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T A B L E O F C O N T E N T S
1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
17DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
22CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
49DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Systemic antibiotic given according to sensitivities versus standard care, Outcome 1 frequency
of complete healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Analysis 1.2. Comparison 1 Systemic antibiotic given according to sensitivities versus standard care, Outcome 2 mean
percentage decrease in ulcer area. . . . . . . . . . . . . . . . . . . . . . . . . . . . 53Analysis 1.3. Comparison 1 Systemic antibiotic given according to sensitivities versus standard care, Outcome 3 bacterial
eradication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Analysis 2.1. Comparison 2 Ciprofloxacin versus standard care / placebo, Outcome 1 frequency of complete healing. 54
Analysis 2.2. Comparison 2 Ciprofloxacin versus standard care / placebo, Outcome 2 clinically improved ulcers (at least
10% reduction in sum of maximum length and width). . . . . . . . . . . . . . . . . . . . 55
Analysis 2.3. Comparison 2 Ciprofloxacin versus standard care / placebo, Outcome 3 emergence of antibiotic resistant
strains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Analysis 2.4. Comparison 2 Ciprofloxacin versus standard care / placebo, Outcome 4 bacterial eradication. . . . . 56
Analysis 3.1. Comparison 3 Ciprofloxacin versus Trimethoprim, Outcome 1 frequency of complete healing. . . . 56
Analysis 3.2. Comparison 3 Ciprofloxacin versus Trimethoprim, Outcome 2 emergence of antibiotic resistant strains. 57
Analysis 4.1. Comparison 4 Trimethoprim versus placebo, Outcome 1 frequency of complete healing. . . . . . 57
Analysis 4.2. Comparison 4 Trimethoprim versus placebo, Outcome 2 emergence of antibiotic resistant strains. . . 58
Analysis 5.1. Comparison 5 Amoxicillin plus compression verus povidone iodine alone, Outcome 1 frequency of completehealing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Analysis 6.1. Comparison 6 Amoxicillin plus compression verus povidone iodine plus compression, Outcome 1 frequency
of complete healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Analysis 7.1. Comparison 7 Levamisole versus placebo, Outcome 1 frequency of complete healing. . . . . . . 59
Analysis 8.1. Comparison 8 Cadexomer iodine versus standard care, Outcome 1 frequency of complete healing. . . 60
Analysis 8.2. Comparison 8 Cadexomer iodine versus standard care, Outcome 2 rate of ulcer area reduction (cm squared
per week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 9.1. Comparison 9 Cadexomer iodine plus compression therapy versus standard care plus compression therapy,
Outcome 1 frequency of complete healing. . . . . . . . . . . . . . . . . . . . . . . . . 62
Analysis 9.2. Comparison 9 Cadexomer iodine plus compression therapy versus standard care plus compression therapy,
Outcome 2 decrease in Staph. aureus bacterial load. . . . . . . . . . . . . . . . . . . . . . 63
Analysis 10.1. Comparison 10 Cadexomer iodine versus dextranomer, Outcome 1 frequency of complete healing. . 64
Analysis 11.1. Comparison 11 Cadexomer iodine versus hydrocolloid dressing, Outcome 1 frequency of completehealing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Analysis 11.2. Comparison 11 Cadexomer iodine versus hydrocolloid dressing, Outcome 2 mean percentage reduction in
ulcer area. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 11.3. Comparison 11 Cadexomer iodine versus hydrocolloid dressing, Outcome 3 rate of ulcer area reduction (%
per week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Analysis 12.1. Comparison 12 Cadexomer iodine versus paraffin gauze, Outcome 1 frequency of complete healing. . 66
Analysis 12.2. Comparison 12 Cadexomer iodine versus paraffin gauze, Outcome 2 mean percentage reduction in ulcer
area. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
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Analysis 12.3. Comparison 12 Cadexomer iodine versus paraffin gauze, Outcome 3 rate of ulcer area reduction (% per
week). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 13.1. Comparison 13 Povidone iodine plus compression versus hydrocolloid plus compression, Outcome 1
frequency of complete healing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Analysis 14.1. Comparison 14 Peroxide-based topical preparation versus control, Outcome 1 mean percentage ulcer area
remaining. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68Analysis 15.1. Comparison 15 Ethacridine lactate versus control, Outcome 1 number of responsive ulcers. . . . . 69
Analysis 15.2. Comparison 15 Ethacridine lactate versus control, Outcome 2 Patient satisfaction (treatment rated as
excellent). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Analysis 16.1. Comparison 16 Mupirocin versus control, Outcome 1 frequency of complete healing. . . . . . . 70
Analysis 16.2. Comparison 16 Mupirocin versus control, Outcome 2 Eradication of G +ve bacteria. . . . . . . 71
71WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
71CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
72INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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[Intervention Review]
Antibiotics and antiseptics for venous leg ulcers
Susan OMeara1
, Deyaa Al-Kurdi2
, Liza G Ovington3
1Department of Health Sciences, University of York, York, UK. 2The Cochrane Wounds Group, University of York, York, UK. 3 Ethicon,
Inc, Somerville, USA
Contact address: Susan OMeara, Department of Health Sciences, University of York, Area 3 Seebohm Rowntree Building, Heslington,
York, YO10 5DD, [email protected]. (Editorial group: Cochrane Wounds Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue:Edited)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD003557.pub2
This version first published online:23 January 2008 in Issue 1, 2008. Re-published online with edits: 21 January 2009 in Issue 1,
2009.
Last assessed as up-to-date: 11 November 2007. (Help document -Dates and Statusesexplained)
This record should be cited as: OMeara S, Al-Kurdi D, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane
Database of Systematic Reviews2008, Issue 1. Art. No.: CD003557. DOI: 10.1002/14651858.CD003557.pub2.
A B S T R A C T
Background
Venous leg ulcers are a type of chronic wound affecting up to 1% of adults in developed countries at some point during their life. Many
of these wounds are colonised by bacteria or show signs of clinical infection. The presence of infection may delay ulcer healing. There
are two main strategies used to prevent and treat clinical infection in venous leg ulcers: systemic antibiotics and topical antibiotics or
antiseptics.
Objectives
The objective of the review is to determine the effects of systemic antibiotics and topical antibiotics and antiseptics on the healing of
venous ulcers.
Search strategy
The following databases were searched up to October 2007: the Cochrane Wounds Group Specialised Register; the Cochrane Central
Register of Controlled Trials; MEDLINE; EMBASE; and CINAHL. In addition, the reference lists of included studies and relevant
review articles were examined.
Selection criteria
Randomised controlled trials recruiting peoplewith venous leg ulcerationthat evaluated at leastone systemic antibiotic, topical antibiotic
or topical antiseptic and 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 three authors working independently.
Data collection and analysis
Information on the characteristics of participants, interventions and outcomes were recorded on a standardised data extraction form.
In addition, aspects of trial methods were extracted, including methods of randomisation and allocation concealment, use of blinded
outcome assessment, intention-to-treat analysis, reporting of patient follow-up and study group comparability at baseline. Data extrac-
tion and validity assessment were conducted by one author and checked by a second.
Main results
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Twenty two trials were identified of different antibiotics and antiseptics, including systemic antibiotics (5 trials). The remainder were
topical preparations: cadexomer iodine (10 trials); povidone iodine (2 trials); peroxide-based preparations (3 trials); ethacridine lactate
(1 trial); and mupirocin (1 trial). For the systemic antibiotics, the only comparison where a statistically significant between-group
difference was detected was that in favour of the antihelminthic levamisole when compared with placebo. This trial, in common with
the other evaluations of systemic antibiotics, was small and so the observed effect could have occurred by chance. In terms of topical
preparations, there is some evidence to suggest that cadexomer iodine generates higher healing rates than standard care. One studyshowed a statistically significant result in favour of cadexomer iodine when compared with standard care (not involving compression)
in terms of frequency of complete healing at six weeks (RR 2.29, 95% CI 1.10 to 4.74). The intervention regimen used was intensive,
involving daily dressing changes, and so these findings may not be generalisable to most everyday clinical settings. When cadexomer
iodine was compared with standard care with all patients receiving compression, the pooled estimate from two trials for frequency
of complete healing at 4 to 6 weeks indicated significantly higher healing rates for cadexomer iodine (RR 6.72, 95% CI 1.56 to
28.95). Surrogate healing outcomes such as change in ulcer surface area and daily or weekly healing rate showed favourable results
for cadexomer iodine, peroxide-based preparations and ethacridine lactate in some studies. These surrogate outcomes may not be
valid proxies for complete healing of the wound. Most of the trials were small and many had methodological problems such as poor
baseline comparability between groups, failure to use (or report) true randomisation, adequate allocation concealment, blinded outcome
assessment and analysis by intention-to-treat.
Authors conclusions
At present, there is no existing evidence to 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. In
terms of topical preparations, there is some evidence to support the use of cadexomer iodine. 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, ethacridine lactate and mupirocin in healing venous leg ulceration. In light of the increasing
problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should only be
used in cases of defined infection and not for bacterial colonisation.
P L A I N L A N G U A G E S U M M A R Y
Antibiotics and antisepticsto 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. antibiotic tablets or injections) and
topical preparations (i.e. applied directly to the wound). Whether systemic or topical preparations are used, patients will also usually
have a wound dressing to cover the wound and maybe a bandage too. This review was undertaken in order to find out whether using
antibiotics and antiseptics works better than usual care for healing venous leg ulcers, and if so, to find out which antibiotic and antiseptic
preparations are better than others. In terms of topical preparations, there is some evidence to support the use of cadexomer iodine.
Further good quality research is required before definitive conclusions can be made about the effectiveness of systemic antibiotics and
topical agents such as povidone iodine, peroxide-based preparations, ethacridine lactate and mupirocin in healing venous leg ulceration.
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B A C K G R O U N D
Venous leg ulcersare a type of chronic wound affectingup to 1% of
adults in developed countries at some point during their life. The
cost to the United Kingdom National Health Service (UK NHS)
of treating patients with venous ulcers was estimated as 300-450million per annum in 1992 (Bosanquet 1992;Podmore 1994).
A range of interventions may be considered for the treatment of
patients with venous leg ulcers. These include compression ban-
daging (Robson 2006), various types of dressings and topical ap-
plications (Robson 2006),debridingagents(Davies 2005), vasoac-
tive drugs (Robson 2006), fibrinolytic therapy (Robson 2006),
and physical therapies (Flemming 2001;Ravaghi 2006;Al-Kurdi
2008). In particular, compression bandaging has been shown to
exert important effects on healing (Cullum 2001;Robson 2006;
Enoch 2006), and may be used concurrently with other therapies.
Moist chronic skin ulcers are an ideal mediumfor bacterial growth
and a variety of micro-organisms can be cultured from these le-sions. Findings from studies suggest that 80% to 100% of leg ul-
cers may be colonised with bacteria (Halbert 1992;Brook 1998;
Harker 2001). The commonest isolates are Staphylococcus aureus
and Pseudomonas aeruginosa (Alinovi 1986; Kontiainen 1988;
Halbert 1992;Brook 1998;Harker 2001).
Ithas been suggestedthatpresenceof infectioncan delayulcerheal-
ing (Doughty 2007). A recent study of 66 patients showed bacte-
rial density to be associated with the probability of non-healing in
venous legulcerswhen infectionwas detected using swabs or tissue
biopsies (Davies 2007). Findings from earlier studies are mostly
supportive of the notion of a positive correlation between bacterial
load and delayed healing (Halbert 1992;Hansson 1995,Madsen1996,Trengove 1996). It has been suggested that chronic wound
healing may be influenced not only by bacterial density but also
by the diversity of micro-organisms present and their interactions
with one another (Trengove 1996,Bowler 2003;Davies 2007).
In addition, delayed healing may occur in the presence of certain
bacterial strains such as Pseudomonas aeruginosa, Staphylococcus
aureus and haemolytic Streptococci (Madsen 1996). Prescribing
guidelines recommend that antibacterial preparations should only
be used in cases of defined infection and not for bacterial coloni-
sation (BNF 2007).
The terms contamination, colonisation, and infection are used
frequently in the wound care literature. The term contamination
describes wounds with non-replicating organisms on their surface
(Dow 1999). Colonisation occurs when bacteria capable of repli-
cating on the ulcer surface, inhabit non-viable tissue in the wound
in theabsence of host immuneresponse (Ayton 1985; Dow 1999).
Clinically significant infection is characterised by sudden onset
of pain or increased pain, spreading erythema, swelling, cellulitis,
appearance of purulent exudate, and odour. The presence of fever
and chills indicate systemic sepsis (Miller 1996;Kunimoto 2001).
There are two main strategies used to prevent and treat clinical
infection in venous leg ulcers: systemic antibiotics and topical
antiseptics/antibiotics.
Systemic antibiotics fall into four main groups: penicillins,
cephalosporins, aminoglycosides, and quinolones. Other drugs in-
clude clindamycin, metronidazole, and trimethoprim.
The penicillins work by interfering with the development of bac-
terial cell walls and cross linkages. Broad spectrum agents such as
ampicillin and amoxicillin are active against certain Gram-positive
and Gram-negative organisms but are inactivated by penicillinases
produced by Staphylococcus aureus and Escherichia coli. Penicil-
linases are enzymes produced by some micro-organisms that limit
thenormal action of penicillin. Amoxacillin combined with clavu-
lanic acid produces an increased range of activity and is effective
against both Staphylococcus aureus and Escherichia coli (BNF
2007).
Thecephalosporins have a similar actionto thepenicillinsandhavea wide range of activity against both Gram-negative and Gram-
positive organisms (BNF 2007).
The aminoglycosides, such as gentamicin, act by interfering with
normal protein synthesis. They have a wide range of action but
are potentially nephrotoxic and ototoxic, and their use should be
monitored via serum levels. They are not absorbed from the gut
and systemic administration is therefore by injection (BNF 2007).
The quinolones, such as ciprofloxacin, prevent the formation of
DNAwithin thecell nucleus. They are highly activeagainst Gram-
negative organisms and moderately active against Gram-positive
organisms. Ciprofloxacin is licensed for skin and soft tissue infec-
tions but there is a high incidence of staphylococcal resistance andit is recommended that its use is avoided in meticillin-resistant
Staphylococcus aureus infections (BNF 2007).
Clindamycin is active against staphylococcal infections, and is
associated with antibiotic-induced colitis; a rare but serious ad-
verse event. Current prescribing guidelines state that clindamycin
should be withdrawn immediately in any patient developing di-
arrhoea (BNF 2007). Metronidazole is active against anaerobic
organisms (BNF 2007). Trimethoprim is commonly used to treat
urinary tract infections (BNF 2007), and has been shown to be
active against Escherichia coli when used to treat urinary tract in-
fections (Minassian 1998).
Topical agents include antibiotics, antiseptics and disinfectants.
Although various definitions exist for these terms, there appears to
be a lack of consensus within the literature as to the characteristics
of each type of preparation. It has been suggested that both an-
tiseptics and disinfectants destroy micro-organisms or limit their
growth in the non-sporing or vegetative state. However, antisep-
tics are usually applied solely to living tissues, whilst disinfectants
may also be applied to equipment and surfaces (Morgan 1993).
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Topical preparationsmay be divided into two categories,according
to their function. Onegroup consists of lotions with antimicrobial
properties, used to irrigate or cleanse wounds. These usually have
only a brief contact time with the wound surface, unless they
are used as a pack or soak. They include the hypochlorites (e.g.
Eusol), hexachlorophane (constituent of somesoaps and otherskincleansers), and substances such as potassium permanganate and
gentian violet (both used in solution for skin cleansing).
The second group consists of preparations designed to stay in
contact with the wound surface for a longer period of time, ideally
until the next dressing change. These include creams, ointments
and impregnated dressings. Most topical antibiotics come into this
category, and include mupirocin (available as 2% cream), active
against Gram-positive organisms, and fusidic acid (available as
2% ointment or cream) for staphylococcal infections. Neomycin
sulphate, available as a cream (0.5%) or ointment (0.25%), is used
to treat bacterial skin infections. If large areas of skin are treated,
ototoxicity is a possible adverse effect. Silver sulphadiazine (1%
cream), has a broad spectrum action and is commonly used fortreating infected burns (BNF 2007).
Some products which are available indifferent forms,fall into both
categories.These include povidone iodine (available in various for-
mulations including 10% solution, 10% ointment, and 2.5% dry
powder spray), chlorhexidine (available as 0.05%solution and also
a constituent of skin cleansers), benzoyl peroxide (lotions, creams
and gels available in various strengths), and hydrogen peroxide
(3% and 6% solutions and 1% cream) (BNF 2007).
It is currently uncertain whether the use of systemic antibiotics,
topical antibiotics or topical antiseptics can promote healing in
venous leg ulcers. An earlier systematic review of antimicrobial
agents used with a range of chronic wounds was not able to gen-
erate definitive conclusions about the use of systemic or topical
agents in venous leg ulcers because of methodological problems
in the primary literature (OMeara 2001). Since the first review,
additional relevant trials have been published and so an updated
body of evidence is now available. Pertinent questions for clinical
practice include whether the use of antibiotics and antiseptics in-
crease healing rates compared with standard care, whether differ-
ent active agents are more or less effective when compared directly
and whether there are any differences in outcomes in relation to
the use of systemic and topical agents.
O B J E C T I V E S
The objective of the review is to determine the effects of systemic
antibiotics and topical antibiotics and antiseptics on the healing
of venous ulcers.
M E T H O D S
Criteria for considering studies for this review
Types of studies
Prospective randomised controlled trials (RCTs) evaluating topical
or systemic antibiotics or antiseptics in the treatment of venous
ulcers were included.Types of participants
Trials recruiting people described in the primary studies as hav-
ing venous leg ulcers were eligible for inclusion. Trials recruiting
people with different types of wounds (e.g. arterial ulcers, diabetic
foot ulcers) were included if the results for patients with venous
ulcers were presented separately or if the majority of participants
(at least 75%) had leg ulcers of venous aetiology. Selection of trials
was not restricted to those with a certain wound status at baseline
(i.e. those with colonised or infected wounds); where information
was given about these variables, it was recorded (see data extrac-
tion).
Types of interventions
The primary intervention is antibiotics (topical or systemic) or
antiseptics (topical) prescribed for venous leg ulceration. Systemic
preparations could be given orally or parenterally (for example by
intravenous administration), and administered singly or in com-
bination. Control regimens could include placebo, an alternative
antibiotic or antiseptic, any other therapy, standard care or no
treatment. Both intervention and control regimens could consist
of combinations of antibiotics and antiseptics. Interventions could
be delivered in any setting (inpatient, outpatient, nursing home
plus any others). Trials evaluating topical silver-based preparations
or the use of honey in wound healing were excluded as these inter-
ventions have been, or will be, covered in other Cochrane reviews
(Jull 2004;Ubbink 2007;Vermeulen 2007).Types of outcome measures
Primary outcomes
Trials reporting any of the following outcomes at any endpoint
were eligible:
1. Time to complete ulcer healing
2. Proportion of ulcers completely healing during the trial
period (frequency of complete healing)
3. Objective measurements of change in ulcer size
4. Healing rate (e.g. mm2 ulcer surface area reduction per
week)
Secondary outcomes
Where reported, the following outcomes were also recorded:
1. Changes in signs and/or symptoms of clinical infection
2. Changes in bacterial flora
3. Development of bacterial resistance
4. Ulcer recurrence rates
5. Adverse effects of treatment
6. Patient satisfaction
7. Quality of life
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1. Study authors
2. Year of publication
3. Country where study performed
4. Study design (RCT)
5. Method of randomisation
6. Unit of randomisation7. Overall sample size and methods used to estimate statistical
power (relates to the target number of participants to be recruited,
the clinical difference to be detected and the ability of the trial to
detect this difference)
8. Outcomes measured
9. Setting of treatment
10. Duration of treatment
11. Participant selection criteria
12. Details of interventions (including specific antibiotics and an-
tiseptics used) per study group, including concurrent interven-
tions such as compression
13. Numbers per study group
14. Baseline characteristics of participants per treatment group(gender, age, ethnicity, baseline ulcer area, ulcer duration, preva-
lence of co-morbidities such as diabetes, prevalence of clinically
infected wounds with definition as used in the trial, prevalence of
colonised wounds with definition as used in the trial, identity of
micro-organisms isolated)
15. Methods used for identifying micro-organisms
16. Statistical methods used for data analysis
17. Results per group for each outcome
18. Withdrawals (per group with numbers and reasons)
Assessment of risk of bias in included studies
Each included study was appraised according to the criteria de-
scribed below. Each validity item was assessed separately; ratings
for each item were not combined into an overall score. Each in-
cluded study was assessed by one author (DAK) and checked by a
second (SO). Disagreements were resolved by discussion.
1. Adequacy of the randomisation process:
A = Adequate sequence generation is reported using random num-
ber tables, computer random number generator, coin tossing, or
shuffling.
B = Did not specify one of the adequate reported methods in (A)
but mentioned randomisation method.
C = Used a system involving dates, names, or admittance numbers
for the allocationof patients.Such studies wereconsidered as quasi-
randomised and were excluded from the review.
2. Adequacy of allocation concealment
A = Adequate: a randomisation method described that would not
allowan investigator/participant to knowor influence an interven-
tion group before an eligible participant entered the study, such
as central randomisation; serially numbered, opaque, sealed en-
velopes.
B = Unclear: trial states that it is randomised, but no information
on the method used is reported or a method is reported that was
not clearly adequate.
C = Inadequate: inadequate method of randomisation used, such
as alternate medical record numbers or unsealed envelopes; or
any information in the study that indicated that investigators or
participants could influence the intervention group.
3. Blinding of outcome assessors
This item was graded as A for blinded outcome assessment, B ifthe relevant information was not stated in the trial report and C
for unblinded outcome assessment.
4. Intention-to-treat (ITT) analysis
A - Yes: Specifically reported by authors that ITT was undertaken
and this was confirmed on study assessment, or not stated but
evident from study assessment that ITT was undertaken.
B - Unclear. Described as ITT analysis, but unable to confirm on
study assessment, or not reported and unable to confirm by study
assessment.
C - No: Lack of ITT confirmed on study assessment (patients who
were randomised were not included in the analysis because they did
not receive the study intervention, they withdrew from the study
or were not included because of protocol violation) regardless ofwhether analysis described as ITT.
5. Reporting of follow-up
A = Adequate, if the numbers and reasons for dropouts and with-
drawals in all intervention groups were described or if it was spec-
ified that there were no dropouts or withdrawals.
B = Unclear, if the report gave the impression that there had been
no dropouts or withdrawals, but this was not specifically stated.
C = Inadequate, if the number or reasons for dropouts and with-
drawals were not described.
6. Comparability at baseline
Were the groups similar at baseline in terms of prognostic factors?
If there were differences, were these adjusted for in the analysis?
A = Yes; B = Unclear; C = NoData synthesis
A narrative synthesis of all studies was presented, with results
grouped according to type of intervention. Statistical pooling was
undertaken on groups of studies considered to be sufficiently sim-
ilar in terms of study design and characteristics of participants,
interventions and outcomes. Data were analysed using Cochrane
RevMan software (version 4.2.8). Estimates for dichotomous out-
comes (e.g. number of ulcers healed) were reported as relative risk
(RR) with associated 95% confidence intervals (CI). Continuous
data (e.g. change in ulcer area) were converted to the standardised
mean difference (or a weighted mean difference (WMD), when
plausible)and overall effect sizes (with 95% CI) were calculated. Itwas planned to analyse time to complete wound healing as survival
(time to event) data, using the appropriate analytical method (as
per the Cochrane Reviewers Handbook version 4.2.5).
Subgroup analysis and investigation of heterogeneity
When statistical pooling was performed, statistical heterogeneity
was assessed using the chi-square test and the extent of hetero-
geneity by I2 (Higgins 2002;Higgins 2003). If substantial hetero-
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geneity was detected studies were not pooled statistically. In the
presence of low to moderate statistical heterogeneity a fixed effect
model was used if pooling was deemed appropriate in light of the
clinical characteristics of trials.
It was planned to conduct subgroup analyses according to differ-
ences in the following variables: mean baseline ulcer area, presenceof signs and/orsymptoms of clinical infectionat baseline, presence
of wound colonisation at baseline and, in the case of studies using
compression, the number of layers used (i.e. single-layer versus
multi-layer bandaging) and level of compression (i.e. high versus
moderate/low compression) (Cullum 2001).
R E S U L T S
Description of studies
See: Characteristicsof included studies; Characteristics of excludedstudies.
The search strategy described above generated 426 records. Of
these, 115 appeared to be of possible relevance and were retrieved
as full reports. Following detailed screening with reference to the
study selection criteria, 22 studies were included in this review.
They have been divided into groups based on the type of antibac-
terial or antiseptic intervention evaluated.
Systemic antibiotics
Five evaluations of oral systemic antibiotics were identified re-
cruiting a total of 232 participants (Alinovi 1986;Daroczy 2006;
Huovinen 1994;Morias 1979;Valtonen 1989). Two trials were
conducted in Finland (Huovinen 1994;Valtonen 1989), one inItaly (Alinovi 1986), one in Hungary (Daroczy 2006) and one
in Belgium (Morias 1979). None was described as multi-centre.
The number of participants allocated per arm ranged between 8
to 30;Morias 1979was the largest trial, recruiting 59 participants
overall. Morias 1979andValtonen 1989recruited people with leg
ulcers of different etiologies, the majority being of venous origin.
The duration of follow up ranged between 20 days and 20 weeks
with 3 out of the 5 trials following the patients up for 12 weeks
or longer (Morias 1979;Valtonen 1989;Huovinen 1994).
Daroczy 2006was a 3 arm trial that compared amoxicillin plus
compression therapy with povidone iodine with and without com-
pression therapy. Huovinen 1994was also a 3 arm study that eval-
uated ciprofloxacin, trimethoprim and placebo. Valtonen 1989evaluated ciprofloxacin versus standard care, Morias 1979evalu-
ated levamisole ( typically an antihelminthic, but may have an-
tibacterial effects in wounds) against placebo, whilst in the fifth
trial, an antibiotic tailored to the sensitivity of colonizing bacteria
(amikacin, co-trimoxazole, and gentamicin) was compared with
standard care (Alinovi 1986).
Cadexomer iodine topical preparations
Ten studies involving 645 participants evaluated cadexomer io-
dine (Hansson 1998;Harcup 1986;Holloway 1989;Kero 1987;
Laudanska 1988; Lindsay 1986; Moss 1987; Ormiston 1985; Skog
1983;Steele 1986).Hansson 1998;Lindsay 1986andSkog 1983
were multi-centre trials. Five trials were based in the United King-
dom (Harcup 1986;Lindsay 1986;Moss 1987;Ormiston 1985;Steele 1986), two in Sweden and Norway (Hansson 1998;Skog
1983), one in Finland (Kero 1987), one in Poland (Laudanska
1988) ,and one in the USA (Holloway 1989). The number of
people allocated to each arm of these studies ranged between 10
and 44.Hansson 1998was the largest study with 153 participants
recruited overall. The duration of follow up ranged from 4 weeks
to 24 weeks. The majority (Harcup 1986;Kero 1987;Laudanska
1988;Lindsay 1986; Moss 1987;Skog 1983;Steele 1986) fol-
lowed up participants for a maximum of eight weeks.
Cadexomer iodine is a topical agent with debriding and anti-
bacterial effects. The comparators were standard care (Skog
1983;Ormiston 1985;Harcup 1986;Lindsay 1986;Steele 1986;
Laudanska 1988; Holloway 1989), dextranomer (Kero 1987;Moss 1987), hydrocolloid (Hansson 1998) and paraffin gauze
dressing (Hansson 1998).
Povidone iodine topical preparations
Two trials involving 300 participants overall evaluated povidone
iodine (Groenewald 1981;Smith 1992). One trial was based in
the United Kingdom (N=200 patients) (Smith 1992) and one in
Germany (N=100 patients) (Groenewald 1981). The duration of
follow up was 21 days (Groenewald 1981) and 4 months (Smith
1992). The comparators were a debriding agent (dextranomer) (
Groenewald 1981) and a hydrocolloid dressing (Smith 1992).
Peroxide-based topical preparationsThree trials recruiting 83 participants overall evaluated peroxide-
based topical antiseptics (Beitner 1985; Belcaro 2003; Belcaro
2007). One trial was based in Sweden (Beitner 1985), and two in
Italy (Belcaro 2003; Belcaro 2007). The number of people in each
arm ranged between 7 and 18; The largest beingBelcaro 2007
with 32 people. Duration of follow up ranged between 10 and 42
days.Beitner 1985evaluated benzoyl peroxide.Belcaro 2003and
Belcaro 2007both used hydrogen peroxide as the intervention
treatment.
Miscellaneous topical preparations
Two trials recruiting 283 participants overall were identified that
did not easily fit into any of the groups described above . One
trial was based in the United Kingdom (single-centre, N=30 pa-
tients) (Cameron 1991) and the other in Germany (multi-centre,
N=253 patients) (Geske 2005).Cameron 1991evaluated topical
mupirocin compared with white soft paraffin tulle gras (follow up
12 weeks)and Geske 2005 investigated ethacridine lactate (an aro-
matic organic compound used as an antiseptic) versus a placebo
preparation (follow up four weeks).
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Table 1. Quality Assessment (Continued)
Steele 1986 A B A A C A
Valtonen 1989 B B C C B A
Adequacy of randomisation
Three out of 22trials (Morias 1979; Ormiston 1985; Steele 1986)
used random sequential numbers and were deemed satisfactory (A
grade). The remaining 19 trials did not describe the method of
randomisation so received B grade.
Adequacy of allocation concealment
Ormiston 1985used a double-layered sealed envelope which was
sequentially numbered and an anonymised code was used in
Morias 1979so they received a grade A. Alinovi 1986andKero
1987used sealed envelopes but neither trial reported whether the
envelopes were opaque or sequentially numbered (grade B). The
other 18 trials did not clearly report any concealment and received
a grade B.
Assessor blinding
Outcome measurement and assessment was performed by either
blinded investigators or digital equipment in 11 trials (Alinovi
1986;Beitner 1985; Belcaro 2003;Belcaro 2007;Cameron 1991;
Groenewald 1981; Huovinen 1994; Laudanska 1988; Morias
1979;Ormiston 1985;Steele 1986). Outcome assessors were not
blinded inKero 1987;Moss 1987andValtonen 1989(grade C)
whilst the remaining 8 trial reports were unclear whether the as-sessor was blinded or not (grade B).
Intention-to-treat analysis
We defined intention to treat (ITT) analysis as being conducted
when all trial participants were analysed in the group to which
they were randomised regardless of which (or how much) of the
treatment they actually received, and regardless of other protocol
irregularities, such as ineligibility.
No withdrawals or protocol violations were reported inBelcaro
2003 and Belcaro 2007. Alinovi 1986; Beitner 1985; Geske
2005; Harcup 1986; Holloway 1989; Huovinen 1994; Kero1987;
Laudanska 1988;Lindsay 1986;Morias 1979;Moss 1987;Skog1983; Smith 1992 and Steele1986 did not use anITT analysisbut
used availablecase analysisso were given a grade C. Ormiston 1985
reported that some withdrawals were included in the analysis but
it was not obvious whether these data were imputed or whether an
ITT analysis had been undertaken so it was given a grade B. In the
other 5 trials it was not obvious whether withdrawals were taken
into consideration when performing the analysis so they were also
given a grade B.
Comparability at baseline
The groups included in the studies conducted byCameron 1991;
Kero 1987; Ormiston 1985and Valtonen 1989were not balanced
for baseline ulcer duration and in the trial bySkog 1983groups
were not balanced for baseline ulcer area (grade C). InHolloway
1989andHuovinen 1994, treatment arms were poorly matched
for both of these prognostic variables (grade C). In the trials by
Beitner 1985,Harcup 1986andLindsay 1986there was no clear
report of baseline characteristics so they were given a grade B.
The remaining 12 trials appeared to show adequate balance of
prognostic factors across groups at baseline (grade A).
Reporting of follow-up
This was inadequate in Beitner 1985; Groenewald 1981 and
Holloway 1989so they were given a grade C. Details were not
clearly reported in Cameron 1991, Daroczy 2006 and Geske 2005
so they received a grade B. The remaining 16 trials adequately
accounted for all people in the study so they received a grade A.
Effects of interventions
Overall, 22 studies were included in this review. Results are pre-
sentedaccording to the type of intervention,starting with systemic
antibiotics. This is followed by topical preparations: cadexomer
iodine, povidone iodine, peroxides, and miscellaneous agents, i.e.those not fitting easily into the other groups (ethacridine lactate
and mupirocin). Subgroup analyses according to presence of signs
and/or symptoms of clinical infection at baseline, and presence of
wound colonisation at baseline were not performed because the
majority of the studies (18 trials) did not report clinical infection
or colonization.
SYSTEMIC ANTIBIOTICS
Five trials recruiting 232 patients overall evaluated various types
of systemic antibiotics (Alinovi 1986;Valtonen 1989;Huovinen
1994;Daroczy 2006;Morias 1979).
Comparison 1: systemic antibiotics given according to
sensitivities compared with standard care
One trial was identified for this comparison (Alinovi 1986).
Primary outcomes
(1) Frequency of complete healing
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One trial was identified (Huovinen 1994).
Primary outcomes
(1) Frequency of complete healing
Oneofthetrialsdescribedinthesectionabovealsoincludedacom-
parison of ciprofloxacin with an alternative antibiotic, trimetho-
prim(Huovinen 1994).At16weeks5/12(42%)ulcershealedwith
ciprofloxacin compared with 3/9 (33%) for trimethoprim (be-
tween-group difference not statistically significant RR 1.25 95%
CI 0.40 to 3.91)(Analysis 03: Outcome 01). The ciprofloxacin
group contained patients who had larger and more chronic ulcers
(average surface area 53cm andwound duration72 months)com-
pared with those receiving trimethoprim (31 cm and 67 months)
thus biasing the trial in favour of trimethoprim.
Secondary outcomes
(1) Development of bacterial resistance
The frequency of emergence of resistant bacterial strains was the
same for both groups, occurring in 8/12 (67%) patients receiving
ciprofloxacin and in 6/9 (67%) patients receiving trimethoprim
(RR 1.00 95% CI 0.54 to 1.84)(Analysis 03: Outcome 02).
(2) Cost of treatment
The cost of a 12 week course of treatment with ciprofloxacin was
US$600 for ciprofloxacin and US$120 for trimethoprim (price
year not stated but presume 1994). The cost of concurrent topical
treatment was not reported.
Comparison 4: Trimethoprim compared with placebo
The trial described in the two preceding sections also compared
trimethoprim with placebo (Huovinen 1994).
Primary outcomes
(1) Frequency of complete healing
At 16 weeks, 3/10 (30%) ulcers healed with placebo compared
with 3/9 (33%) with trimethoprim (between-group difference not
statistically significant. RR 1.11, 95%CI 0.30 to 4.17)(Analysis
04: Outcome 01). In terms of baseline prognostic factors, average
wound area appeared to be similar between groups but wound
duration was longer in the trimethoprim group (67 versus 29
months).
Secondary outcomes
(2) Development of bacterial resistance
The frequency of emergence of resistant bacterial strains was lower
in patients receiving placebo (1/10 (10%)) compared with those
receiving trimethoprim 6/9 (67%) but the between-group differ-
ence just failed to reach statistical significance (RR 6.67 95% CI
0.98 to 45.29)(Analysis 04: Outcome 02).
Comparison 5: Amoxicillin plus compression compared with
povidone iodine alone
One trial was identified for this comparison (Daroczy 2006).
Primary outcomes
(1) Frequency of complete healing
A three-arm trial (N=63 patients) compared topical povidone io-
dine alone, povidone iodine plus compression and oral amoxicillin
pluscompression (setting of treatmentnot stated) (Daroczy 2006).
It was not stated whether the ulcers were infected at baseline. The
number of ulcers healed was 13/21 (62%) in the group treatedwith povidone iodine alone and 18/21 (86%) in the amoxicillin
plus compression group but the difference was not statistically sig-
nificant (RR 1.38, 95% CI 0.95 to 2.02)(Analysis 05: Outcome
01). Since few details of trial methods were provided, a full validity
assessment was not possible.
Comparison 6: Amoxicillin plus compression compared with
povidone iodine plus compression
The trial described above also included a comparison between sys-
temic amoxicillin and topical povidone iodine, with both groups
receiving compression (Daroczy 2006).
Primary outcomes
(1) Frequency of complete healing
Thenumber of ulcershealedwas 17/21 (81%) in the group treated
with povidone iodine plus compression and 18/21 (86%) in the
amoxicillin plus compression group. The between-group differ-
ence was not statistically significant (RR 1.06, 95% CI 0.81 to
1.39)(Analysis 06: Outcome 01).
(2) Recurrence of infection
Recurrence of infection was assessed five months after trial com-
pletion comparingthe group receivingamoxicillinwith allof those
prescribed povidone iodine (i.e. the groups receiving povidone io-
dine alone and povidone iodine plus compression combined) (
Daroczy 2006). The recurrence rate was lower in the group treated
with povidone iodine (11%) compared with amoxicillin (32%)
(statistical significance of the between-group difference not re-
ported by the trial authors and not evaluable by the review authors
because of the limited nature of data reported in the paper).
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Comparison 7: Levamisole compared with placebo
One trial was identified (Morias 1979).
Primary outcomes
(1) Frequency of complete healing
Morias 1979undertook a trial comparing levamisole with placebo
in an outpatient setting (N=59 patients). Levamisole, a treatment
for roundworm infestation (BNF 2007), is thought to have an
antibacterial action in wounds (Wilton 1978;Morias 1979). Both
active drug and identical placebo were given twice daily for two
days a week for 20 weeks or until complete healing. It was unclear
whether the ulcers were infected at baseline. The study groups ap-
peared to be comparable in terms of baseline prognostic factors.
At 20 weeks all ulcers in the levamisole group had healed com-
pared with 76% for placebo, the difference being statistically sig-
nificant (RR 1.32, 95% CI 1.07 to 1.62)(Analysis 07: Outcome
01). Patients with leg ulcers of varying aetiologies were eligible forinclusion in the trial. Although results were not presented sepa-
rately foreach wound aetiology, the majority were of venous origin
(76.3%) and so it was decided to include this trial in the review.
Ten patients withdrew because of treatment failure (defined as no
observed improvement): two receiving levamisole group and eight
from the control group. The withdrawals were not included in the
analysis.
CADEXOMER IODINE
Ten trials recruiting 645 patients in total evaluated the effect of
cadexomer iodine. Seven trials compared cadexomer iodine with
standard care (Skog 1983; Ormiston 1985; Harcup 1986; Lindsay1986;Steele 1986;Laudanska 1988;Holloway 1989) of which
three provided compression therapy to all recruited patients (Skog
1983; Harcup 1986; Steele 1986). Two trials evaluated cadexomer
iodine against an alternative debridement agent, dextranomer (
Kero 1987;Moss 1987) whilst the final trial, which incorporated
three arms, used hydrocolloidand paraffin gauze dressings as com-
parators (Hansson 1998).
Comparison 1: cadexomer iodine compared with standard
care
Four trials were identified for this comparison (Ormiston 1985;
Lindsay 1986;Laudanska 1988;Holloway 1989). None reported
baseline ulcer infection status.
Primary outcomes
(1) Frequency of complete healing
One trial (N = 28 women) incorporated a standard care arm us-
ing a variety of interventions which included topical antimicrobial
agents in some cases (Lindsay 1986). Interventions were delivered
in a community setting with dressings changed every other day.
After four weeks of treatment, some patients crossed over to the
alternative treatment in light of clinicians judgement that the re-
sponse to the randomised regimen had been unsatisfactory. The
analysis was based on outcomes at four weeks (N = 25). No sta-tistically significant difference was detected between groups. The
number of ulcers healed was 4/12 (33%) in the cadexomer io-
dine-treated group and 1/13 (8%) in the standard care group (RR
4.33, 95% CI 0.56 to 33.53) (Analysis 08: Outcome 01). Details
of baseline characteristics and other methodological details were
lacking.
Laudanska 1988recruited 67 patients and admitted them to hos-
pital to receive six weeks of bedrest and daily dressings. Four pa-
tients withdrew before assessment and a further three were ex-
cludedfrom the analysis due to difficulty in assessing the outcome.
A statistically significant between-group difference was observed
in favour of cadexomer iodine. The number of ulcers healed or be-
coming very superficial in the cadexomer iodine group was 16/30(57%) compared with 7/30 (20%) in the standard care group (RR
2.29, 95% CI 1.10, 4.74) (Analysis 08: Outcome 01). This trial is
likely to lack external validity in light of the intensive nature of the
study regimen (i.e. hospital admission, bedrest and daily dressing
changes).
It was decided not to pool data from the two above trials for
frequency of complete healing at 4-6 weeks because of differences
in intervention settings and frequency of dressing changes.
Ormiston 1985recruited 61 people with venous leg ulcers to be
treated in an outpatient setting. Treatment was delivered for 24
weeks or until healing, with an optional cross-over point at 12
weeks. Analysis was based on the outcomes observed at 12 weeks.
Thenumber of ulcershealedwas 12/30 (40%) in the group treatedwith cadexomer iodine and 7/30 (23%) in the standard care group
but the between-group difference was not statistically significant
(RR 1.71, 95% CI 0.78 to 3.75)(Analysis 08: Outcome 01). The
mean duration of the ulcer was longer in the cadexomer iodine
group which the trial authors attributed to four patients who had
their ulcers for more than 10 years.
The fourthtrial involvinga comparisonbetween cadexomer iodine
and standard care (N = 75, outpatient setting) did not report the
frequency of complete healing (Holloway 1989).
(2) Change in ulcer surface area
Two trials reported a greater average percentage reduction in ulcer
area in thegroup receiving cadexomer iodine when compared with
standard care but did not provide sufficient data for estimation of
effect sizes with confidence intervals: at four weeks 33.6% versus
4.2%, p
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(3) Rate of reduction in ulcer surface area
When data from two trials were pooled, those receiving cadexomer
iodine achieved a significantly faster healing rate compared with
standard care (WMD 0.47 cm squared per week, 95% CI 0.26 to
0.69) (Ormiston 1985,Holloway 1989). (Analysis 08: Outcome
02).
Secondary outcomes
(1) Bacterial eradication
Holloway 1989reported no statistically significant difference be-
tween groups in terms of reducing ulcer bacterial load, but esti-
mates were not provided.
Comparison 2: cadexomer iodine plus compression
compared with standard care plus compression
Three trials were identified (Steele 1986; Harcup 1986; Skog1983). None reported ulcer infection status at baseline.
Primary outcomes
(1) Frequency of complete healing
One trial recruited 60 people with venous leg ulcers (Steele 1986).
Dressings were changed three times per week for six weeks, treat-
ment being delivered in the community by district nurses. The
number of ulcers healed was 3/28 (11%) in the cadexomer iodine
group and 1/29 (3%) in the control group. A second trial recruited
patients with exuding venous leg ulcers (N = 72)(Harcup 1986).
Having been treated in an outpatient setting, patients were fol-lowed up forfour weeks at which point they were eitherwithdrawn
or switched to the alternative treatment. Analysis was based on
outcomes at four weeks.Few details of trial methods were provided
and so a full validity assessment was not possible. When data from
these two trials were pooled for frequency of complete healing
at 4-6 weeks, a statistically significant difference was observed in
favour of cadexomer iodine (RR 6.72, 95% CI 1.56 to 28.95, I2
=0%, fixed effect model) (Analysis 09: Outcome 01). A third trial
(N = 93 patients, outpatient setting) did not report the frequency
of complete healing (Skog 1983).
(2) Change in ulcer surface area
None of the trials in this comparison group reported sufficient
data to calculate effect sizes for change in surface area. In two
trials, authors reported statistically significant mean reductions in
ulcer area in the cadexomer iodine group relative to controls: 44%
compared with 66% reduction at eight weeks, p
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Primary outcomes
(1) Frequency of complete healing
A multi-centre trial incorporated three arms comparing cadex-
omer iodine, hydrocolloid dressing and paraffin gauze (Hansson
1998). Interventions were delivered in an outpatient setting. Pa-
tients with exuding, non-infected venous legulcers(N = 153) were
followed up for 12 weeks or until exudation ceased. The number
of ulcers healed were 8/56 (14%) in the cadexomer iodine group
and 5/48 (10%) in the hydrocolloid group. The between-group
difference was not statistically significant (RR 1.37, 95% CI 0.48
to 3.91)(Analysis 11: Outcome 01).
(2) Change in ulcer surface area
The mean percentage reduction in ulcer area was significantly
greater in the group receiving cadexomer iodine (WMD 20.90%,
95% CI 2.22 to 39.58)(Analysis 11: Outcome 02).
(3) Rate of reduction in ulcer surface area
Hansson 1998 reported that the weekly rate of percentage ul-
cer area reduction was not significantly different between groups
(WMD 1.00%, 95% CI -2.52 to 4.52)(Analysis 11: Outcome
03).
Secondary outcomes
(1) Cost
This trial reported cost of treatment based on data from 38 par-
ticipants taking into account staff time, materials, and transport.
The cost presented in terms of US$ per % ulcer area reduction
was lower in the cadexomer iodine group relative to hydrocolloid
(US$8.8 compared with US$32.5). The price year was not stated
but could be presumed to be 1998 (Hansson 1998).
Comparison 5: cadexomer iodine compared with paraffin
gauze
Thetrialdescribed in thesection above also included a comparison
of cadexomer iodine with paraffin gauze (Hansson 1998).
Primary outcomes
(1) Frequency of complete healing
The frequency of complete healing was similar for both groups:
8/56 (14%) in the cadexomer iodine group compared with 7/49
(14%) for those treated with paraffin gauze (RR 1.00, 95% CI
0.39 to 2.56)(Analysis 12: Outcome 01)(Hansson 1998).
(2) Change in ulcer surface area
The mean percentage reduction in ulcer area was significantly
greater in the grouptreatedwith cadexomer iodine when compared
with paraffin gauze (WMD 37.70%, 95% CI 8.77 to 66.63)(Anal-
ysis 12: Outcome 02).
(3) Rate of reduction in ulcer surface areaThe weekly rate of percentage ulcer area reduction in the group
receiving cadexomer iodine was significantly greater than that with
paraffin gauze (WMD 6.00%, 95% CI 1.56 to 10.44)(Analysis
12: Outcome 03).
Secondary outcomes
(1) Cost
The cost in terms of US$ / percent of ulcer healed was US$8.8 for
cadexomer iodine and US$12.9 for paraffin gauze (price year not
stated but presume 1998) (Hansson 1998).
POVIDONE IODINE
Two trials recruiting a total of 300 participants evaluated the effect
of povidone iodine in venous leg ulcers (Groenewald 1981;Smith
1992). A third trial including a treatment group receiving povi-
done iodine has been discussed in the earlier section on systemic
antibiotics (Daroczy 2006).
Comparison 1: Povidone iodine compared with dextranomer
One trial was identified (Groenewald 1981).
Primary outcomes
(1) Time to complete healing
One hundred patients were recruited (Groenewald 1981). Most
of the ulcers were colonised by bacteria at baseline but it was
not clear how many were clinically infected. The interventions
appeared to be provided in an outpatient setting. The trial authors
reported that the mean time to healing was significantly shorter
in the group receiving dextranomer: 4.4 weeks compared with 5.3
weeks, p
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data were provided for estimation on an effect size with associated
confidence intervals.
Comparison 2: povidone iodine plus compression compared
with hydrocolloid plus compression
One trial was identified (Smith 1992).
Primary outcomes
(1) Time to healing
Smith 1992recruited 200 patients (140 completed the trial) and
stratified randomisation according to baseline maximum ulcer di-
ameter (2 to 4 cm and >4 cm). It was not reported whether the
ulcers were infected at baseline. Interventions were delivered in an
outpatient setting and consisted of application of 10% povidone
iodine paint to the wound which was then covered with paraffin
gauze compared with hydrocolloid dressing. All patients receivedtwo-layer compression or a compression stocking. Interventions
were provided for four months. The trial authors reported that, for
larger ulcers, 10% healed in less than four months in the povidone
iodine group compared with 34% in the hydrocolloid group (p =
0.02). Values for the smallerulcers were not reported butexamina-
tion of the survival plot suggested that the majority in both groups
(>80% reading from plot) had healed within the four-month trial
period.
(2) Frequency of complete healing
The between-group difference in terms of dichotomous healing
data at the trial endpoint was not statistically significant: 50/99
(51%) healed in the hydrocolloid group compared with 47/101
(47%) in the povidone iodine group (RR 0.92, 95% CI 0.69 to
1.23)(Analysis 13: Outcome 01).
(3) Rate of reduction in ulcer surface area
The trial authors reported the healing rate during the first month
of treatment based on data from 151 patients (Smith 1992). Re-
sults were reported according to the two randomisation strata for
ulcer diameter. For smaller ulcers the median healing rate was
0.062 cm squared /day (interquartile range 0.039, 0.086) forpovi-
done iodine and 0.056 cm squared /day (interquartile range 0.027,
0.085) for hydrocolloid. The values for larger ulcers were 0.017
cm squared /day (interquartile range 0.001, 0.267) and 0.184 cmsquared /day (interquartile range 0.115, 0.338) respectively. Nei-
ther difference was reported as being statistically significant.
Secondary outcomes
(1) Cost
Data on the total cost of dressings and total cost of nursing time
were reported separately for patients with an initial ulcer diameter
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Change in ulcer surface area
The estimate of effect for benzoyl peroxide 20% compared with
saline dressing was: WMD -34.10%, 95% CI -46.22 to -21.98
(Analysis 14: Outcome 02). Although both estimates from this
trial show a statistically significant effect in favour of benzoyl per-
oxide, the very small numbers recruited mean that findings mayhave occurred by chance.
Comparison 3: hydrogen peroxide plus compression
compared with standard care plus compression
Two trials with similar study protocols were performed by the
same research group on two different study groups (Belcaro 2003;
Belcaro 2007).
Primary outcomes
(1) Change in ulcer surface areaBoth trials comprised the following treatment regimen. An initial
run-in period involved the administration of systemic antibiotics
for 15 to 20 days to clear any underlying infection. Patients were
then randomised to receive hydrogen peroxide 1% cream applied
to the ulcer and periwound area or a placebo cream. For all pa-
tients, the wound was covered with tissue paper and a compres-
sion bandage applied. The study treatments were delivered in out-
patient settings. Outcomes were assessed after 10 days. In both
trials, study groups appeared to be comparable at baseline, and
no withdrawals were reported. Insufficient data were presented to
enable calculation of effect sizes and so data could not be pooled.
The earlier trial recruited 20 patients (Belcaro 2003). The trial
authors reported a statistically significant difference in ulcer areareductionbetween groupsin favourof hydrogen peroxide (median
decrease 35%, range 12% to 44%) when compared with placebo
(median decrease 11%, range 0% to 23.5%), p
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Limitations of the review
Although the search strategy was comprehensive, the effect of pub-
lication bias cannot be discounted. However, given the poor qual-
ity of most of the published evidence, it is difficult to envisage
that inclusion of unpublished data that has not had the benefit of
peer review, could add further useful information to this body ofevidence.
A U T H O R S C O N C L U S I O N S
Implications for practice
At present, there is no existing evidence to 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.
In terms of topical preparations, there is some evidence to sup-port the use of cadexomer iodine. Further good quality research is
required before definitive conclusions can be made about the ef-
fectiveness of systemic antibiotics and topical preparations such as
povidone iodine, peroxide-based preparations, ethacridine lactate
and mupirocin in healing venous leg ulceration. In light of the
increasing problem of bacterial resistance to antibiotics, current
prescribing guidelines recommend that antibacterial preparations
should only be used in cases of defined infection and not for bac-
terial colonisation (BNF 2007).
Implications for research
Most of the trials were small and had methodological problems.
Much of the research requires replication in larger, well designedstudies. Future research should pay attention to the following:
clearly defined participant selection criteria particularly with refer-
ence 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 en-
sure 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. ulcer area, complete healing rates, survival
analysis) and use of the intention-to-treat protocol.Further research is required to clarify the relationship between
healing and colonisation / infection of wounds 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 also
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
where the presence of infection does not exclude patients, num-
bers of patients with and without the clinical signs of infectionshould be reported at baseline, and groups should be comparable
for infection rates and types.
A C K N O W L E D G E M E N T S
We are very grateful to the following peer referees who provided
valuable feedback on the draft of the review: Anne-Marie Bagnall,
Nicky Cullum, Carmel Hughes and Gill Worthy. Thanks are also
due to Angela Lai, Mario Cruciani, Joanna Zakrzewska and Pawel
Kanturski for assistance with translation. Finally, we should like
to express appreciation for the support we have received from thestaff of the Cochrane Wounds Group - to Ruth Foxlee for advising
on the search strategy and running the database searches and to
Sally Bell-Syer for helpful advice and assistance with preparing the
draft review.
R E F E R E N C E S
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