antibiotici ed ulcere venose

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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

iAntibiotics and antiseptics for venous leg ulcers (Review)

Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


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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 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiAntibiotics and antiseptics for venous leg ulcers (Review)



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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)


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

1Antibiotics and antiseptics for venous leg ulcers (Review)

mailto:[email protected]://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdfhttp://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdfmailto:[email protected]


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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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14/75

One trial was identified (Huovinen 1994).

Primary outcomes


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


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


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


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


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


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


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).


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


17/75

Primary outcomes


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).


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).


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


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).


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


18/75

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.


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).


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


19/75

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


20/75


21/75

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

References to studies included in this review

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Journal of the AmericanAcademy of Dermatology1986;15(2):18691.

Alinovi A, Bassissi P, Pini M, Talignani G. Systemic administration of

antibiotics in the management of chronic venous ulcers. 14th World

Congress International Union of Angiology 6-11 July 1986 Munich,

West Germany. 1986:52728.

Beitner 1985 {published data only}

Beitner H. Treatment of chronic leg ulcers with topical application

of benzoyl peroxide lotion. Current Therapeutic Research 1985;38

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Belcaro 2003 {published data only}

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controlled study. Angiology2003;54(4):32530.

Belcaro 2007 {published data only}

Belcaro G, Cesarone MR, Errichi BM, Di Renzo A, Errichi S, Ricci

A, et al.Improvement of microcirculation and healing of venous hy-

pertension and ulcers with Crystacide: Evaluation with a micro-




22/75

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Cameron 1991 {published data only} Cameron J, Cherry GW, Poewll S, Ryan TJ. The efficacy of

mupirocin (pseudomonic acid) in the management of venous leg ul-

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Daroczy 2006 {published data only}

Daroczy J. Quality control in chronic wound management: the role

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827.

Geske 2005 {published data only}

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lactate in venous leg ulcers: A prospective, randomized, placebo-

controlled, single-blind study. Vasomed2005;17(3):99103.

Groenewald 1981 {published data only}Groenewald JH. An evaluation of dextranomer as a cleansing agentin

the treatment of the post-phlebitic stasis ulcer.South African Medical

Journal1980;57(20):80915. Groenewald JH. The treatment of varicose stasis ulcers: a con-

trolled trail. Schweizerische Rundschau fur Medizin Praxis1981;70

(28):12738.

Hansson 1998 {published data only} Hansson C. The effects of cadexomer iodine paste in the treatment

of venous leg ulcers compared with hydrocolloid dressing and paraf-

fin gauze dressing. Cadexomer Iodine Study Group. International

Journal of Dermatology1998;37(5):3906.

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symptomatic parameters in exudative venous leg ulcers. 5th Euro-

pean Conference on Advances in Wound Management November1995. 1996:1602.

Harcup 1986 {published data only}

Harcup JW, Saul PA. A study of the effect of Cadexomer iodine in

the treatment of venous leg ulcers. Brit ish Journal of Clinical Practice

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Holloway 1989 {published data only}

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Huovinen 1994 {published data only}

Huovinen S, Kotilainen P, Jarvinen H, Malanin K, Sarna S, Helander

I, et al.Comparison of ciprofloxacin or trimethoprim therapy for

venous leg ulcers: results of a pilot study. Journal of the AmericanAcademy of Dermatology1994;31(2):27981.

Kero 1987 {published data only} Kero M, Tarvainen K, Hollmen A, Pekanmaki K. A comparison of

cadexomer iodine with dextranomer in the treatment of venous leg

ulcers. Current Therapeutic Research1987;42(5):7617.

Tarvainen K. Cadexomer iodine (Iodosorb) compared with dextra-

nomer (Debrisan) in thetreatment of chronic leg ulcers. ActaChirur-

gica Scandinavica (Supplementum1988;544:579.

Laudanska 1988 {published data only}

Laudanska H, Gustavson B. In-patient treatment of chronic varicose

venous ulcersA randomizedtrial of cadexomer iodine versusstandard

dressings.Journal of International Medical Research1988;16(6):428

35.

Lindsay 1986 {published data only}

Lindsay G, Latta D, Lyons KGB, Livingstone ED, Thomson W. A

study ingeneralpractice ofthe efficacyof cadexomeriodinein venous

leg ulcers treated on alternate days. Acta Therapeutica1986;12:141

7.

Morias 1979 {published data only} Morias J, Peremans W, Campaert H, Mertens RL. Levamisole treat-

ment in ulcus cruris. A double-blind placebo-controlled. Arzneimit-

tel-Forschung1979;29(7):10502.

Moss 1987 {published data only}

Moss C, Taylor A, Shuster S. Controlled trial of Iodosorb in chronic

venous ulcers. BMJ1985;297(6499):902. Moss C, Taylor AEM, Shuster S. Comparison of cadexomer iodine

and dextranomer for chronic venous ulcers. Clinical and Experimen-

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anddextranomerin chronic legulcers. Scottish Medical Journal1984;

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Ormiston 1985 {published data only}

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randomised comparison of cadexomer iodine and a standard treat-

ment in out-patients with chronic venous ulcers. Cadexomer Iodine.

Stuttgart: Schattauer Verlag, 1983:639. Ormiston MC, Seymour MT, Venn GE, Cohen RI, Fox JA. Con-

trolled trial of Iodosorb in chronic venous ulcers. BMJ1985;291

(6491):30810.

Skog 1983 {published data only}

Hillstrom L. Iodosorb compared to standard treatment in chronic

venous leg ulcers--a multicenter study. Acta Chirurgica Scandinavica- Supplementum1988;544:536. Skog E, Arnesj B, Trong T, Gjres JE, Bergljung L, Gundersen J,

et al.A randomized trial comparing cadexomer iodine and standard

treatment in the out-patient management of chronic venous ulcers.

The British journal of dermatology1983;109(1):7783.

Troeng T, Skog E, Arnesjo B, Gjores JE, Bergljung L, Gundersen, et

al.A randomised multicentre trial to compare the efficacy of cadex-

omer iodine and standard treatment in the management of chronic

venous ulcers in out-patients. Personal Communication 4350.

Smith 1992 {published data only}

Smith JM, Dore CJ, Charlett A, Lewis JD. A randomized trial of

biofilm dressing for venous leg ulcers. Phlebology1992;7(3):10813.

Steele 1986 {published data only} Steele K, IrwinG, DowdsN. Cadexomeriodinein the management

of venous leg ulcers in general practice. The Practitioner1986;230

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Valtonen 1989 {published data only}

Valtonen V, Karppinen L, Kariniemi AL. A comparative study of

Ciprofloxacin and conventional therapy in the treatment of patients

with chronic lower leg ulcers infected with Pseudomonas aeruginosa

or other gram-negative rods. Scandinavian Journal of Infectious Dis-

eases Supplement1989;60:7983.




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References to studies excluded from this review

Altman 1976 {published data only}

Altman MA, Richter IH, Kaplan LH. Use of an aqueous triple io-

dine solution in the treatment of chronic leg ulcers and gangrene.

Angiology1976;76(27):1817.

Bazzigaluppi 1991 {published data only}

Bazzigaluppi F, Biraghi MG, Fano M, Moschin AM, Toscani P, Cer-

vone C, et al.Cadexomer iodine in the treatment of cutaneous ulcers

Open, multicentric trial. Gazetta Medica Italiana - Archivo per le

Scienze Mediche1991;150(11):47180.

Bishop 1992 {published data only}

Bishop JB, Phillips LG, Mustoe TA, VanderZee AJ, Wiersema L,

Roach DE, et al.A prospective randomized evaluator-blinded trial of

two potential wound healing agents for the treatment of venous stasis

ulcers. Journal of Vascular Surgery1992;16(2):2517.

Bourgeois 1963 {published data only}

Bourgeois P. Clinical Trials of Kitasamycin. Gazette Medicale de

France1963;70:225.

Brzeziska 1990 {published data only}

Brzeziska Wcislo L, Krauze E, Suwala Jurczyk B. Levamisole in the

treatment of crural ulcers. Przeglad Dermatologiczny1990;77(1):51

5.

Chaparro 2003 {published data only} Chaparro M, Alvarez de los Heros F, Novo E, Rodriguez-Alvarez

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varicose ulcers with sterile single-dose ciprofloxacin ampoules versus

physiologic serum. Revista Espanola de Geriatriay Gerontologia2003;

38(3):14552.

Daltrey 1981 {published data only}

Daltrey DC, Cunliffe WJ. A double-blind study of the effects of

benzoyl peroxide 20% and eusol and liquid paraffin on the microbial

flora ofleg ulcers. Acta Dermatologica Venereologica1981;61(6):5757.

Danielsen 1997 {published data only}

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in ulcers colonised by Pseudomonas aeruginosa. Journal of Wound

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Fox 1966 {published data only}

Fox DB. Trial of betamethasone 17-valerate with neomycin tulle in

thetreatmentof gravitationaleczemaand ulcerationof theleg. British

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Friedman 1984 {published data only}

Friedman SJ, Su WP. Management of leg ulcers with hydrocolloid

occlusive dressing. Archives of dermatology1984;120(10):132936.

Garcia 1984 {published data only}

Garcia HGG, Cobian RR, Martin JR, Konaizeh S, Rahola JG. The

effect on the reparation process of dextranomer (Debrisan) in peri-

malleolar ulcers due to chronic venous insufficiency. Clinical Trials

Journal1984;21(3):12134.

Hanft 2006 {published data only}

Hanft JR, Serena T, Snyder R. A study to evaluate the clinical ef-

fectiveness of a Collagen-ORC Antimicrobial Matrix in venous leg

ulcers. Wound Repair and Regeneration2006;14(2):A64.

Heggers 2003 {published data only}

Heggers JP. Assessing and controlling wound infection. Clinics in

Plastic Surgery2003;30(1):2535.

Howell-Jones 2005 {published data only}

Howell Jones RS, WilsonMJ, HillKE, HowardAJ, Price PE,Thomas

DW. A review of the microbiology, antibiotic usage and resistance in

chronic skin wounds. Journal of Antimicrobial Chemotherapy2005;

55(2):1439.

Kosicek 2004 {published data only}

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Lischka 1980 {published data only}

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healing leg ulcers A double-blind study. Munchener Medizinische

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