Clinical manifestation of infection

PEDIS grade

IDSA infection
severity

No symptoms or signs of infection

1

Uninfected

Infection present, as defined by the presence of at least 2 of the following items:

• local swelling or induration

• erythema

• local tenderness or pain

• local warmth

• purulent discharge (thick, opaque‐to‐white or sanguineous secretion)

Local infection involving only the skin and the subcutaneous tissue (without involvement of deeper tissues and without systemic signs as described below). If erythema, must be > 0.5 cm to ≤ 2 cm around the ulcer.
Exclude other causes of an inflammatory response of the skin (e.g. trauma, gout, acute Charcot neuro‐osteoarthropathy, fracture, thrombosis, venous stasis)

2

Mild

Local infection (as described above) with erythema > 2 cm, or involving structures deeper than skin and subcutaneous tissues (e.g. abscess, osteomyelitis, septic arthritis, fasciitis), and no systemic inflammatory response signs (as described below)

3

Moderate

Local infection (as described above) with the signs of SIRS, as manifested by ≥ 2 of the following:

• temperature > 38°C or < 36°C

• heart rate > 90 beats/min

• respiratory rate > 20 breaths/min or PaCO₂ < 32 mmHg

• white blood cell count > 12,000 or < 4000 cells/μL or ≥ 10% immature (band) forms

4

Severe*

Product and formulations

Formulations

Bacterial spectrum

Advantages

Disadvantages

Cost^a

Indications^b and comments

Acetic acid

0.25%, 0.5%, and 1% solutions

Bactericidal against most gram‐positive and gram‐negative organisms, including Pseudomonas aeruginosa

Inexpensive; shown to eliminate P aeruginosa colonisation from burn

Cytotoxic in vitro although maybe not in vivo; limited activity against biofilm

$

No longer as widely used as in the past

Cadexomer iodine

Gel,^c ointment, and dressing

Polysaccharide starch lattice; active agent is slowly released free iodine; broad spectrum of activity (same as iodine)

Reduced local toxicity compared to iodine; elemental iodine released on exposure to exudate

Application may cause stinging and erythema, but less tissue damage than other iodine products; effect may not persist, and efficacy may be reduced in body fluids.

$$

Indicated for use in cleaning wet ulcers and wounds and reducing microbial load in the wound environment

Cetrimide

Solution, 40%

Active against bacteria and fungi; not active against P aeruginosa

May be less toxic to wound tissues than other antiseptics

May be corrosive and is potentially harmful if swallowed

$

Not available in the USA

Chlorhexidine

gluconate

Solution, 2% and 4%; liquid, 2% and 4%; hand rinse, 0.5%; wipes, 0.5%; sponge/brush, 4%; and foam, 4%

Active against gram‐positive bacteria (e.g. Staphylococcus aureus) and gram‐negative bacteria, including P aeruginosa

Persistent activity up to 6 h after application; few adverse effects

Hypersensitivity, including anaphylaxis, generalised

urticaria, bronchospasm, cough, dyspnoea, wheezing, and malaise; may cause serious injury to the eye and middle ear; avoid contact with face or head; some resistance reported

$

2% chlorhexidine indicated as surgical hand scrub, hand wash, skin and wound cleanser; polyhexanide is a similar, newer biguanide.

Hexachlorophene

Liquid, 3%; foam, 0.23% with 56% alcohol

Biguanide that is bacteriostatic against Staphylococcus species and other gram‐positive bacteria

May retain residual effect on skin for several days

Rapidly absorbed and may result in toxic blood levels; application to burns has resulted in neurotoxicity and death; may cause central nervous system stimulation and convulsions, dermatitis, and photosensitivity reactions

$$$

Not recommended for routine use on wounds due to potential toxicity

Iodine compounds and iodine tincture^c

Solution (aqueous) 2% and 2.4%; and tincture (44% to 50% alcohol) 2% and 2.4%

Microbicidal against bacteria, fungi, viruses, spores, protozoa, and yeasts

Broad spectrum

Highly toxic if ingested or significantly absorbed; do not use with occlusive dressings; causes pain and stains skin and clothing; use cautiously in people with thyroid disorders

$

Iodine compounds are now rarely used for wound management; cadexomer iodine and povidone iodine products are less toxic.

Povidone iodine^c

Ointment, 1%, 4.7%, 10%; solution, 1% and 10%; also wash, scrub, cleanser, gel, aerosol, gauze pad, swab, and other forms

Broad spectrum includes S aureus and enterococci; active ingredient is liberated free iodine; shares spectrum but is less potent than iodine

Less irritating to skin and allergenic than iodine. Can be covered with dressings. Clinically significant resistance very rare

Antibacterial action requires at least 2 min contact; may cause stinging and erythema; effect may not persist, and efficacy may be reduced in body fluids; prolonged use may cause metabolic acidosis; stains skin and clothing; possible interaction with starches in dressings

$

Indicated for perioperative skin cleansing and for cleansing and prevention of infection in superficial burns, incisions, and other superficial wounds

Sodium hypochlorite

(Dakin’s solution

and EUSOL)

Solution, 0.0125%, 0.125%, 0.25%, and 0.5%

Vegetative bacteria, viruses, and some spores and fungi

Inexpensive

No known systemic toxicity. May require prolonged contact for antibacterial action; inactivated by pus; toxic to fibroblasts and keratinocytes, and may cause pain or lyse blood clots

$

A concentration of 0.025% is both bactericidal and non‐toxic to tissues (Heggers 1991).

Hydrogen peroxide^c

Solution, 1% and 3%; and cream, 1%

Oxidizing agent active against many gram‐positive and gram‐negative bacteria

Broad‐spectrum, bactericidal, inexpensive; no known 1q11

May cause some discomfort

$

Commonly used, but few clinical studies

Silver nitrate

Solution 0.5%, 10%, 25%, and 50%; ointment, 10%; and swabs, 25% to 50%

Silver ions are bactericidal against a broad spectrum of gram‐positive and gram‐negative bacteria.

Low cost; easily applied

Painful on application; stains tissues; may delay healing; concentrations 10.5% cause cauterisation; inactivated by wound exudates and chlorine

$

Previously widely used, but now largely replaced by other compounds, including newer silver dressings

Silver dressings

At least 6 approved products with different properties

Slowly released silver ions have broad spectrum, including MRSA and VRE.

Provide sustained levels of active silver ions; microbial resistance is rare; less painful and few adverse effects than silver nitrate; variety of products adaptable to different types of wounds; infrequent application required

Levels of silver ions at wound interface not well defined; may cause silver staining of tissues; may delay epithelialisation; relatively expensive; few published comparative trials

$$

Should not substitute for non‐medicated dressings for uninfected wounds; may be useful for subclinically infected, highly colonised wounds or for wounds being prepared for skin grafting

Product and
formulations

Formulations

Bacterial spectrum

Advantages

Disadvantages

Cost^a

Indications^b and comments

Bacitracin c

Ointment, 500 units/g; and powder combinations with neomycin, polymyxin B, and zinc

Many gram‐positive organisms, including aerobic staphylococci and streptococci, corynebacteria, anaerobic cocci, and clostridia; inactive against most gram‐negative organisms

Activity not impaired by blood, pus, necrotic tissue, or large bacterial inocula; resistance is rare but increasing among staphylococci; no cross‐resistance with other antibiotics; minimal absorption

May cause allergic reactions, contact dermatitis, and (rarely) anaphylactic reactions; may lead to overgrowth of drug‐resistant organisms, including fungi

$

Widely used for many years; indicated for prevention of infection in minor skin wounds

Fusidic acid

Cream, 2%; ointment, 2%; and gel, 2%

Staphylococcus aureus, streptococci (in topical concentrations), corynebacteria, and clostridia

Penetrates intact and damaged skin as well as crust and cellular debris

Occasional hypersensitive reactions; resistance among staphylococci is emerging; must apply 3 times daily

$$

Not available in the USA

Gentamicin

Cream, 0.1%; and ointment, 0.1%

Streptococci, staphylococci, Pseudomonas aeruginosa, Enterobacter aerogenes, Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniae

Broad spectrum; inexpensive

Must be applied 3 to 4 times daily; may drive resistance to an agent used systemically

$

Indicated for primary skin infections (pyodermas) and secondary skin infections, including infected excoriations, and for bacterial superinfections

Mafenide acetate

Solution, 5%; and cream, 85 mg/g

A sulfonamide that is bacteriostatic against many gram‐negative organisms, including P aeruginosa, and some gram‐positive organisms, but minimal activity against staphylococci and some obligate anaerobes

Remains active in the presence of pus and serum, and its activity is not affected by acidity of environment

Systemic absorption may occur; drug and metabolites may inhibit carbonic anhydrase, potentially causing metabolic acidosis; use cautiously in patients with renal impairment; pain on application; hypersensitive reactions.

$$$

Indicated as adjunctive therapy in second‐ and third‐degree burns; may be used in rapidly progressing bacterial necrotising fasciitis; limited use in other wounds

Metronidazole

Cream, 0.75%; gel, 1%; lotion, 0.75%

Many clinically important anaerobic bacteria

May reduce odour associated with anaerobic infections; application only 1 to 2 times daily

Relatively expensive; systemic formulations available; could drive resistance to these

$–$$

Indicated for inflammatory papules and pustules of rosacea

Mupirocin and mupirocin calcium

Ointment, 2%; for mupirocin calcium, cream, 2.15%; and nasal ointment,
2.15% (equivalent to 2% mupirocin)

Gram‐positive aerobes, including S aureus (most MRSA), Staphylococcus epidermidis, Staphylococcus saprophyticus, and streptococci (groups A, B, C, and G) but not enterococci, some gram‐negative aerobes (not P aeruginosa), corynebacteria, and obligate anaerobes

Minimal potential for allergic reactions

Rare local burning and irritation; applying ointment to large wounds in azotaemic patients can cause accumulation of polyethylene glycol; long‐term use can lead to resistance among staphylococci, which is increasing

$$

Indicated for topical treatment of impetigo and eradication of nasal colonisation with S aureus

Neomycin sulfate^c

Powder; cream, 0.5%; combinations with polymyxin B and pramoxine, and ointment, 0.5%; combinations with bacitracin, polymyxin B, lidocaine, and pramoxine

Good for gram‐negative organisms but not P aeruginosa; active against some gram‐positive
bacteria, including S aureus, but
streptococci are generally resistant; inactive
against obligate anaerobes

Low cost; applied only 1 to 3 times daily; may
enhance re‐epithelialisation

Topical powder in wound irrigating solution
may cause systemic toxicity (FDA banned); use other formulations cautiously on large wounds, especially with azotaemia; hypersensitive reaction in 1% to 6%, often with chronic use or history of allergies.

$

Use of topical powder alone or in solution is not recommended; cream and ointment, in combination with other agents, are indicated for prevention of infection in minor skin injuries.

Nitrofurazone

Solution, 0.2%; ointment, 0.2%; and cream, 0.2%

Broad gram‐positive and gram‐negative activity,
including S aureus and streptococci, but not P aeruginosa

Used mainly for burn wounds

Hypersensitive reactions; polyethylene glycols (in some formulations) may be absorbed and can cause problems in azotaemic patients

$$

Indicated as adjunctive to prevent infections in people with second‐ and third‐degree
burns

Polymyxin B^c

Cream, 5000 units/g or
10,000 units/g, in combination
with other agents

Bactericidal against many gram‐negative organisms,
including P aeruginosa; minimal activity against gram‐positive bacteria; activity may be neutralised by divalent cations

Inexpensive

Some hypersensitive and neurological or
renal adverse reactions reported; may show cross‐reaction with bacitracin.

$

Only available in combination with other agents, including bacitracin and neomycin;
indicated for prevention

Retapamulin

Ointment, 1%

Active against staphylococci (but uncertain
for MRSA) and streptococci and some obligate
anaerobes

May be active against some mupirocin‐resistant S aureus strains; broader activity than mupirocin

Not evaluated for use on mucosal surfaces; may cause local irritation

$$$

Indicated for impetigo due to S aureus (methicillin‐susceptible only) or Streptococcus pyogenes

Silver sulphadiazine

Cream, 1%

A sulfonamide; the released silver ions are the primary active ingredient; active against many gram‐positive and gram‐negative organisms, including P aeruginosa
.

Applied only once or twice daily; soothing
application; low rate of hypersensitive reaction

Potential cross‐reaction with other sulphonamides; may rarely cause skin staining

$

Indicated as adjunctive treatment to prevent
infections in people with second‐ and third‐degree burns

Sulfacetamide Na+

Lotion, 10%

Bacteriostatic against many gram‐positive and gram‐negative pathogens

Broad spectrum; can be combined with sulphur

Systemic absorption and rarely severe side
effects occur with application to large, denuded areas; hypersensitive reactions
may occur.

$$$

Indicated for secondary bacterial skin infections
due to susceptible organisms and for acne vulgaris in adults

Title (comparator)

Current status

Relevant outcomes listed

Database

Results (# enrolled)

Listed contact

Company and any further information received

Phase IIa Randomised, Placebo Controlled Trial to Investigate Antimicrobial Photodynamic Therapy in Chronic Leg Ulcers and Diabetic Foot Ulcers (placebo = “cream”)

Prematurely ended (date unclear)

Photodynamic therapy using the combined effect of 3,7‐bis(N,N‐dibutylamino) phenothiazin‐5‐ium bromide (PPA904) and light; measure reduction of bacterial content of diabetic foot ulcers

ClincialTrialsRegister.eu

EudraCT number: 2005‐001363‐58

None (not listed)

None listed.

Photopharmacia

Pexiganan Versus Placebo Control for the Treatment of Mild Infections of Diabetic Foot Ulcers (OneStep‐1 and 2)

Completed (August 2016)

1°: clinical response (resolution of infection);

2°: microbiological response; safety

ClinicalTrials.gov; NCT01594762

No results (200 for each of the 2 trials) reported on website.

Robert Deluccia, Dipexium

Dipexium Pharmaceuticals, Inc.

Multicentre study; all sites

outpatient centre in USA

Comparison of Resin Salve and Octenidine in Patients with Neuropathic Diabetic Foot Ulcers (comparator: octenidine dihydrochloride‐impregnated gauze)

Completed (May 2015)

Investigate healing rate and healing time of neuropathic diabetic foot ulcer in people suffering from infected fore‐ or mid‐foot ulceration. 2°: eradication of bacteria; wound healing and infection

ClinicalTrials.gov;

NCT02169167

No results on website (n = 35)

(see addendum in “comments”)

Janne J Jokinen

Salve prepared from

Norway spruce (Repolar Ltd.)

Clinical Outcomes for Diabetic Foot Ulcers Treated With Clostridial Collagenase (SANTYL®) Ointment or With a Comparator Product Containing Silver (investigator choice of silver)

Running until January 2017 (last updated November 2016)

Randomly assigned to apply SANTYL or a topical treatment containing silver to their to foot ulcer. 1°: mean change in ulcer area at end of treatment; 2°: target ulcer infection rate

ClinicalTrials.gov; NCT02581488

No results (102)

Jaime E Dickerson, PhD (Smith & Nephew)

(Smith & Nephew)

Information from the sponsor received end of December 2016 stated that the trial is not yet complete but last participant out will be achieved in the next week. The trial enrolled its target number of participants, with the last participant completed December 2016. The evaluability will be carried out prior to the scheduled database lock in January 2017. As intention‐to‐treat is the analysis set for primary inference, it is anticipated that all participants will be included. Final study report is timed for April 2017 (15 December 2016).

Waiting for further information to assess eligibility for review

Randomized, Controlled Study to Investigate the Efficacy and Safety of a Topical Gentamicin‐Collagen Sponge in Combination with Systemic Antibiotic Therapy in Diabetic Patients With a Moderate or Severe Foot Ulcer Infection

Recruiting (as of September 2013)

1°: "clinical cure" at the test of cure; 2°: clinical response; time to clinical cure; eradication of baseline pathogen

ClinicalTrials.gov; NCT01951768

No results (estimate 144)

Ilker Uckay, MD; Hospital of the University of Geneva

Innocoll, Inc.

Comparison of the Efficacy of Standard Treatment Associated with Phage Therapy Versus Standard Treatment Plus Placebo for Diabetic Foot Ulcers Monoinfected by Staphylococcus aureus: a Randomized, Multi‐centre, Controlled, 2‐parallel‐group, Double‐blind, Superiority Trial

Starting January 2017

1°: reduction in wound surface area;

2°: safety; changes in resistance and virulence of S aureus isolates; production of anti‐phage antibodies

ClinicalTrials.gov; NCT026647401

No results (estimate 60)

Albert Sotto, MD, PhD

+33.(0)6.09.56.66.55

Centre Hospitalier Universitaire de Nīmes; Pherecydes Pharma.

Per correspondence from Prof Sotto on 8 January 2017, National Agency for the Safety of Medicines and Health Products requested “pre‐clinical phase complements”, causing a postponement of the start of the clinical trial.

A Phase I/IIa, Randomized Double Blind, Placebo‐Controlled, Dose Escalating Study to Evaluate the Safety and Tolerability of Topically Applied Bisphosphocin Nu‐3 on Infected Diabetic Ulcers of Subjects With Type I or II Diabetes Mellitus (placebo)

Enrolling by invitation only (last verified April 2016)

Diabetic foot ulcers; infection localised to area of ulcer and mild.

1° outcome: treatment‐related adverse events, safety

2°: microbiological activity evaluated by wound assessments, presence of pathogenic bacteria

ClinicalTrials.gov; NCT02737722

No results (estimate 30)

Paul DiTullio, MSc

Lakewood‐Amedex, Inc.

A Phase II, Randomized, Parallel, Double‐blind, Placebo‐controlled Study to Assess Prevention of Infection Using a Topical Gentamicin‐Collagen Sponge in Diabetic Patients With Uninfected Lower Extremity Skin Ulcers (placebo sponge)

Terminated (last verified March 2012)

1° outcome: uninfected diabetic foot ulcers that remain free of signs/symptoms of infection to end of study

2°: days to wound closure; time to any signs/symptoms of infection; decrease in wound area; pathogen burden in infected wounds

ClinicalTrials.gov; NCT00658957

No results (49)

David Prior, PhD; Chesapeake Foot and Ankle Center, Pasadena (MD), USA

Innocoll Pharmaceuticals

A Phase 3 Randomized, Placebo‐Controlled, Blinded Study to Investigate the Safety and Efficacy of a Topical Gentamicin‐Collagen Sponge in Combination With Systemic Antibiotic Therapy in Diabetic Patients With an Infected Foot Ulcer (COACT 1 and 2) (placebo is no sponge)

Last updated June 2016

Sponge is adjunctive treatment to systemic antibiotic therapy.

1° outcome: per cent of participants with a clinical outcome of clinical cure (resolution of all clinical signs and symptoms of infection) ˜10 days after end of treatment;

2° outcomes: baseline pathogen eradication; re‐infection; time to clinical cure; amputation; ulcer closure

ClinicalTrials.gov:

NCT02447172

No results posted.

Nigel Jones, VP, Global Clinical Operations, Innocoll Pharmaceuticals

Innocoll Pharmaceuticals

Study of the Efficacy of Topical Application of Royal Jelly and Panthenol (PedyPhar® Ointment) on the Diabetic Foot Ulcers, an Open Label, Randomized, Non‐placebo‐controlled Study (active comparator panthenol ointment)

Terminated; (last updated February 2015)

Diabetic foot ulcers at any stage after proper surgical treatment (if needed)

1° outcome: healing of ulcer;

2°: reduction of infection in ulcer site; local reaction possibly related to study drug

ClinicalTrials.gov; NCT01531517

No results (estimate 120; 47 enrolled)

(?)

European Egyptian Pharmaceutical Industries

Platelet Rich Fibrin in Combination With Topical Antibiotics or Antiseptics in the Treatment of Chronic Wounds ‐ a Prospective, Randomized, Active Controlled, Double Blind Pilot Trial With an Observer‐blinded Control Group (3 platelet rich fibrin arms & 1 active comparator (Acticoat))

Recruiting (last verified January 2016)

People with infected chronic wounds (unclear if diabetic foot)

1° outcome: reduction of wound area; 2°: number requiring systemic antimicrobial therapy; C‐reactive protein level; wound volume; occurrence of drug‐resistant bacteria

ClinicalTrials.gov; NCT02652169

No results (estimate 120)

Florian Thalhammer, Medical University of Vienna; 0043140400 ext 44400; [email protected]

Medical University of Vienna

Double Blind, Randomized, Placebo Controlled Clinical Trial for the Treatment of Diabetic Foot Ulcers, Using a Nitric Oxide Releasing Patch: PATHON

Completed (last verified November 2012)

1° outcome: per cent reduction in ulcer size;

2°: complete cure of any infection; development of infection during treatment; adverse events

ClinicalTrials.gov; NCT00428727

No results (?)

Fundación Cardiovascular de Colombia

(?)

A Phase I/II, Open Label, Controlled Study to Evaluate the Safety and Efficacy of AppliGel‐G (Gentamicin Sulfate Topical Gel) for Treatment of Mild to Moderately Infected Diabetic Foot Ulcers in Patients With Type 1 and Type 2 Diabetes (comparator oral ciprofloxacin and doxycycline alone)

Terminated (last verified May 2015)

For mild to moderately infected diabetic foot ulcers

1°: complete wound clearing of infection

2°: incidence infection cleared; wound volume and area change

ClinicalTrials.gov; NCT02036528

No results

Royer Biomedical, Inc.

Royer Biomedical, Inc.

A Randomised, Double‐blind, Dose‐response, Placebo‐controlled, Multicenter, Phase IIA Clinical Study to Evaluate the Efficacy and Safety of Topical Application of G.68.y/EtOH in Patients with Type 1 or Type 2 Diabetes With Infected Foot Ulcers (placebo topical gel)

Completed

Enrolling patients with infected “grade 2 PEDIS” diabetic foot ulcers

1°: reduction of bacterial load

2°: maintenance of efficacy; tolerability and safety

EudraCT number: 2010‐019598‐13

No results (plan for 60)

[email protected]

Molteni

Trial to Assess Safety and Efficacy of Topical MBN‐101 (BisEDT ) in Patients With Moderate/ Severe Diabetic Foot Infections (placebo – vehicle‐controlled)

Not yet open for participant recruitment (last update March 2016)

Part I, participants will be enrolled into 1 of 3 escalating dose cohorts at a ratio of 3:1 (active to placebo). In Part II, participants will be randomised in a 1:1 ratio (active to placebo) based on the optimal dose demonstrated in Part I. People with infected foot ulcer

ClinicalTrials.gov; NCT02723539

No results (plan for 88)

Department of Vascular Surgery, Rigshospitalet

Copenhagen, Denmark, 2100

Microbion Corporation

Intervention 1

Intervention 2

Foot ulcer grade

Infection status at baseline

Follow‐up

Review‐relevant

outcomes with reportable data

Ahmed 2014

Group 1: (n = 30) Pyodine bath and saline and vaseline gauze dressing

Group 2: (n = 30) Phenytoin powder

Grade I or II

Not reported

8 weeks

None reported

Apelqvist 1996

Group 1: (n = 19) Gentamicin solution

Group 2: (n = 22) Cadexomer iodine ointment

Grade I or II

Not reported

12 weeks

1. Proportion of ulcers healed

2. Surgical resection

3. Adverse events

Bergqvist 2016

Group 1: (n = 19) Standard care

Group 2: (n = 21) Chloramine plus standard care

Not reported

Infected

24 weeks

1. Proportion of ulcers healed

2. Resolution of infection

3. Surgical resection

Bowling 2011

Group 1: (n = 10) Saline solution

Group 2: (n = 10) Super‐oxidised aqueous solution

Grade I or II

Not infected

4 weeks

1. Adverse events

Gottrup 2013

Group 1: (n = 15) Foam dressing

Group 2: (n = 24) Silver collagen/oxidised regenerated cellulose dressing

Grade II or III

Not infected

14 weeks

1. Proportion of ulcers healed

2. Incidence of wound infection

3. Adverse events

He 2016

Group 1: (n = 40) Routine debridement plus standard care (including blood glucose control, nutritional support, improve microcirculation

Group 2: (n = 40) Silver ion dressing plus standard care

Not reported

Not reported

4 weeks

1. Proportion of ulcers healed

Hwang 2010

Group 1: (n = not reported) Iodine gauze

Group 2: (n = not reported) Hydrofiber dressing with silver

Ulcers with bone and tendon exposure

Not reported

Not reported

Not reported

Imran 2015

Group 1: (n = 180) Saline dressing

Group 2: (n = 195) Honey dressing

Grade I or II

Not reported

17 weeks

1. Proportion of ulcers healed

2. Time to healing

Jacobs 2008

Group 1: (n = 20) Silver sulphadiazine cream

Group 2: (n = 20) Formulation of benzoic acid, 6%; salicylic acid, 3%; and extract of oak bark (Quercus rubra), 3% (Bensal HP with QRB7), with silver sulphadiazine cream

Grade I or II

Not reported

6 weeks

1. Proportion of ulcers healed

Jeffcoate 2009

Group 1: (n = 108) Non‐adherent dressing, viscose filament gauze

Group 2: (n = 103) Hydrocolloid (Hydrofiber) dressing

Group 3: (n = 106) Iodine‐containing dressing

Not reported

Not reported

24 weeks

1. Proportion of ulcers healed

2. Health‐related quality of life (Cardiff Wound Impact Schedule and SF‐36)

3. Surgical resection (amputations (minor and major))

4. Adverse events (serious and non‐serious)

Jude 2007

Group 1: (n = 67) Calcium‐alginate dressing

Group 2: (n = 67) Fibrous‐hydrocolloid (Hydrofiber) dressing with 1.2% ionic silver

Grade I or II

Mixed infected and not infected

8 weeks

1. Proportion of ulcers healed

2. Incidence of wound infection

3. Adverse events

Khandelwal 2013

Group 1: (n = 20) Hyperbaric oxygen therapy (not considered further)

Group 2: (n = 20) Recombinant human platelet‐derived growth factor

Group 3: (n = 20) Antiseptic treatments (EUSOL, hydrogen peroxide, and povidone iodine)

Grade III or IV

Not reported

More than 8 weeks

1. Proportion of ulcers healed

Landsman 2011

Group 1: (n = 21) Topical saline solution plus 750 mg levofloxacin once per day

Group 2: (n = 21) Super‐oxidised aqueous solution (topical Microcyn) alone (not considered)

Group 3: (n = 21) super‐oxidised aqueous solution (topical Microcyn) therapy plus 750 mg levofloxacin once per day

Eligible foot ulcers involved skin and deeper soft tissue

Infected

4 weeks

1. Resolution of infection

2. Adverse events

Lipsky 2008a

Group 1: (n = 246) Ofloxacin (200 mg) oral tablets and a topical placebo (vehicle) cream

Group 2: (n = 247) Topical pexiganan cream (1% or 2%) and placebo oral tablets

Not reported

Infected

Up to 42 days

1. Surgical resection

2. Adverse events

Lipsky 2008b

Group 1: (n = 171) Ofloxacin (200 mg) oral tablets and a topical placebo (vehicle) cream

Group 2: (n = 171) Topical pexiganan cream (1%) and placebo oral tablets

Full‐thickness wounds

Infected

Up to 42 days

1. Surgical resection

2. Adverse events

Lipsky 2012a

Group 1: (n = 38) Systemic antibiotic therapy alone

Group 2: (n = 18) Daily topical application of the gentamicin‐collagen sponge combined with systemic antibiotic therapy

Not reported

Infected

Up to 42 days

1. Resolution of infection

2. Adverse events

Martinez‐De Jesus 2007

Group 1: (n = 16) Povidone iodine and saline

Group 2: (n = 21) Neutral pH super‐oxidised aqueous solution

Not reported

Infected

20 weeks

1. Resolution of infection

Ramos Cuevas 2007

Group 1: (n = 25) Conventional treatment (no further details translated)

Group 2: (n = 25) Zinc hyaluronate

Not reported

Unclear

20 weeks

1. Proportion of ulcers healed

Shukrimi 2008

(30 participants randomised, but number in each group not specified)

Group 1: Standard‐dressing group (povidone iodine solution 10%) (n not reported)

Group 2: Honey dressing group (n not reported)

Grade II

Not reported

Not reported

No useable data

Tom 2005

Group 1: Normal saline solution, 11 ulcers (in 10 participants)

Group 2: Tretinoin group, 13 ulcers (in 12 participants)

Not reported

Not reported

16 weeks

1. Proportion of ulcers healed

Ullal 2014

Group 1: (n = 2) Povidone iodine and metronidazole 1% gel dressing

Group 2: (n = 2) Honey and metronidazole 1% gel dressing

Grade I and II

Not reported

Not reported

1. Proportion of ulcers healed

Viswanathan 2011

Group 1: (n = 19) Polyherbal formulation

Group 2: (n = 19) silver sulphadiazine cream

Grade I, II, and III

Unclear

20 weeks

No useable data

Resolution of infection

Incidence of wound infection

Time to healing

Proportion of wounds healed

Microbial counts

Health‐related quality of life

Need for surgical resection, including partial or complete lower limb amputation

Safety (adverse events)

Ahmed 2014

Group 1: (n = 30)

Povidone iodine bath and saline Vaseline gauze dressing

Group 2: (n = 30) Phenytoin powder plus povidone iodine bath and saline Vaseline gauze dressing

Not infected at baseline

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Apelqvist 1996

Group 1: (n = 19) Gentamicin solution

Group 2: (n = 22) Cadexomer iodine ointment

Baseline infection status not reported.

Not reported

Not reported

Not reported

Group 1:

2/18

Group 2:

5/17

Not reported

Not reported

Surgical resection was reported:

Group 1: 5/19

Group 2: 3/22

Study reports that no adverse

reactions related to the topical treatment were documented.

Bergqvist 2016

Group 1: (n = 19) Standard care alone

Group 2: (n = 21) Chloramine plus standard care

Infected at baseline

Group 1: 7/15

Group 2: 9/13

Not reported

Time‐to‐event data presented with no reported hazard ratio. Given the small number of participants and events, no further attempts were made to calculate time‐to‐event values.

Healed at 24 weeks

Group 1: 9/17

Group 2: 10/17

Not reported

Not reported

Vascular procedure or amputation

Group 1: 3/17

Group 2: 5/17

Adverse event data reported but unable to get a per‐participant value, as it is noted that some participants had more than 1 event.

Bowling 2011

Group 1: (n = 10) Saline solution

Group 2: (n = 10) Super‐oxidised aqueous solution

Not infected at baseline

Not reported

Not reported

Not reported

Study notes that 15% of the study ulcers

were healed, but this information not reported by group.

The bacterial load in the wound bed was defined as

scattered (0/+), light (+), medium (++), or heavy (+++).

At week 4 there was a reduction of

33% in the bacterial load versus baseline.

Figure presented but difficult to interpret data by group.

Not reported

Not reported

No safety concerns were reported in either the

super‐oxidised aqueous solution group or the saline

group; no adverse reactions were recorded.

Gottrup 2013

Group 1: (n = 15) Foam dressing

Group 2: (n = 24) Silver collagen/oxidised regenerated cellulose dressing

Not infected at baseline

Not reported

Wound infection

Group 1: 4/13

Group 2: 0/23

Not reported

Healed by week 14

Group 1: 4/13

Group 2: 12/23

Not reported

Not reported

Not reported

Limited details of adverse events (in addition to infection data already recorded). There were no reported adverse events related to the use of collagen/oxidised regenerated cellulose/silver dressing, and 5 cases of adverse events (no further details) related to foam dressing.

He 2016

Group 1: (n = 40) Routine debridement plus standard care

Group 2: (n = 40) Silver ion dressing plus standard care

Baseline infection status not reported.

Not reported

Not reported

Mean wound healing time in days:

Group 1: 47.4 ± 11.5

Group 2: 31.3 ± 8.2

Mean granulation tissue occurrence time in days:

Group 1: 10.8 ± 1.9

Group 2: 6.4 ± 0.72

Group 1: 15/40

Group 2: 24/40

Not reported

Not reported

Not reported

Not reported

Hwang 2010

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Imran 2015

Group 1: (n = 180) Treated with normal saline dressing

Group 2: (n = 195) Treated with honey dressing

Not reported

Not reported

Median healing time in honey group is 18 days (IQR is 6 to 120), and in the saline group is 29 days (IQR 7 to 120).

Data do not seem to have been calculated using correct time‐to‐event approaches and were not considered further.

Group 1: 97/169

Group 2: 136/179

Not reported

Not reported

Not reported

Not reported

Jacobs 2008

Group 1: (n = 20) Silver sulphadiazine

Group 2: (n = 20) Formulation of benzoic acid, 6%; salicylic acid, 3%; and extract of oak bark (Quercus rubra), 3% (Bensal HP with QRB7), with silver sulphadiazine cream

Baseline infection status not reported.

Not reported

Not reported

Not reported

Healed by week 6

Group 1: 6/20

Group 2: 8/20

Not reported

Not reported

Not reported

Not reported

Jeffcoate 2009

Group 1: (n = 108) Non‐adherent dressing, viscose filament gauze (Johnson & Johnson)

Group 2: (n = 103) Hydrocolloid (Hydrofiber) dressing (Aquacel, ConvaTec)

Group 3: (n = 106) Iodine‐containing dressing (Inadine, Systagenix)

Baseline infection status not reported.

Not reported

Number of infected ulcers at 24 weeks: not reported by group

Study reports the number of episodes of infection listed as serious adverse events, but it is unclear if foot infections, and not clear how many people had how many infection events.

Mean time to healing in days (SD) (fixed at max of 168 days)
Group 1: 130.7 (52.4)

Group 2: 125.8 (55.9)

Group 3: 127.8 (54.2)

Not all ulcers healed, so mean is inappropriate measure of time to healing.

Number of ulcers healed at 24 weeks:
Group 1: 41/108

Group 2: 46/103

Group 3: 48/106

Not reported

Mean Cardiff Wound Impact Schedule score at 24 weeks (SD)

Group 1: Physical functioning: 68.9 (19.1). Social functioning: 69.8 (23.5). Well‐being: 50.2 (21.1)

Group 2: Physical functioning: 71.4 (19.5). Social functioning: 70.3 (25.4). Well‐being: 53.1 (19.9)
Group 3: Physical functioning: 67.1 (23.6). Social functioning: 69.7 (24.1). Well‐being: 51.0 (22.3)

Other
Study also reports mean and SD for each of the 8 domains of the SF‐36. There was no significant difference between the groups for any domain.

Minor amputations (below ankle):
Group 1: 1/108
Group 2: 3/103
Group 3: 1/106
Major amputations (above knee)
Group 1: 1/108

Group 2: 1/103
Group 3: 0/106

n not clear; assumed to be all participants

Non‐serious adverse events
Group 1: 244/108

Group 2: 227/103

Group 3: 239/106

Serious adverse events
Group 1: 35/108

Group 2: 28/103

Group 3: 37/106

Not clear how many participants had how many events, but seems to be more than 1 per person; data not analysed further

Jude 2007

Group 1: (n = 67) Calcium‐alginate dressing

Group 2: (n = 67) Fibrous‐hydrocolloid (Hydrofiber) dressing with 1.2% ionic silver

Mixed wound infection status at baseline

Not reported

Group 1: 11/67

Group 2: 8/67

Time to 100% healing also reported, but this is only for a subset of those that healed, so not a useful pan‐study measure. Not reported

Mean time to healing in days

Group 1: 52.6 ± 1.8

Group 2: 57.7 ± 1.7

Number of ulcers healed in 8 weeks
Group 1: 15/67
Group 2: 21/67

Not reported

Not reported

Not reported

Group 1: 26/67 participants experienced adverse event. Death = 1; Infection = 8. 13 participants discontinued treatment due to adverse event.

Group 2: 25/67 participants experienced 1 or more events. Death = 1; Infection = 14. 8 participants discontinued treatment due to adverse event.

Khandelwal 2013

Group 1: (n = 20) Hyperbaric oxygen therapy (not considered in review)

Group 2: (n = 20) Recombinant human platelet‐derived
growth factor

Group 3: (n = 20) Antiseptic dressings

Not reported

Not reported

Mean time to healing in weeks (standard error)

Group 1: 6.83 (2.5)

Group 2:

7.6 (2.5)

Group 3: 6.75 (2.7)

Not all ulcers healed, so mean is inappropriate measure of time to healing.

Number of ulcers healed

Group 1: 12/20

Group 2: 16/20

Group 3: 8/20

Review authors calculated figures from graph.

Not reported

Not reported

Not reported

Not recorded

Landsman 2011

Group 1: (n = 21) Levofloxacin plus saline

Group 2: (n = 21) Super‐oxidised aqueous solution alone (not considered)

Group 3: (n = 25) Levofloxacin plus super‐oxidised aqueous solution

Ulcers infected at baseline.

Group 1: 6/21

Group 2: 11/21

Group 3: 11/25

Not reported

Not reported

Mentioned, but data not presented.

Not reported

Not reported

Not reported

Adverse events (number of participants with 1 or more event)

Group 1: 7/21

Group 2: 7/21

Group 3: 9/25

Lipsky 2008a

Group 1: (n = 246) Ofloxacin

Group 2: (n = 247) Pexiganan

Ulcers infected at baseline.

Not reported

Resolution ("cure") and improvement data presented together, so unclear how many participants had resolution.

Not reported

Not reported

Not reported

Not reported

Not reported

See below ‐ results presented by study authors cumulatively for these 2 studies only.

Adverse events (number of participants with > 1 adverse event)

Group 1: 109/246

Group 2: 98/247

Lipsky 2008b

Group 1: (n = 171) Ofloxacin

Group 2: (n = 171) Pexiganan

Ulcers infected at baseline.

Not reported

Resolution ("cure") and improvement data presented together, so unclear how many participants had resolution.

Not reported

Not reported

Not reported

Not reported

Not reported

Group 1: 9/417

Group 2: 11/418 (cumulative of two RCTs reported in single paper)

Adverse events (number of participants with > 1 adverse event)

Group 1: 84/171

Group 2: 76/171

Lipsky 2012a

Group 1: (n = 18) Systemic antibiotic therapy alone

Group 2: (n = 38) Topical application of the gentamicin‐collagen sponge + systemic antibiotic therapy

Ulcers infected at baseline.

Resolution of infection by 7 days

Group 1: 7/18

Group 2: 22/38

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Adverse events (number of participants with 1 or more events)

Group 1: 5/18

Group 2: 11/38

Martinez‐De Jesus 2007

Group 1: (n = 16) Standard management with

chemical

antiseptics such as soap or povidone iodine

Group 2: (n = 21) Super‐oxidised aqueous solution

Advances from

infection to granulating tissue:

Group 1: 10/16

Group 2: 19/21

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Not reported

Ramos Cuevas 2007

Group 1: (n = 25) Conventional treatment (no further details translated)

Group 2: (n = 25) Zinc hyaluronate

Not reported/translated

Not reported/translated

Mean time to healing in weeks (not clear if standard deviation or standard error presented)

Group 1: Only 2 ulcers healed; no time‐to‐event data reported

Group 2: 7.80 (3.49) with all ulcers healing

Group 1: 2/25

Group 2: 25/25

Not reported/translated

Not reported/translated

Not reported/translated

Not reported/translated

Shukrimi 2008

Group 1: Standard‐dressing group (povidone iodine solution 10%)

Group 2: Honey dressing group

30 participants randomised, but number in each group not specified.

Not reported

Not reported

Time to healing in days

Group 1: 15.4 days (range 9 to 36 days)

Group 2: 14.4 days (range 7 to 26 days)

Comment: mean and range, but no measure of variation provided.

Unclear how many participants in each group and how many ulcers healed, thus if this measure is a valid time‐to‐healing measure

Not reported

Not reported

Not reported

Not reported

Not reported

Tom 2005

Group 1: Normal saline solution, 11 ulcers (in 10 participants)

Group 2: Tretinoin group, 13 ulcers (in 12 participants)

Not reported

Not reported

Data presented as time‐to‐event figure with no further data. Given the small number of participants and events, we have not tried to analyse further.

16 weeks

Group 1: 2/10

Group 2: 6/12

Unclear if ulcers were healed in the same or different participants; for the analysis we have assumed in different participants

Not reported

Not reported

Not reported

Not reported

Ullal 2014

Group 1: (n = 2) Povidone iodine and metronidazole 1% gel dressing

Group 2: (n = 2) Honey and metronidazole 1% gel dressing

Not reported

Not reported

Not reported

Group 1: 0/2

Group 2: 2/2

Not reported

Not reported

Not reported

Not reported

Viswanathan 2011

Group 1: (n = 19) Polyherbal formulation

Group 2: (n = 19) Silver sulphadiazine cream

Not reported

Not reported

"Number of days taken for healing of the wound:

Group 1: 43.1 ± 26.8 Group 2: 43.6 ± 30.7"

Not clear what sort of analysis was conducted

Healing was defined as complete epithelialisation either by secondary intention or by split skin graft. However, figures are not reported.

"the microbiological investigations were not done"

Not reported

Not reported

"There were no adverse events reported in both the groups."