Antibiotics and antiseptics for venous leg ulcers: Cochrane systematic review
Venous leg ulcers are a type of chronic wound affecting up to 1% of adults in developed countries at some point during their lives. Many of these wounds are colonised by bacteria or show signs of clinical infection. The presence of infection may delay ulcer healing. Two main strategies are used to prevent and treat clinical infection in venous leg ulcers: systemic antibiotics and topical antibiotics or antiseptics.
The objective of this review was to determine the effects of systemic antibiotics and topical antibiotics and antiseptics on the healing of venous ulcers.
In May 2013, for this second update, we searched the Cochrane Wounds Group Specialised Register (searched 24 May 2013); the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4); Ovid MEDLINE (1948 to Week 3 May 2013); Ovid MEDLINE (In-Process & Other Non-indexed Citations, 22 May 2013); Ovid EMBASE (1980 to Week 20 2013); and EBSCO CINAHL (1982 to 17 May 2013). No language or publication date restrictions were applied.
Randomised controlled trials (RCTs) recruiting people with venous leg ulceration, evaluating at least one systemic antibiotic, topical antibiotic or topical antiseptic that reported an objective assessment of wound healing (e.g. time to complete healing, frequency of complete healing, change in ulcer surface area) were eligible for inclusion. Selection decisions were made by two review authors while working independently.
Data collection and analysis
Information on the characteristics of participants, interventions and outcomes was recorded on a standardised data extraction form. In addition, aspects of trial methods were extracted, including randomisation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data and study group comparability at baseline. Data extraction and validity assessment were conducted by one review author and were checked by a second. Data were pooled when appropriate.
Forty-five RCTs reporting 53 comparisons and recruiting a total of 4486 participants were included, Many RCTs were small, and most were at high or unclear risk of bias. Ulcer infection status at baseline and duration of follow-up varied across RCTs. Five RCTs reported eight comparisons of systemic antibiotics, and the remainder evaluated topical preparations: cadexomer iodine (11 RCTs reporting 12 comparisons); povidone-iodine (six RCTs reporting seven comparisons); peroxide-based preparations (four RCTs reporting four comparisons); honey-based preparations (two RCTs reporting two comparisons); silver-based preparations (12 RCTs reporting 13 comparisons); other topical antibiotics (three RCTs reporting five comparisons); and other topical antiseptics (two RCTs reporting two comparisons). Few RCTs provided a reliable estimate of time to healing; most reported the proportion of participants with complete healing during the trial period.
More participants were healed when they were prescribed levamisole (normally used to treat roundworm infection) compared with placebo: risk ratio (RR) 1.31 (95% CI 1.06 to 1.62). No between-group differences were detected in terms of complete healing for other comparisons: antibiotics given according to antibiogram versus usual care; ciprofloxacin versus standard care/placebo; trimethoprim versus placebo; ciprofloxacin versus trimethoprim; and amoxicillin versus topical povidone-iodine.
Topical antibiotics and antiseptics
Cadexomer iodine: more participants were healed when given cadexomer iodine compared with standard care. The pooled estimate from four RCTs for complete healing at four to 12 weeks was RR 2.17 (95% CI 1.30 to 3.60). No between-group differences in complete healing were detected when cadexomer iodine was compared with the following: hydrocolloid dressing; paraffin gauze dressing; dextranomer; and silver-impregnated dressings.
Povidone iodine: no between-group differences in complete healing were detected when povidone-iodine was compared with the following: hydrocolloid; moist or foam dressings according to wound status; and growth factor. Time to healing estimates for povidone-iodine versus dextranomer, and for povidone-iodine versus hydrocolloid, were likely to be unreliable.
Peroxide-based preparations: four RCTs reported findings in favour of peroxide-based preparations when compared with usual care for surrogate healing outcomes (change in ulcer area). There was no report of complete healing.
Honey-based preparations: no between-group difference in time to healing or complete healing was detected for honey-based products when compared with usual care.
Silver-based preparations: no between-group differences in complete healing were detected when 1% silver sulphadiazine ointment was compared with standard care/placebo and tripeptide copper complex; or when different brands of silver-impregnated dressings were compared; or when silver-impregnated dressings were compared with non-antimicrobial dressings.
Other topical antibiotics: data from one RCT suggested that more participants healed at four weeks when treated with an enzymatic cleanser (a non-antibiotic preparation) compared with a chloramphenicol-containing ointment (additional active ingredients also included in the ointment): RR 0.13 (95% CI 0.02 to 0.99). No between-group differences in complete healing were detected for framycetin sulphate ointment versus enzymatic cleanser; chloramphenicol ointment versus framycetin sulphate ointment; mupirocin ointment versus vehicle; and topical antibiotics given according to antibiogram versus an herbal ointment.
Other topical antiseptics: data from one RCT suggested that more participants receiving an antiseptic ointment (ethacridine lactate) had responsive ulcers (defined as > 20% reduction in area) at four weeks when compared with placebo: RR 1.45 (95% CI 1.21 to 1.73). Complete healing was not reported. No between-group difference was detected between chlorhexidine solution and usual care.
At present, no evidence is available to support the routine use of systemic antibiotics in promoting healing of venous leg ulcers. However, the lack of reliable evidence means that it is not possible to recommend the discontinuation of any of the agents reviewed. In terms of topical preparations, some evidence supports the use of cadexomer iodine. Current evidence does not support the routine use of honey- or silver-based products. Further good quality research is required before definitive conclusions can be drawn about the effectiveness of povidone-iodine, peroxide-based preparations, ethacridine lactate, chloramphenicol, framycetin, mupirocin, ethacridine or chlorhexidine in healing venous leg ulceration. In light of the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should be used only in cases of clinical infection, not for bacterial colonisation.
O'Meara Susan, Al-Kurdi Deyaa, Ologun Yemisi, Ovington Liza G, Martyn-St James Marrissa, Richardson Rachel
Antibiotics and antiseptics to help healing venous leg ulcers
Venous leg ulcers are a type of wound that can take a long time to heal. These ulcers can become infected, and this might cause further delay to healing. Two types of treatment are available to treat infection: systemic antibiotics (i.e. antibiotics taken by mouth or by injection) and topical preparations (i.e. treatments applied directly to the wound). Whether systemic or topical preparations are used, patients will also usually have a wound dressing and bandage over the wound. This review was undertaken to find out whether using antibiotics and antiseptics works better than usual care in healing venous leg ulcers, and if so, to find out which antibiotic and antiseptic preparations are better than others. In terms of topical preparations, some evidence is available to support the use of cadexomer iodine (a topical agent thought to have cleansing and antibacterial effects). Current evidence does not support the use of honey- or silver-based products. Further good quality research is required before definitive conclusions can be drawn about the effectiveness of antibiotic tablets and topical agents such as povidone-iodine, peroxide-based products and other topical antibiotics and antiseptics in healing venous leg ulceration.
Implications for practice
At present, the evidence does not support the routine use of systemic antibiotics to promote healing in venous leg ulcers. However, the lack of reliable evidence means that it is not possible to recommend the discontinuation of any of the agents reviewed. There was some evidence to suggest that systemic antibiotics were associated with emergence of antibiotic-resistant micro-organisms compared with non-antibiotic treatment. Few data were available on adverse effects. Levamisole (an oral antimicrobial product normally used to treat roundworm infection) was the only systemic agent where data showed a benefit in terms of healing. Levamisole is unlicensed in the UK, and is only available from 'special order' suppliers for use in treating roundworm infection (BNF 2013). It was withdrawn from the US market in 1999. In terms of topical preparations, some evidence supports the use of cadexomer iodine. However, cadexomer iodine is associated with more frequent adverse effects than standard care. Current evidence does not support the routine use of honey- and silver-based preparations. Further good quality research is required before definitive conclusions can be made about the effectiveness of systemic antibiotics and topical preparations such as povidone-iodine, peroxide-based preparations, chloramphenicol, framycetin sulphate, mupirocin, topical antibiotics given according to antibiogram, ethacridine lactate and chlorhexidine in healing venous leg ulceration. Honey-based products and silver-impregnated dressings may not be cost-effective; otherwise, there were few reliable data on cost-effectiveness. In light of the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should be used only in cases of clinical infection, not for bacterial colonisation (BNF 2013).
Implications for research
Most of the trials were small, and most of the evidence was of high or unclear risk of bias. Much of the research requires replication in larger, well-designed studies. Future research should pay attention to the following: clearly defined participant selection criteria, particularly with reference to baseline infection and colonisation of wounds, sample size with sufficient power to detect true treatment effects, use of true randomisation with allocation concealment, measures to help ensure comparability of treatment arms at baseline (e.g. stratification for ulcer size and ulcer duration), blinded outcome assessment, use of objective outcome measurement and appropriate methods for data analysis (e.g. complete healing rates and survival analysis using appropriate methods of estimation) and use of the intention-to-treat protocol.
Further research is required to clarify the relationship between healing and infection, colonisation, and critical colonisation of ulcers and to clarify these definitions in terms of chronic wounds. Attention should also be paid to the potential development of resistance to antimicrobial agents, and follow-up should include an assessment of this. The cost-effectiveness of both systemic and topical antimicrobials needs to be established, taking into account the patterns of healing and recurrence that can occur with chronic wounds.
Future studies should make inclusion and exclusion criteria clear with reference to infection and colonisation of wounds. In trials in which the presence of infection does not exclude patients, numbers of participants with and without the clinical signs of infection should be reported at baseline, and groups should be comparable for infection rates and types.