinical Review & Education

JAMA Clinical Evidence Synopsis

Topical and Systemic Antimicrobial Therapy for Venous Leg Ulcers Susan O’Meara, PhD; Rachel Richardson, MA, MBA; Benjamin A. Lipsky, MD, FRCP

CLINICAL QUESTION Is treatment with topical or systemic antimicrobial agents associated with better venous leg ulcer healing compared with usual care (dressings and bandages without antimicrobials) or an alternative topical or systemic antimicrobial agent? BOTTOM LINE Available evidence, from underpowered pooled data, neither supports nor refutes an association of systemic antibiotic therapy with improved venous leg ulcer healing. Among topical antimicrobials, cadexomer iodine may be associated with better healing compared with usual care.

Venouslegulcersaffectupto1%ofadultsindevelopedcountries.1 These ulcersareassociatedwithsubstantialmorbidity,impairedhealth-related quality of life, and health care costs. Although all venous leg ulcers are bacteriallycolonizedandsomedevelopovertinfection,theassociation of these conditions with healing is unclear.1 Nevertheless, systemic or topical antibiotics or topical antiseptics are commonly used to treat infected (and sometimes uninfected) venous leg ulcers.2-5 These agents have the potential for adverse outcomes, and it is unknown whether theyimprovehealing.ThisJAMAClinicalEvidenceSynopsissummarizes a Cochrane review1 of randomized clinical trials (RCTs) evaluating topical or systemic antimicrobial agents used to manage venous leg ulcers.

Summary of Findings Two pooled RCTs (50 patients) found that ciprofloxacin was not associated with better venous leg ulcer healing at 12- to 16-week follow-up compared with usual care or placebo (8 of 31 patients [26%] Evidence Profile No. of randomized clinical trials: 45 Study years: Published 1979-2010 No. of patients: 4486 Men: 39% Women: 61% Race/ethnicity: Unavailable Age, mean (range): 68 years (23-99) Settings: Hospital inpatients, outpatient clinics, community Countries/regions: Africa, Asia, Europe, North America, Oceania, South America Comparisons: Systemicantibiotics(ciprofloxacin,trimethoprim,amoxicillin, or antibiotics selected by antibiotic sensitivity) vs usual care, placebo, or an alternative topical or systemic antimicrobial; topical antibiotics and antiseptics vs usual care and alternative antimicrobial agents Primary outcomes: Time to complete healing; complete healing during trial; change in wound area Secondary outcomes: Change in signs or symptoms of clinical infection; change in bacterial flora; development of bacterial resistance; ulcer recurrence; adverse effects; patient satisfaction; healthrelated quality of life; costs

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receiving ciprofloxacin vs 3 of 19 patients [16%] receiving usual care/ placebo; risk ratio [RR], 1.74 [95% CI, 0.57-5.30]; Figure). Single RCTs found no association with healing for antibiotics selected by antibioticsensitivitycomparedwithusualcare;trimethoprimcomparedwith placebo; ciprofloxacin compared with trimethoprim; or amoxicillin compared with topical povidone iodine. Limited data (2 pooled RCTs; 48 patients) suggest that antibiotic-resistant microorganisms emerge more frequently with ciprofloxacin treatment than without. In 4 pooled RCTs (212 patients), cadexomer iodine was associated with better healing rates compared with usual care at 4- to 12-week follow-up (35 of 106 patients [33%] receiving cadexomer iodine vs 16 of 106 patients [15%] receiving usual care; RR, 2.17 [95% CI, 1.30-3.60]) (Figure). In 2 pooled RCTs (134 patients), cadexomer iodine was associated with more adverse events (eg, pain or itching) than usual care, with adverse events in 14 of 68 patients (21%) receiving cadexomer iodine vs 3 of 66 patients (5%) receiving usual care (RR, 4.59 [95% CI, 1.40-15.05]). Silver-impregnated dressings were not associated with better healing at 4- to 12-week follow-up compared with usual care (4 pooled RCTs; 424 patients; Figure). There was no difference in adverse event rates between the groups. Single RCTs demonstrated no association with better healing for cadexomer iodine compared with silver dressing; povidone iodine compared with usual care; or mupirocin compared with placebo.

Discussion Current evidence, albeit limited, does not support that systemic antibiotics or topical antiseptics (except cadexomer iodine) are associated with improved healing of venous ulcers. Given their potential for adverse effects, systemic antibiotics should not be routinely prescribed for venous leg ulcers. Treatment with cadexomer iodine should be considered in light of both potential benefits and adverse effects. Limitations

Although searches were updated through May 2013, the most recent eligible RCT was published during 2010. All analyses were statistically underpowered. Most RCTs had high or unclear risk of bias; most had a short follow-up (ⱕ16 weeks); and few reported infectionrelated baseline and outcome variables.

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JAMA Clinical Evidence Synopsis Clinical Review & Education

Figure. Risk Ratios for Complete Venous Leg Ulcer Healing Among Patients Treated With Systemic or Topical Antimicrobial Agent vs Usual Care Antimicrobial Treatment

Usual Care

Events, Total No. of Events, Study or Subgroup No. Participants No. Ciprofloxacin vs usual care or placebo (12- to 16-week follow-up) Huovinen, 1994a 5 13 3 Valtonen, 1989a 3 18 0 Subtotal 8 31 3 Cadexomer iodine vs usual care (4- to 12-week follow-up) 16 33 7 Laudanska, 1988a Lindsay, 1986a 4 14 1 Ormiston, 1985a 12 31 7 Steele, 1986a 3 28 1 Subtotal 35 106 16 Silver-impregnated dressing vs usual care (4- to 12-week follow-up) 17 21 10 Dimakakos, 2009b Jørgensen, 2005c 5 65 5 Michaels, 2009d 62 107 59 Wunderlich, 1991a 6 20 2 Subtotal 90 213 76

Favors Usual Care

Risk Ratio (95% CI)

Total No. of Participants

Favors Antimicrobial Treatment

Weight, %

11 8 19

1.41 (0.43-4.61) 3.32 (0.19-57.61) 1.74 (0.57-5.30)

82.7 17.3 100.0

33 14 30 29 106

2.29 (1.08-4.82) 4.00 (0.51-31.46) 1.66 (0.76-3.64) 3.11 (0.34-28.12) 2.17 (1.30-3.60)

43.5 6.2 44.2 6.1 100.0

21 64 106 20 211

1.70 (1.04-2.79) 0.98 (0.30-3.24) 1.04 (0.82-1.32) 3.00 (0.69-13.12) 1.17 (0.95-1.45)

13.1 6.6 77.7 2.6 100.0 0.1

1.0

10

100

Risk Ratio (95% CI)

Source: Data adapted with permission from Wiley.1 Risk ratio estimates were plotted on a log scale. Control treatment was most often usual care (cleansing, dressings, and bandages without antimicrobial therapy). a

No mention or unclear report of ulcer infection at baseline.

Comparison of Findings With Current Practice Guidelines

Guidelines from the Association for the Advancement of Wound Care (AAWC)6 and the Scottish Intercollegiate Guidelines Network (SIGN)7 suggest using systemic antibiotics only for clinically infected (ie, inflamed) wounds. Of 5 RCTs evaluating systemic antibiotics, 1 restricted enrollment to uninfected ulcers (postulating improved healing by inhibiting ulcer bacterial contamination) and the others did not report baseline ulcer infection status. Among topical agents, the AAWC recommends using either cadexomer iodine or silver.6 Consistent with the findings in the Cochrane review,1 the SIGN guidance does not recommend using silver ARTICLE INFORMATION Author Affiliations: School of Healthcare, Baines Wing, University of Leeds, England (O’Meara); Cochrane Wounds Group, Department of Health Sciences, University of York, York, England (Richardson); Department of Medicine, University of Washington, Seattle (Lipsky); Department of Infectious Diseases, University of Geneva, Geneva, Switzerland (Lipsky); Green Templeton College, University of Oxford, Oxford, England (Lipsky). Corresponding Author: Susan O’Meara, PhD, School of Healthcare, Baines Wing, University of Leeds, Leeds LS2 9JT, UK ([email protected]). Section Editor: Mary McGrae McDermott, MD, Senior Editor. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Sponsor: This work was funded by the National Institute for Health Research (NIHR).

b

Eligible patients had clinically infected ulcers at baseline.

c

Eligible patients had ulcers described as “critically colonized.”

d

Patients using systemic antibiotics were excluded.

and notes insufficient evidence to recommend topical mupirocin or peroxides. Unlike these findings, SIGN does not recommend cadexomer iodine.7 The baseline ulcer infection status in RCTs evaluating topical antimicrobials varied, but was often either not reported or reported unclearly (Figure). Areas in Need of Future Study

Larger, better-quality trials are needed that include longer followup, clinically relevant outcomes, and cost-effectiveness analyses. These trials should report on ulcer infection status (using an accepted definition)5 at baseline.

Role of the Sponsor: The NIHR had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and decision to submit the manuscript for publication. The NIHR was involved in the review and approval of the manuscript prior to publication. Disclaimer: The views expressed in this article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

3. Öien RF, Forssell HW. Ulcer healing time and antibiotic treatment before and after the introduction of the Registry of Ulcer Treatment. BMJ Open. 2013;3(8):e003091. 4. Lorimer KR, Harrison MB, Graham ID, Friedberg E, Davies B. Venous leg ulcer care. J Wound Ostomy Continence Nurs. 2003;30(3):132-142.

REFERENCES

5. Zenilman J, Valle MF, Malas MB, et al. Chronic venous ulcers. http://www.effectivehealthcare.ahrq .gov/ehc/products/367/1736/venous-ulcerstreatment-executive-erratum-140127.pdf. Accessed May 22, 2014.

1. O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG, Martyn-St James M, Richardson R. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database Syst Rev. 2014;1(1):CD003557.

6. Association for the Advancement of Wound Care (AAWC) venous ulcer guideline. http://www .guideline.gov/content.aspx?id=36081. Accessed May 22, 2014.

2. Howell-Jones RS, Wilson MJ, Hill KE, Howard AJ, Price PE, Thomas DW. A review of the microbiology, antibiotic usage, and resistance in chronic skin wounds. J Antimicrob Chemother. 2005;55(2):143149.

7. Scottish Intercollegiate Guidelines Network. Management of chronic venous leg ulcers. http: //www.sign.ac.uk/pdf/sign120.pdf. Accessed May 22, 2014.

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Topical and systemic antimicrobial therapy for venous leg ulcers.

Is treatment with topical or systemic antimicrobial agents associated with better venous leg ulcer healing compared with usual care (dressings and ban...
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