Topical antimicrobial agents for preventing and treating foot

infections in people with diabetes (Protocol)

Lipsky BA, Hoey C, Cruciani M, Mengoli C

This is a reprint of a Cochrane protocol, prepared and maintained by The Cochrane Collaboration and published in The
Cochrane Library 2014, Issue 3
http://www.thecochranelibrary.com

TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) Copyright © 2014
The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) Copyright © 2014
The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Topical antimicrobial agents for preventing and treating foot

infections in people with diabetes

Benjamin A Lipsky1, Christopher Hoey2, Mario Cruciani3, Carlo Mengoli4

1
Medicine, University of Washington, Seattle, Washington, USA. 2Pharmacy Service, VA Puget Sound, Seattle, WA, USA.
3
Center of Community Medicine and Infectious Diseases Service, ULSS 20 Verona, Verona, Italy. 4Department of Histology,
Microbiology and Medical Biotechnology, Università di Padova, PADOVA, Italy

Contact address: Carlo Mengoli, Department ofHistology, Microbiology and Medical Biotechnology, Università di Padova, Via
Aristide Gabelli, 63, PADOVA, 35121, Italy. carlo.mengoli@unipd.it.

Editorial group: Cochrane Wounds Group.

Publication status and date: New, published in Issue 3, 2014.

Citation: LipskyBA,HoeyC,CrucianiM,MengoliC.Topical antimicrobial agentsforpreventing andtreatingfootinfectionsin people

with diabetes. Cochrane Database of Systematic Reviews 2014, Issue 3. Art. No.: CD011038. DOI:
10.1002/14651858.CD011038.

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

This is the protocol for a review and there is no abstract. The objectives are as follows:

To evaluate the effects of topical antimicrobial agents on the resolution of signs and symptoms of infection, and the healing of
infected diabetic foot ulcers, and to examine their effect on preventing infection in clinically uninfected diabetic foot ulcers.
BACKGROUND infected foot wounds. This often requires antimicrobial
therapy, which may be given systemically (i.e. to the whole
Chronic skin wounds are very common in people with
body via oral or parenteral (e.g. intravenous) antibiotics), or
diabetes and usually related to peripheral neuropathy (nerve
topically (i.e. locally, through antiseptic, antimicrobial or
damage), vasculopathy (blood vessel disease), or trauma
antibiotic preparations (e.g. creams)).
(Davies 2007; Lipsky 2009). Most people with diabetes
mellitus eventually develop peripheral neuropathy, peripheral
arterial disease or both (American Diabetes Association
2003). Many also have poorlydefined defects in host defense Description of the condition
(the ability to resist or fight infection) (Delamaire 1997). Virtually all open wounds become rapidly colonized by
Therefore, it is not surprising that people with diabetes are at microorganisms; this usually has no clinical consequences as
high risk of developing foot ulcers, or that these ulcers often thereseems to be no clinical evidence of infection and healing
become infected. These wounds cause substantial morbidity, occurs as expected (White 2006). However, some wounds
especially when infected. Foot infections are now responsible exhibit a host response to isolated organisms suggesting that
for more days of hospitalization than any other complication they are clinically infected (Cutting 2005). The likelihood of a
of diabetes (Pecoraro 1990; Singh 2005). These diabetic foot wound becoming infected increases with size of microbial
infections are also the main precipitating factor for inoculum, greater virulence of the colonizing organisms and
lowerextremity amputation, with its attendant financial cost, worsening of the host’s local and systemic immunological
reduced quality of life and early mortality (Lipsky 2012). To resistance (Heinzelmann 2002). Characterizing a wound as
avoid these bad outcomes it is crucial to prevent or treat

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 1Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
infected or not is a key clinical challenge. Published studies
show that about half of all people with a diabetic foot ulcer
have no clinical signs of infection; these people do not need to
have cultures taken from their wound, nor do they require
antimicrobial therapy (Lavery 2006; Prompers 2007). Since
treatment with antibiotics is associated with an increase in
adverse effects, cost and microbial resistance, avoiding
unnecessary treatment is a key goal. There are many
classification schemes for diabetic foot complications, but
most categorize infection only as ’present’ or ’absent’, and do
not specify how the condition is defined. Classification
systems that provide more information on infection have been
developed by the International Working Group on the
Diabetic Foot (IWGDF) and the Infectious Diseases Society
of America (IDSA) (IIWGDF 2003; Lipsky 2012) (Table 1).
These classification systems, which are all very similar, have
been validated as predictive of the need for hospitalization
and amputation, and should be used routinely to classify the
presence and clinical severity of foot infections (Lipsky
2012).
In lightof thehigh prevalenceof risk factors for infection in
people with diabetes, clinicians should consider the possibility
that infection is present when such patients present with any
foot wound. Evidence of infection is generally defined by the
presence of at least two classic symptoms or signs of
inflammation (i.e. redness, warmth, swelling or induration
(hardness), pain or tenderness) or purulent secretions (pus).
The presence of neuropathy or vasculopathy may obscure
these findings, so some authorities accept additional or
secondary signs of infection (e.g. non-purulent secretions,
friable or discoloured granulation tissue, undermining of
wound edges, foul odor) (Cutting 2005; Gardner 2001; Lipsky
2012). Using a Delphi approach an international group of
wound
careexpertsreachedconsensusoncriteriatheydeemedcommonto
infection in all chronic wounds, namely:’cellulitis’ (sub-
cutaneous skin infection), malodor, pain, delayed healing,
deterioration or breakdown of the wound, and increased
exudate (Moore 2007). However, this recommendation is
limited by the fact that they compared the clinical criteria to
inadequately-validated microbiological definitions of
infection (Gardner 2009). This relates to the fact that some
approach the diagnostic problem of defining infection
microbiologically, suggesting that apparently uninfected but
non-healingwoundsmaydemonstrateeither’critical
colonization’ (which may occur at lower levels with certain
virulent species) or a heavy bacterial ’bio-burden’, usually
defined as > 105 colony forming units (CFU) per gram of
tissue (White 2006b). The concept that wound infection can
be diagnosed microbiologically remains controversial. Recent
studies suggest that the critical issue in moving a wound from
being considered colonized to infected may be less the density
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
of organisms than: 1) the presence of particularly pathogenic
species (e.g. Pseudomonas aeruginosa, Peptostreptococcus
species, or Morganella morganii) (White 2006b); 2) a
diversity of bacteria; or 3) a reduced host immunological
response to colonizing organisms (Davies 2007). More recent
studies in people with a diabetic foot ulcer have shown that
the presence in bacteria of certain virulence genes (at least in
strains of Staphylococcus aureus) is associated with a higher
risk of wounds developing evidence of clinical infection
(Sotto 2012).
Cultures of wound specimens usually grow bacteria called
Grampositive cocci (GPC (that absorb Gram stain)); these are
often the only bacteria causing infection. However, in chronic
wounds, or when a patient has recently been treated with
antibiotics, these GPCsareoftenmixedwith
otherbacteriathatmayrequirebroader spectrum antibiotic
therapy to combat. Recently, molecular diagnostic studies of
wounds have shown that they harbour an even greater variety
of organisms than had previously been recognized (Davies
2004; James 2008), but the clinical importance of this finding
is, as yet,unclear (Lipsky 2013). Furthermore,recent studies
have demonstrated that,in many chronic wounds, bacteria
persist as so-called ’small colony variants’ (von Eiff 2006),
which are more difficult to culture and to eradicate. Finally,
microorganisms in chronic wounds often exist in states that
are particularly difficult to treat, such as an adhesive,
polymeric matrix called biofilm
communities,whichinduceschronicinflammation,delayshealin
g and makes the organisms more resistant to antimicrobial
therapy (Rhoads 2008). These findings, combined with a wish
to avoid unnecessary systemic antibiotic therapy, have led to
suggestions that clinicians should consider topical
antimicrobial therapy for wounds that fail to heal despite best
treatment. ,
Description of the intervention
Clinicallyinfectedwoundsusuallyrequiresystemicantibioticther
apy, whereas clinically uninfected wounds that are healing
normally do not (Lipsky 2009). There is controversy,
however, over how to treat poorly-healing wounds that
display ’secondary’ signs - that suggest infection - and which
may benefit from topical antimicrobial agents. Also,some
superficial infections (e.g.impetigo, fungal dermatitis) may
respond to first line topical antimicrobial therapy without
recourse to systemic therapy. The rationale for using a topical
antimicrobial is to kill, or at least halt the replication of,
pathogenic microorganisms on the skin, mucosae or in the
wound, without causing clinically significant damage to the
host cells. Topical antimicrobials may be used on their own,
or in combination with other topical or systemic agents.
2Copyright © 2014 The Cochrane
There are several classes of topical agents that inhibit or kill
microorganisms (Lipsky 2009). Disinfectants are non-specific
agents with activity against virtually all disease-causing
microorganisms, including those existing as spores. Since
these may be toxic to host tissues, they are used primarily for
sterilizing inanimate surfaces. Most topical antimicrobials for
clinical use can be divided into one or other of two major
groups:
• Antiseptics: these are a type of disinfectant that can
be used on intact skin and on some open wounds to kill or
inhibit microorganisms. They often have multiple microbial
targets, a broad antimicrobial spectrum, and residual anti-
infective activity, but are often toxic to one or more of the
host tissues (e.g. fibroblasts, keratinocytes, and possibly
leukocytes).
Chlorhexidine and povidone iodine have commonly been
used as wound antiseptics, however a variety of products that
release silver ions are now being promoted for wound
management. Toxicity and availability of safer agents has
limited the use of formerly-used agents such as
hexachlorophene and iodine.
• Antibiotics: these are chemicals produced either
naturally (by a microorganism), or synthetically, that in dilute
solution inhibit or kill other microorganisms. They usually act
on one specific cell target, have a narrower spectrum of
activity than antiseptics, are relatively nontoxic, and are more
susceptible to losing their effectiveness to bacterial
resistance. Most available topical antibiotics have efficacy
against Gram-positive bacteria (bacitracin, mupirocin,
retapamulin) with a smaller number demonstrating efficacy
against Gram-negative bacteria (neomycin, silver sulfadiazine
(Gram-negative bacteria do not absorb Gram stain)).
A summary of the principal characteristics of available
antiseptics and topical antibiotics is provided in (Table 2) and
(Table 3)
How the intervention might work
For millennia, healers have applied various compounds to
infected wounds, some of which (e.g. silver, honey) are still in
use today. Use of a topical application has many potential
advantages compared with giving systemic antibiotic therapy,
including: high and sustained concentration of the
antimicrobial agent at thesite of infection; the requirement for
a limited amount of antimicrobial to be used; limited
likelihood of systemic absorption and its potential toxicity;
use of novel agents not available for systemic use; easy
application in the outpatient setting; and better adherence to
treatment. Topical treatments may also prove helpful with the
increasing problem of multidrug-resistant organisms that are
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
untreatable with most systemic agents. A recent study of 47
multidrug-resistant organisms from burn wounds found that
most were susceptible to 11 commonly-used topical
antibiotics and antiseptics, although the rates of resistance
were higher than to non-multidrugresistant organisms (Neely
2009).This approach to therapy has some potential
disadvantages as well, including: few agents have been
proven to be effective in clinical trials; almost all have
minimal penetration into intact skin or soft tissue, which
limits use to open wounds without cellulitis or deep soft-tissue
spread of infection; systemic absorption of some agents may
occur if used on large wounds; agents may induce local
hypersensitivity or contact dermatitis reactions; some agents
may interfere with normal wound healing processes; treatment
may produce an alteration of normal cutaneous flora that leads
to other problems; topical applications are difficult to dose
accurately; frequent applications may be needed; agents may
be difficult to apply or aesthetically unacceptable to some
patients; and, the stored agent can become contaminated
(Gelmetti 2008; Lio 2004).
Topical antimicrobials have traditionally been formulated in
one of two ways. Firstly, ointments, which are more
occlusive, often contain petrolatum, and are best used for dry
lesions, and secondly, creams, which are less occlusive, wash
off with water, are less messy, and are best for moist lesions.
Newer technologies incorporate antimicrobials into dressings,
such as alginates, foams, collagen and sponges, allowing
controlled release to occur at the wound surface. One major
problem with topical therapies is that no official oversight
agency has standardized and approved specific tests to
establish the efficacy and safety of these agents (Cooper
2004).
Why it is important to do this review
The lack of Available data makes it difficult to assess the
efficacy of topical antimicrobials for diabetic foot ulcers
(Drucker 2012; Lipsky 2009). A systematic review of
antimicrobial agents for chronic wounds (diabetic foot ulcers,
pressure ulcers, chronic leg ulcers, etc.) concluded that few
systemic agents improved outcomes, but several topical
substances hastened healing, including silver-containing
compounds for venous ulcers and oxyquinoline ointment for
stage 1 to 2 pressure ulcers (O’Meara 2001). A Cochrane
systematic review of antibiotics and antiseptics for venous leg
ulcers concluded that some evidence supports the use of
cadexomer iodine. The authors also concluded that current
evidence does not support the routine use of honey- or
silverbased products and that further evidence is required
before conclusions can be drawn about the effectiveness of
povidone-iodine, peroxide-based preparations, ethacridine
lactate, chloramphenicol, framycetin, mupirocin, ethacridine
3Copyright © 2014 The Cochrane
or chlorhexidine in healing venous leg ulceration (O’Meara
2014). A systematic review of theeffectivenessof various
interventions for enhancing thehealing of chronic diabetic foot
ulcers found a single study that
demonstratednobenefitofcadexomer-
iodineincavitarywoundsandone suggesting that zinc oxide
tape improved necrotic wounds more than a hydrocolloid
(Hinchliffe 2008). Another Cochrane review of silver-based
wound dressings and topical agents for treating diabetic foot
ulcers found no randomized controlled trials (RCTs) that
reported outcomes on healing rates or infection resolution
(Bergin 2006). Likewise, a Cochrane review of silver-
containing dressings or topical agents for treating infected or
contaminated chronic wounds concluded there was
insufficient evidence, on the basis of three randomized trials,
to recommend these treatments
(Vermeulen2007).ACochranesystematicreviewontopicalhoney
for treating wounds concluded, on the basis of data from 19
trials, that honey may reduce the healing time for mild-to-
moderate superficial and partial thickness burns, but did not
significantly hasten leg ulcer healing. The authors deemed
that there was insufficient evidence to guide clinical practice
(Jull 2008). Finally, a recent a systematic review of the
effectiveness of interventions in the management of diabetic
foot infections found three studies that investigated the use of
topical agents (Peters 2012). One of two small RCTs
compared topical treatment with super-oxidized water with
povidone iodine in peoplewith diabetic foot ulcers,but the
methods and results did not allow any definitive conclusions
to be drawn (Peters 2012).
Given the high frequency of these wounds, the potentially
serious adverse outcomes, thepossibility of benefit in
preventing or curing infection or accelerating wound healing
and of reducing unnecessary use of systemic antibiotics, we
think a systematic review of all the available evidence of the
use of topical antimicrobial agents for preventing or treating
infection in diabetic foot ulcers is both timely and important.
OBJECTIVES
To evaluate the effects of topical antimicrobial agents on the
resolution of signs and symptoms of infection, and the healing
of infected diabetic foot ulcers, and to examine their effect on
preventing infection in clinically uninfected diabetic foot
ulcers.
METHODS
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
Criteria for considering studies for this review
Types of studies
Randomized controlled trials (RCTs), in any setting (inpatient
or outpatient). Quasi-randomised studies will only be included
where RCTs are not available.
Types of participants
People with diabetes mellitus (according to the World Health
Organization criteria) who have been diagnosed with a full-
thickness ulcerof thefoot (i.e.below themalleolus,the bony
prominence on each side of the ankle), whether clinically
infected or uninfected. Studies with a mixed population of
participants with foot ulcers ulcers who do, as well as those
who do not, have diabetes will be included if the results for
the diabetic patient subset are separately provided.
Types of interventions
Studies evaluating treatment with any topical antimicrobial
agent, including antiseptics and antibiotics. Likely
comparisons will include:
• two or more different topical antimicrobial agents;
• a topical antimicrobial agent plus standard care (e.g.
debridement, wound dressings, pressure off-loading)
compared with standard care alone, or with a placebo;
• a topical antimicrobial agent (with or without
systemic antimicrobial agent) compared with a systemic
antimicrobial agent.
Types of outcome measures
Primary outcomes
For studies involving wounds that are clinically infected at
baseline, the primary outcomes for the review will be:
• resolution of signs and symptoms of infection (i.e.
investigators’ assessment of erythema (redness), warmth,
pain/ tenderness, induration/swelling, purulent secretions)
(Lipsky
2012), , (Table 1); • time to
complete wound healing.
For studies involving wounds that are clinically uninfected at
baseline, the primary outcomes for the review will be:
• risk of new clinical infection (i.e. investigators’
assessment of erythema, warmth, pain/tenderness,
induration/swelling, purulent secretions); and
• time to complete wound healing.
4Copyright © 2014 The Cochrane
Secondary outcomes
• Microbial counts (CFUs/gram of tissue or
semiquantitative counts of number of colonies (graded from 1
to 4), when these microbiologic data are available).
• Quality of life (as measured by a validated scale).
• Risk of any surgical resection, including partial- or
complete-lower limb amputation.
• Safety: we plan to attempt to classify this as
’treatmentrelated’ and ’not treatment-related’ when these
results are reported, or can be clearly deduced, in the study.
Treatmentrelated adverse events (i.e. an adverse drug
reaction) will be defined as: “a response to a drug that is
noxious and unintended and which occurs at doses normally
used in man for prophylaxis, diagnosis, or therapy of disease,
or for the modification of physiologic function” (Nebeker
2004). Adverse events that are not related to treatment will be
defined as “any untoward medical occurrence that may
present during treatment with a pharmaceutical product but
which does not necessarily have a causal relationship with
this treatment” (Nebeker 2004).
Search methods for identification of studies
A comprehensive, unbiased search strategy will be developed
in an attempt to find all relevant studies. We will seek all
studies regardless of language or publication status. RCTs of
topical antibiotics and antiseptics for diabetic foot ulcers will
be identified from the electronic databases listed below. The
literature search will be conducted with the assistance of the
Trials Search Coordinator of the Cochrane Wounds Group.
Electronic searches
The following electronic databases will be searched to
identify reports of relevant RCTs:
• The Cochrane Wounds Group Specialised Register;
• The Cochrane Central Register of Controlled Trials
(CENTRAL) (latest issue);
• MEDLINE (1946 to date);
• EMBASE (1974 to date);
• CINAHL (1982 to date);
• LILACS (1982 to date).
ThestandardWoundsGroupstringtodescribeDFUswill beused,
namely:
#1 MeSH descriptor Foot Ulcer explode all trees
#2 MeSH descriptor Diabetic Foot explode all trees
#3 (diabet* NEAR/3 ulcer*):ti,ab,kw
#4 (diabet* NEAR/3 (foot or feet)):ti,ab,kw
#5 (diabet* NEAR/3 wound*):ti,ab,kw
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
#6 (diabet* near/3 amputat*):ti,ab,kw
#7 (diabet* NEAR/3 defect*):ti,ab,kw
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
The search strategies are summarized in Appendix 1 and will
be adapted for the different databases.
The following websites will also be searched:
• International Working Group on the Diabetic Foot
(http:// www.iwgdf.org/);
• Evidence in Health and Social Care (http://
www.evidence.nhs.uk/).
We will also search the following websites for ongoing and
unpublished trials:
• EU Clinical Trials Register (https://
www.clinicaltrialsregister.eu/index.html);
• ClinicalTrials.gov (http://www.clinicaltrials.gov/);
• WHO International Clinical Trials Registry
Platform
(ICTRP) (http://www.who.int/ictrp/en/)
Searching other resources
We will also check the reference lists of all the relevant trials
identified by the above methods. We will contact other
authors and trialists in the field and relevant manufacturers.
Data collection and analysis
We plan to summarize data using standard Cochrane
Collaboration methodologies (Higgins 2011).
Selection of studies
Independently, two review authors will assess each reference
identified by the search against the Inclusion criteria. We will
resolve any disagreements that may arise through discussion.
Those references that appear to, or potentially meet the
Inclusion criteria will be retrieved in full for further
independent assessment by two review authors. We will
resolve any disagreements that may arise at this stage through
discussion.
Data extraction and management
One review author will extract data from the included trials
using a spreadsheet data extraction form and two review
authors will check the data entered.
Overall, we will extract the following data:
• trial ID (first author’s name and year of main
publication);
• setting of care;
• participant eligibility criteria;
5Copyright © 2014 The Cochrane
 • participant demographics (age, gender, country);
• total number of participants recruited;
• number of participants per group;
• characteristic of the ulcers (anatomic site, size,
number of ulcers, presence of infection, duration of
ulceration);
• ulcer treatments (antimicrobial and other);
• details of concurrent interventions such as off-
loading;
• duration of treatment;
• duration of follow-up;
• outcomes as defined above at the end of therapy and
last follow-up post therapy and
• withdrawals and losses to follow up, with reasons,
by treatment group.
We will discuss any discrepancies between review authors
and will achieve a final consensus.
Assessment of risk of bias in included studies
Independently, each review author will assess the risk of bias
of eachtrial,andwillfollowthedomain-
basedevaluationasdescribed in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). We will
discuss any discrepancies between review authors and will
achieve consensus on the final assessment. We will assess the
following domains for theirrisk of bias and mark each as
being at low risk of bias, unclear risk of bias or high risk of
bias.
• Random sequence generation.
• Allocation concealment.
• Blinding of participants and personnel.
• Blinding of outcome assessors.
• Incomplete outcome data.
• Selective reporting.
• Other bias.
We will use the following definitions.
Generation of allocation sequence (checking for possible selection
bias)
For each included study, we will describe the method used to
generate the allocation sequence in sufficient detail to allow
an assessment of whether it should produce comparable
groups. We will assess the method as being at:
• low risk of bias (any truly random process, e.g.
random number table; computer random-number generator);
• high risk of bias (any non-random process, e.g. odd
or even date of birth; hospital or clinic record number);
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
• unclear risk of bias, if the trial was described as
randomized, but the method used for the allocation sequence
generation was not described.
Allocation concealment (checking for possible selection bias)
For each included study, we will describe the method used to
conceal the allocation sequence in sufficient detail and
determine whether intervention allocation could have been
foreseen in advance of, or during recruitment, or changed
after assignment. We will assess the methods as being at:
• low risk of bias (e.g. telephone or central
randomization; consecutively-numbered sealed opaque
envelopes);
• high risk of bias (open random allocation; unsealed
or nonopaque envelopes, alternation; date of birth);
• unclear risk of bias, if the trial was described as
randomized, but the method used to conceal the allocation
was not described.
Blinding or masking (checking for possible performance bias)
domains
For each included study, we will describe the methods used ,
if any, to blind study participants and personnel from
knowledge of which intervention a participant received. We
will judge studies as being at low risk of bias if they were
blinded, or if we judged that the lack of blinding could not
have affected the results. We will assess blinding separately
for different outcomes or classes of outcomes.
We will assess each trial as being at low risk, unclear risk, or
high risk of bias with regard to the following levels of
blinding:
• blinding of personnel (person delivering treatment)
and participant to treatment allocation;
• blinding of outcome assessor to treatment allocation
Incomplete outcome data (checking for possible attrition bias
through withdrawals, dropouts, protocol deviations)
We will assess the methods as being at:
• low risk of bias, if there is any one of the following:
no missing outcome data; reasons for missing outcome data
are unlikely to be related to true outcome (for survival data,
censoring unlikely to be introducing bias); missing outcome
data are balanced in numbers across intervention groups, with
similar reasons for missing data across groups; for
dichotomous outcome data, the proportion of missing
outcomes compared with the observed event risk is not
enough to have a clinically relevant impact on the
intervention effect estimate; for continuous outcome data, the
plausible effect size (difference in means or standardized
6Copyright © 2014 The Cochrane
difference in means) among missing outcomes is not enough
to have a clinically relevant impact on observed effect size;
missing data have been imputed using appropriate methods.
• high risk of bias, if there is any one of the
following: reason for missing outcome data is likely to be
related to true outcome, with either imbalance in numbers or
reasons for missing data across intervention groups; for
dichotomous outcome data, the proportion of missing
outcomes compared with the observed event risk is enough to
induce clinically relevant bias in intervention effect estimate;
for continuous outcome data, the plausible effect size
(difference in means or standardized difference in means)
among missing outcomes is enough to induce clinically
relevant bias in observed effect size; ‘As-treated’ analysis
done with substantial departure of the intervention received
from that assigned at randomization; potentially inappropriate
application of simple imputation.
• unclear risk of bias, if there is any one of the
following: insufficient reporting of attrition/exclusions to
permit judgement of ‘low risk’ or ‘high risk’ to be made (e.g.
number randomized not stated, no reasons for missing data
provided); the study did not address this outcome.
Selective reporting bias (reporting bias due to selective outcome
reporting)
For each included study, we will describe how we will
investigate the possibility of selective outcome reporting bias
and what we found.
We will assess the methods as being at:
• low risk of bias, if there is any one of the following:
the study protocol is available and all of the study’s pre-
specified (primary and secondary) outcomes that are of
interest in the review have been reported in the pre-specified
way, or the study protocol is not available but it is clear that
the published reports include all expected outcomes,
including those that were prespecified (convincing text of this
nature may be uncommon).
• high risk of bias, if there is any one of the
following: not all of the study’s pre-specified primary
outcomes have been reported; one or more primary outcomes
is reported using measurements, analysis methods or subsets
of the data (e.g. sub scales) that were not pre-specified; one or
more reported primary outcomes were not pre-specified
(unless clear justification for their reporting is provided, such
as an unexpected adverse effect); one or more outcomes of
interest in the review are reported incompletely so that they
cannot be entered in a meta-analysis; the study report fails to
include results for a key outcome that would be expected to
have been reported for such a study.
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
• unclear risk of bias if there is: insufficient
information to permit a judgement of ‘low risk’ or ‘high risk’
to be made.
Free of other bias
For each included study, we will describe any important
concerns we have about other possible sources of bias
(baseline imbalance, inappropriate administration of an
intervention, etc.). Each study will be judged as being at:
• low risk of bias, if the trial appears to be free of
other components that could put it at risk of bias;
• unclear risk of bias, if the trial might or might not
be free of other components that could put it at risk of bias;
• high risk of bias, if there are other factors in the trial
that could put it at risk of bias, e.g. no sample size calculation
made, academic fraud, industry involvement, or extreme
baseline imbalance.
Overall risk of bias
We will make explicit judgements about whether studies are
at high risk of bias, according to the criteria given in the
Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011). With reference to the seven domains outlined
above, we will assess the likely magnitude and direction of
the bias and whether we consider it is likely to impact on the
findings. We will explore the impact of the level of bias
through undertaking sensitivity analyses (see Sensitivity
analysis).
Trials that achieved a ’low risk’ grading for adequate
generation of allocation sequence, allocation concealment,
blinding, handling of incomplete outcome data, and no
selective outcome reporting, and that were without other risks
of bias, will be considered to be at overall low risk of bias,
while trials that score either ’high risk’ or ’unclear risk’ on
one or more of these domains will be considered to be at a
high risk of bias overall.
Measures of treatment effect
The evidence will be reviewed separately for the different
topical antimicrobial agents.
For binary outcomes, such as healed (yes/no), amputation, and
adverseevents,theauthorsplantocalculatetheriskratio(RR)with
95% confidence intervals (CI) for each.For continuous
outcomes, such as quality of life measures, we will present
results as summary standardized mean differences (SMD)
with 95% CI. For timeto-event outcomes, such as time to
complete healing, we plan to calculate the hazard ratios (HR)
with 95% CI for each outcome.
7Copyright © 2014 The Cochrane
Unit of analysis issues
The unit of analysis will be the individual person.We will
collect and analyse a single measurement for each outcome
from each patient.We will selectonly studies that randomize
patients and not those using legs or ulcers as unit of
randomization.
Dealing with missing data
We will carry out analyses for all outcomes, as far as possible,
on an intention-to-treat basis, that is we will attempt to
include all participants randomized to each group in the
analyses. When there are missing data, we will contact the
trial authors. If we are unsuccessful in obtaining the missing
data, our main analysis will be based on those participants
who were assessed for the outcome of interest. When
appropriate, we will perform sensitivity analysis for worst-
and best-case scenarios by imputation of the missing data.
Assessment of heterogeneity
We will quantify statistical heterogeneity using the I 2 statistic,
which describes the percentage of total variation across trials
due to heterogeneity rather than sampling error (Higgins
2003). We will consider moderate statistical heterogeneity to
be present if I2 is greater than 50% (Higgins 2011).
Assessment of reporting biases
We will also attempt to assess whether the review is subject to
publication bias by using a funnel plot to illustrate variability
graphically between trials. If asymmetry is detected, causes
other than publication bias will be explored. A funnel plot will
be conducted if 10 or more RCTs are included in the review.
Data synthesis
If the eligible trials are sufficiently comparable, we will
summarize their findings using a fixed-effect model; if not,
that is, where I2 is greater than 50%, wewill use a random-
effects model, and, should I 2 exceed 75%, we will not
undertake pooling. We will attempt to explain the cause of an
identified heterogeneity according to the
CochraneHandbookofSystematicReviewsforInterventions(Cha
pter 9) (Higgins 2011).
REFERENCES
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
Subgroup analysis and investigation of heterogeneity
We anticipate clinical heterogeneity in the effect of the
intervention and we propose to conduct the following
subgroup analyses if the data are available:
• severity and depth of wound: severity classification
will be chosen according to the reports of the included RCTs;
• duration of follow-up: we will use the duration of
follow-up provided in the study. Ideally, this might be a year,
but at present we anticipate that only a few studies will have
follow-up of this duration. Therefore, we will define “short-
term follow-up” as 1 to 4 weeks after the end of therapy, and
“longer term follow-up” as being >4 weeks after the end of
therapy.
Sensitivity analysis
If sufficient trials are identified, we plan to conduct sensitivity
analysis stratifying studies according to the risk of bias
(Higgins 2011). We will consider the risk of bias along all the
possible items assessed (e.g., sequence generation, allocation
concealment, blinding, incomplete data, and selective
outcome reporting), and evaluate if exclusion of studies at
high risk of bias from the overall analysis affects the effect
size for the outcomes of interest.
’Summary of findings’ tables
We will use the principles of the GRADE system to assess the
quality of the body of evidence associated with specific
outcomes (amputation and adverse events) in our review
(Guyatt 2008), and will construct a ’Summary of findings’
(SoF) table using the GRADE software. The GRADE
approach appraises the quality of a body of evidence on the
basis of the extent to which one can be confident that an
estimate of effect or association reflects the item being
assessed. The quality of a body of evidence considers the
within-study risk of bias (methodologic quality), the
directness of
theevidence,heterogeneityofthedata,precisionofeffectestimates
and risk of publication bias.
ACKNOWLEDGEMENTS
The authors would like to
acknowledge the
contribution of the
peerreferees(JaneBurch,SusanO’Meara,MarialenaTrivellaand
a clinical expert who wishes to remain anonymous) and copy
editor Elizabeth Royle.
8Copyright © 2014 The Cochrane
Additional references
American Diabetes Association 2003
American Diabetes Association. Peripheral arterial disease in
people with diabetes. Diabetes Care 2003;26(12):3333–41.
Bergin 2006
Bergin SM, Wraight P. Silver based wound dressings and
topical agents for treating diabetic foot ulcers. Cochrane
Database of Systematic Reviews 2006, Issue 1. [DOI:
10.1002/14651858.CD005082.pub2]
Cooper 2004
Cooper R. A review of the evidence for the use of topical
antimicrobial agents in wound care. World Wide Wounds.
http://www.worldwidewounds.com/2004/february/
Cooper/Topical-Antimicrobial-Agents.html 2004.
Cutting 2005
Cutting KF, White RJ. Criteria for identifying wound
infection-revisited. Ostomy/Wound Management 2005;51:
28–34.
Davies 2004
Davies CE, Hill KE, Wilson MJ, Stephens P, Hill CM,
Harding KG, et al.Use of 16S ribosomal DNA PCR and
denaturing gradient gel electrophoresis for analysis of the
microfloras of healing and nonhealing chronic venous leg
ulcers. Journal of Clinical Microbiology 2004;42(8):
3549–57.
Davies 2007
Davies CE, Hill KE, Newcombe RG, Stephens P, Wilson
MJ, Harding KG, et al.A prospective study of the
microbiology of chronic venous leg ulcers to reevaluate the
clinical predictive value of tissue biopsies and swabs. Wound
Repair and Regeneration 2007;15(1):17–22.
Delamaire 1997
Delamaire M, Maugendre D, Moreno M, Le Goff MC,
Allannic H, Genetet B. Impaired leucocyte functions in
diabetic patients. Diabetic Medicine 1997;14(1):29–34.
Drucker 2012
Drucker CR. Update on topical antibiotics in dermatology.
Dermatologic Therapy 2012;25:6–11.
Gardner 2001
Gardner SE, Frantz RA, Doebbeling BN. The validity of the
clinical signs and symptoms used to identify localized
chronic wound infection. Wound Repair and Regeneration
2001;9(3):178–86.
Gardner 2009
Gardner SE, Hillis S, Frantz R. Clinical signs of infection
in diabetic foot ulcers with high microbial load. Biologic
Research for Nursing 2009;11(2):119–28.
Gelmetti 2008
Gelmetti C. Local antibiotics in dermatology. Dermatologic
Therapy 2008;21:187–95.
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
Guyatt 2008
Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y,
Schunemann HJ. What is “quality of evidence”and why is it
important to clinicians. BMJ 2008;336(7651):995–8.
Heggers 1991
Heggers JP, Sazy JA, Stenberg BD, Strock LL, McCauley
RL, Herndon DN, et al.Bactericidal and Wound-Healing
Properties of Sodium Hypochlorite Solutions: The 1991
Lindberg Award. Journal of Burn Care and Rehabilitation
1991;12(5):420–4.
Heinzelmann 2002
Heinzelmann M, Scott M, Lam T. Factors predisposing to
bacterial invasion and infection. American Journal of
Surgery 2002;183(2):179–90.
Higgins 2003
Higgins JPT, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ 2003;327
(7414):557–60.
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Hinchliffe 2008
Hinchliffe RJ, Valk GD, Apelqvist J, Armstrong DG,
Bakker K, Game FL, et al.A systematic review of the
effectiveness of interventions to enhance the healing of
chronic ulcers of the foot in diabetes. Diabetes/Metabolism
Research and Reviews 2008;24(Suppl.1):S119–44.
IIWGDF 2003
International Working Group on the Diabetic Foot.
International consensus on the diabetic foot. CD-ROM.
Brussels, 2003.
James 2008
James GA, Swogger E, Wolcott R, Pulcini E, Secor P,
Sestrich J, et al.Biofilms in chronic wounds. Wound Repair
and Regeneration 2008;16(1):37–44.
Jull 2008
Jull AB, Rodgers A, Walker N. Honey as a topical treatment
for wounds. Cochrane Database of Systematic Reviews
2013, Issue 2. [DOI: 10.1002/14651858.CD005083.pub3]
Lavery 2006
Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ,
Wendel CS, Lipsky BA. Risk factors for foot infections in
individuals with diabetes. Diabetes Care 2006;29(6): 1288–
93.
Lio 2004
Lio PA, Kaye ET. Topical antibacterial agents. Infectious
Disease Clinics of North America 2004;18:717–33.
Lipsky 2009
Lipsky BA, Hoey C. Topical antimicrobial therapy for
treating chronic wounds. Clinical Infectious Diseases 2009;
49(10):1541–9.
9Copyright © 2014 The Cochrane
Lipsky 2012
Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ,
Armstrong DG, et al.2012 Infectious Diseases Society of
America clinical practice guideline for the diagnosis and
treatment of diabetic foot infections. Clinical Infectious
Diseases 2012;54(12):e132–73.
Lipsky 2013
Lipsky BA, Richard JL, Lavigne JP. Diabetic foot ulcer
microbiome: one small step for molecular microbiology .
. . One giant leap for understanding diabetic foot ulcers?.
Diabetes 2013;62(3):679–81.
Moore 2007
Moore Z, Cowman S. Effective wound management:
identifying criteria for infection. Nursing Standard 2007;21
(124):68, 70, 72 passim. [PUBMED: PMID:17345911]
Nebeker 2004
Nebeker JR, Barach P, Samore MH. Clarifying adverse drug
events:a clinician’s guide to terminology, documentation,
and reporting. Annals of Internal Medicine 2004;140(10):
795–801.
Neely 2009
Neely AN, Gardner J, Durkee P, Warden GD, Greenhalgh
DG, Gallagher JJ, et al.Are topical antimicrobials effective
against bacteria that are highly resistant to systemic
antibiotics?. Journal of Burn Care and Research 2009;30(1):
19–29.
O’Meara 2001
O’Meara SM, Cullum NA, Majid M, Sheldon TA.
Systematic review of antimicrobial agents used for chronic
wounds. British Journal of Surgery 2001;88:4–21.
O’Meara 2014
O’Meara S, Al-Kurdi D, Ologun Y, Ovington LG,
Martyn-St James M, Richardson R. Antibiotics and
antiseptics for venous leg ulcers. Cochrane Database of
Systematic Reviews 2014, Issue 1. [DOI: 10.1002/
14651858.CD003557.pub5]
Pecoraro 1990
Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic
limb amputation:basis for prevention. Diabetes Care 1990;
13:513–21.
Peters 2012
Peters EJ, Lipsky BA, Berendt AR, Embil JM, Lavery LA,
Senneville E, et al.A systematic review of the effectiveness
of interventions in the management of infection in the
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol)
Collaboration. Published by John Wiley & Sons, Ltd.
diabetic foot. Diabetes/Metabolism Research & Reviews
2012; 28(Suppl. 1):142–62.
Prompers 2007
Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A,
Bakker K, et al.High prevalence of ischaemia, infection and
serious comorbidity in patients with diabetic foot disease in
Europe. Baseline results from the Eurodiale study.
Diabetologia 2007;50(1):18–25.
Rhoads 2008
Rhoads DD, Wolcott RD, Percival SL. Biofilms in wounds:
management strategies. Journal of Wound Care 2008;17:
502–8.
Singh 2005
Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers
in patients with diabetes. Journal of the American Medical
Association 2005;293(2):217–28.
Sotto 2012
Sotto A, Richard JL, Messad N, Molinari N, Jourdan
N, Schuldiner S, et al. French Study Group on the Diabetic
Foot. Distinguishing colonization from infection with
Staphylococcus aureus in diabetic foot ulcers with
miniaturized oligonucleotide arrays: a French multicenter
study. Diabetes Care 2012;35(3):617–23.
Vermeulen 2007
Vermeulen H, van Hattem JM, Storm-Versloot MN,
Ubbink DT. Topical silver for treating infected wounds.
Cochrane Database of Systematic Reviews 2007, Issue 1.
[DOI: 10.1002/14651858.CD005486.pub2] von Eiff
2006
von Eiff C, Peters G, Becker K. The small colony variant
(SCV) concept -- the role of staphylococcal SCVs in
ADDITIONAL TABLES
persistent infections. Injury 2006;37(Suppl 2):S26–33.
White 2006
White RJ, Cutting K, Kingsley A. Topical antimicrobials
in the control of wound bioburden. Ostomy/Wound
Management 2006;52(8):26–58.
White 2006b
White RJ, Cutting KF. Critical colonization-the concept
under scrutiny. Ostomy/Wound Management 2006;52(11):
50–6.
∗
Indicates the major publication for the study
10Copyright © 2014 The Cochrane
Table1. Infectious Diseases Society of America and International Working Grouponthe Diabetic Foot classification of
diabetic foot infection
Table1. Infectious Diseases Society of America and International Working Grouponthe Diabetic Foot classification of
diabetic foot infection (Continued)
thefollowing:
•temperature>38°Cor<36°C
•heartrate>90beats/min
•respiratoryrate>20breaths/minor
PaCO 2 <32 mmHg
•whitebloodcellcount>12000or<4000
cells/µ Lor ≥ 10%immature(band)forms
Abbreviations: IDSA, Infectious Diseases Society of America; PaCO 2, partial pressure of arterial carbon dioxide; PEDIS,
perfusion, extent/size, depth/tissue loss, infection, and sensation; SIRS, systemic inflammatory response syndrome
* Ischemia may increase the severity of any infection, and the presence of critical ischemia often makes the infection severe.
Systemic infection may sometimes manifest with other clinical findings, such as hypotension, confusion, vomiting, or evidence
of metabolic disturbances, such as acidosis, severe hyperglycemia, and new-onset azotemia

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 11Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Topical antiseptic products available for treating chronic wounds

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 12Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Topical antiseptic products available for treating chronic wounds(Continued)

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 13Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Topical antiseptic products available for treating chronic wounds(Continued)

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 14Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Topical antiseptic products available for treating chronic wounds(Continued)

EUSOL, Edinburgh University Solution of Lime; MRSA, methicillin-resistant S aureus; VRE, vancomycin-resistant
enterococci. a
Costs are approximate in USD per day for treating 100-cm2 wound, as follows: $, < USD 3; $$, USD 3-15; and $$$, > UDS 15.
b

US Food and Drug Administration-approved indications. c Available without prescription. Modified from Lipsky 2009

Table 3. Topical antibiotic products available for treating chronic wounds

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 15Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 3. Topical antibiotic products available for treating chronic wounds (Continued)

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 16Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 3. Topical antibiotic products available for treating chronic wounds (Continued)

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 17Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Table 3. Topical antibiotic products available for treating chronic wounds (Continued)

There are no published studies supporting the use of topical erythromycin, clindamycin, aminoglycosides other than neomycin,
gramicidin, or tetracyclines for treating chronically infected wounds. FDA, US Food and Drug Administration; MRSA,
methicillin-resistant S aureus.
a
Costs are approximate in USD per day for treating 100-cm 2 wound, as follows: $, < USD 3; $$, USD 3-15; and $$$, > USD
15. b FDA-approved indications. c Available without prescription.

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 18Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
APPENDICES

Appendix 1. search strategy

The following shows the search strategy that will be used in Medline
1. exp Acetic Acid/
2. (acetic acid$ or acetate$ or acetamide$).ti,ab.
3. (or piracetam$ or pyracetam$ or gadolinium$ or technetium$ or dichloroacetate$ or fluoroacetate$ or iodoacetate$).ti,ab.
4. (thioglycolate$ or acetic anhydride$).ti,ab.
5. ((aminooxyacetic$ or edetic$ or egtazic$ or iodoacetic$ or nitrilotriacetic$ or pentetic$ or peracetic$ or phosphonoacetic$
or trichloroacetic$ or trifluoroacetic$).ti,ab.
6. exp ANTIFUNGAL AGENTS/
7. (therapeutic fungicide$ or antifungal agent$ or antifungals$ or fungistatic).ti,ab.
8. (benzoate$ or butenafine$ or chlorquinaldol$ or cyclosporine$ or dichlorophen$ or naftifine$ or amphotericin$ or
griseofulvin$ or ciclopirox$ or haloprogin$ or undecenoic acid$ or griseofulvin$ or micafungin$ or caspofungin$ or
anidulifungin$ or voriconazole$ or posaconazole$ or fluconazole$ or flucytosine$ or glycyrrhizic acid$ or hexetidine$ or
itraconazole$ or monensin$ or nifuratel$ or pentamidine$).ti,ab.
9. (sodium benzoate$ or thimerosal$ or thiram$ or thymol$ or tolnaftate$ or tomatine$ or triacetin$ or trimetrexate$).ti,ab.
10. (amorolfine$ or benzoic acid$ or clotrimazole$ or econazole$ or ketoconazole$ or miconazole$ or nystatin$ or Salicylic
acid$ or sulconazole$ or terbinafine$ or tioconazole$ or butoconazole$ or terconazole$ or luliconazole$ croconazole$ or
boric acid$ or borate$ or cinnamon$ or candicidin$ or natamycin$ or undecenoate$).ti,ab.
11. (antiviral$ or anti viral$ or idoxuridine$).ti,ab.
12. (foscarnet$ or acetylcysteine$ or acyclovir$ or amantadine$ or aphidicolin$ or aprotinin$ or brefeldin$ or
bromodeoxyuridine$ or cytarabine$ or deoxyglucose$ or dextran sulfate$).ti,ab.
13. (dideoxyadenosine$ or dideoxynucleoside$ or dihematoporphyrin ether$ or ditiocarb$ or filipin$ or floxuridine$ or
ganciclovir$ or inosine pranobex or interferon alfa$ or interferon type$ or interferon beta$ or interferon gamma$ or
interferons$ or saquinavir$).ti,ab. 14. (methisazone$ or phosphonoacetic acid$ or poly a-u$ or poly i-c$ or pyran
copolymer$ or ribavirin$ or rimantadine$ or streptovaricin$ or tenuazonic acid$ or tilorone$ or trifluridine$ or
tunicamycin$ or vidarabine$ or docosanol$ or brivudine$ or penciclovir$ or cidofovir$ or vidarabine$ or imiquimod$ or
famciclovir$ or valacyclovir$ or valganciclovir$ or azelaic acid$).ti,ab.
15. exp BACITRACIN/
16. exp Povidone-Iodine/
17. (bacitracin$ or povidone iodine$ or betaisodona$ or polyvinylpyrrolidone iodine$ or betadine$ or disadine$ or isodine$ or
pvpi$ or pharmadine$).ti,ab.
18. exp Cetrimonium Compounds/
19. (cetyltrimethylammonium$ or cetrimide$ or Cetrimonium$).ti,ab.
20. exp Chlorine Compounds/
21. (chlorate$ or hydrochloric acid$ or chloride$ or hypochlorous acid$ or hypochlorite$ or perchloric acid$ or ruthenium red$
or Dakins$ or Dakin’s$).ti,ab.
22. exp “Eosine Yellowish-(YS)”/
23. (eusol$ or phenoxyethanol$or dextranomer$ or mandelic acid$ or tetrabromofluorescein$ or eosin$ or eosine$ or
chlortetracycline$ or chloroxylenol solution$).ti,ab.
24. (edinburgh adj university adj solution adj2 Lime$).ti,ab.
25. exp Framycetin/
26. exp Mandelic Acids/
27. (cyclandelate$ or vanilmandelic acid$).ti,ab.
28. exp Hexachlorophene/29. hexachloroph#ne$.ti,ab.
30. exp Triclosan/
31. exp Polymyxin/
32. (triclosan$ or polymyxin$ or polynoxylin$).ti,ab.
33. (silver adj2 dressing$).ti,ab.

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 19Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
34. exp Gentian Violet/
35. (gentian violet$ or crystal violet$ or methyl Violet$ or methylrosaniline chloride$ or hexamethylpararosanine
chloride$).ti,ab.
36. exp Potassium Permanganate/
37. (potassium permanganate$ or permanganic acid$ or potassium salt$).ti,ab.
38. exp Mupirocin/
39. (mupirocin$ or pseudomonic acid$ or bactroban$).ti,ab.
40. exp Neomycin/
41. (neomycin$ or fradiomycin$ or neamin$).ti,ab.
42. exp Benzoyl Peroxide/
43. (benzyol peroxide$ or benzyol superoxide$ or diphenylglyoxal superoxide$ or panoxyl$).ti,ab.
44. exp Hydrogen Peroxide/
45. (hydrogen peroxide$ or hydroperoxide$ or oxydol$ or perhydrol$ or superoxol$ or diphenylglyoxal superoxide$ or
panoxyl$).ti,ab.
46. (fucithalmic$ or fusidate$ or fusidin$ or stanicide$).ti,ab.
47. (liposome$ adj hydrogel$).ti,ab.
48. (fusidic acid$ or inadine$ or betadine$).ti,ab.
49. exp Chlorhexidine/
50. (cadexomer iodine$ or chlorhexidine$ or novalsan$ or sebidin$ or tubulicid$).ti,ab.
51. exp oils, volatile/ or exp plant oils/
52. exp Sucrose/
53. exp HONEY/
54. (manuka$ or essential oil$ or plant oil$ or tea tree$ or lavender$ or chamomile$ or camomile or rosemary$).ti,ab.
55. (sucrose$ or sugar paste$ or granulated Sugar$).ti,ab.
56. exp Propolis/
57. (propolis$ or honey$ or beebread$ or bee bread$ or bee glue$).ti,ab.
58. exp Disinfectants/
59. exp Anti-Infective Agents, Local/
60. exp Antiviral Agents/
61. (disinfect$ or antisept$ or anti-sept$ or antiseptic$ or antiviral$ or anti-viral$).ti,ab.
62. ((neuroisch?emic or isch?emic or diabetic or neuropathic) adj3 (foot or feet or ulcer$)).ti,ab.
63. ((pedal or plantar or foot or feet or heel) adj3 (ulcer$ or septic or wound$)).ti,ab.
64. ((foot or feet) adj6 diabet$).ti,ab.
65. deep foot infection$.ti,ab.
66. exp Foot Ulcer/
67. or/63-66
68. Leg Ulcer/
69. Varicose Ulcer/
70. ((crural or leg) adj5 ulcer$).ti,ab.
71. ((venous or stasis or varicos$) adj5 (leg or ulcer$)).ti,ab.
72. ((venous or stasis or leg) adj5 wound$).ti,ab
73. ((lower extremit$ or lower limb$) adj5 (ulcer$ or wound$)).ti,ab.
74. or/68-73
75. 67 or 74
75. random allocation/ or randomized controlled trials/
76. exp clinical trials/
77. single-blind method/ or double-blindmethod/ or publication bias/ or meta-analysis/
78. comparative study/
79. (controlled clinical trial or randomized controlled trial or review).pt.
80. meta-analysis.pt.
81. random$.ti,ab.

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 20Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
82. ((clinical adj trial$) or control$).ti,ab.
83. ((standard adj treatment$) or compar$ or (single adj blind$) or (double adj blind$)).ti,ab.
84. (placebo$ or (systematic adj review$)).ti,ab.
85. or/75-84
86. 67 and 85
87. exp Penicillins/
88. (penicillin$ or amdinocillin$ or amox#cillin$ or ampicillin$ or azlocillin$ or co-amoxiclav$).ti,ab.
89. (carbenicillin$ or carfecillin$ or cloxacillin$ or dicloxacillin$ or floxacillin$ or flucloxacillin$ or methicillin$ or
mezlocillin$ or nafcillin$ or oxacillin$ or penicillanic acid$).ti,ab.
90. (penicillic acid$ or phenoxymethylpenicillin$ or benzylpenicillin$ or piperacillin$ or pivampicillin$ or sulbencillin$ or
talampicillin$ or sultamicillin$ or ticarcillin$ or ticercillin$).ti,ab.
91. exp Cephalosporins/
92. (cefaclor$ or cefadroxil$ or cefalexin$ or cefazolin$ or cefamandole$ or cefixime$ or cefotaxime$ or cefoxitin$ or
cefpirome$ or cefpodoxime$ or cefprozil$).ti,ab.
93. (cefradine$ or ceftazidime$ or ceftizoxime$ or ceftriaxone$ or cefuroxime$).ti,ab.
94. (cefonicid$ or cefmenoxine$ or cefoperazone$ or cefotiam$ or cefsulodin$ or cephacetrile$ or cephalexin$ or
cephaloglycin$ or cephaloridine or loracarbef$ or cefotetan$ or cefmetazole$ or cefdinir$ or cefditoren$ or ceftibuten$ or
cefepime$ or cefpirome$ or ceftaroline$ or ceftobiprole$ or cephalosporanic acid$ or cephalothin$ or cephapirin$ or
cephradine$).ti,ab.
95. exp Lactams/
96. (beta lactam$ or aztreonam$ or cilastin$ or imipenem$ or meropenem$ or ertapenem$ or sulbactam$ or tazobactam$ or
clavulanic acid$ or clavulanate$).ti,ab.
97. (clavulan$ or moxalactam$).ti,ab.
98. exp Aminoglycosides/99. (Aminoglycoside$).ti,ab.
100. (framycetin sulphate$ or gentamicin$ or neomycin$ or netilmicin$ or tobramycin$ or amikacin$ or streptomycin$ or
kanamycin$ or paromomycin$ or spectinomycin$ or sisomicin$ or sisomycin$ or dibekacin$ or isepamicin$ or
arbekacin$).ti,ab.
101. exp Macrolides/
102.(dirithromycin$ortelithromycin$orfidaxomicin orantimycin$ or roxithromycin$ or josamycin$
orleucomycin$orrokitamycin$ or kitasamycin$ or lucensomycin$ or maytansine$ or mepartricin$ or miocamycin$ or
midecamycin$).ti,ab.
103. (oleandomycin$ or troleandomycin$ or oligomycin$ or rutamycin$ or sirolimus$ or tacrolimus$ or tylosin$ or
propiolactone$
).ti,ab.
104. (azithromycin$ or clarithromycin$ or erythromycin$ or spiramycin$).ti,ab.
105. exp Quinolones/
106. (moxifloxacin$ or quinolone$ or ciprofloxacin$ or clinafloxacin$ or fluoroquinolone$ or levofloxacin$ or ofloxacin$ or
gatifloxacin$).ti,ab.
107. (fleroxacin$ or enoxacin$ or norfloxacin$ or pefloxacin$ or gemifloxacin$ or sparfloxacin$ or besifloxacin$ or
lomefloxacin$ or tosufloxacin or balofloxacin$ or prulifloxacin$ or grepefloxacin$ or trovafloxacin$ or temefloxacin$ or
rufloxacin$ or flumequine$ or nalidixic acid$ or nedocromil$ or oxolinic acid$ or quinpirole$ or quipazine$) ti,ab.
108. exp Sulfonamides/
109. exp Trimethoprim/
110.(dmso$orsulfoxide$or sulphoxide$ or sulfonamide$ or sulphonamide$ or trimethoprim$ or
sulfamethoxazole$orsulphamethoxazole$orco-trimoxazole$orcotrimoxazole$orsulfadiazine$orsulphadiazine$or
sulfamethopyrazine$orsulfalene$orsulphamethopyrazine$ or sulphalene$).ti,ab.
111. (sulfachlorpyridazine$ or sulfadimethoxine$ or sulfadoxine$ or sulfaguanidine$ or sulfamerazine$ or sulfameter$ or
sulfamethazine$ or sulfamethoxypyridazine$ or sulphachlorpyridazine$ or sulphadimethoxine$ or sulphadoxine$ or
sulphaguanidine$ or sulphamerazine$ or sulphameter$ or sulphamethazine$ or sulphamethoxypyridazine$).ti,ab.
112. (sulfamonomethoxine$ or sulfamoxole$ or sulfaphenazole$ or sulfapyridine$ or sulfaquinoxaline$ or sulfathiazole$ or
sulfamethizole$ or sulfisomidine$ or sulfisoxazole$ or sulfasalazine$ or sulphamonomethoxine$ or sulphamoxole$ or
sulphaphenazole$ or sulphapyridine$ or sulphaquinoxaline$ or sulphathiazole$ or sulphamethizole$ or sulphisomidine$ or
Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 21Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
 sulphisoxazole$ or sulphasalazine$ or sulfacytine$ or sulphacytine$ or sulfadiazine$ or sulphadiazine$ or silver
sulfadiazine$ or SSD$ or sulfamylon$ or sulphamylon$ or mafenide$).ti,ab.
113. exp Tetracyclines/
114. (tetracycline$ or demeclocycline$ or doxycycline$ or lymecycline$ or minocycline$ or oxytetracycline$ or
tigecycline$).ti,ab.
115. (chlortetracycline$ or methacycline$ or rolitetracycline$).ti,ab.
116. exp Chloramphenicol/
117. (cloranfenicol$ or chloramphenicol$).ti,ab.
118. (thiamphenicol$ or kloramfenikol$ or levomycetin$ or chlornitromycin$ or chlorocid$ or chloromycetin$ or detreomycin$
or ophthochlor$ or syntomycin$).ti,ab.
119. exp Clindamycin/
120. (clindamycin$ or lincomycin$ or dalacin c$ or cleocin$ or chlo?lincocin$).ti,ab.
121. exp Metronidazole/
122. (trivazol$ or vagilen$ or clont$ or danizol$ or flagyl$ or ginefavir$ or metrogel$ or metrodzhil$ or satric$ or trichazol$ or
trichopol$).ti,ab.
123. exp Fusidic Acid/
124. (granulocyte colony stimulating factor$ or gcsf$ or ozone$).ti,ab.
125. (fusidate$ adj (sodium or silver)).ti,ab.
126. exp Antibiotics/
127. (antibiotic$ or antimicrobial$).ti,ab.
128. (griseofulvin$ or synercid$ or dalfopristin$ or quinupristin$).ti,ab.
129. Daptomycin
130. linezolid$
131. or/87-130
132. or/1-61
133. 86 and (131 or 132)

CONTRIBUTIONS OF AUTHORS
Benjamin A Lipsky: conceived the review question and developed the protocol. Wrote, edited and advised on the protocol.
Approved final version of the protocol.

Christopher Hoey: conceived the review question and developed the protocol. Performed part of writing the protocol, edited
and advised on the protocol. Approved final version of the protocol prior to submission.

Mario Cruciani: developed the protocol. Performed part of writing and editing the protocol. Advised on part of the protocol.
Approved final version of the protocol prior to submission.

Carlo Mengoli: Developed and coordinated the protocol. Wrote, edited and advised on the protocol. Approved final version of
the protocol prior to submission.

Contributions of editorial base:

Nicky Cullum: edited the protocol; advised on methodology, interpretation and protocol content. Approved the final protocol
prior to submission.
Sally Bell-Syer: coordinated the editorial process. Advised on methodology, interpretation and content. Edited the protocol.
Ruth Foxlee: designed the search strategy and edited the search methods section.

DECLARATIONS OF INTEREST
Christopher Hoey: nothing to declare

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 22Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.
Mario Cruciani: nothing to declare
Carlo Mengoli: nothing to declare
Benjamin A Lipsky has been a member of an advisory board or speakers bureau for, served as a consultant to, received research
funding from: Merck, Pfizer, Innocoll, Dipexium, Cerexa, Oculus. He asserts that none of these activities will present any
conflict of interest for this review.
SOURCES OF SUPPORT

Internal sources
• No sources of support supplied

External sources
• The National Institute for Health Research (NIHR) is the sole funder of the Cochrane Wounds Group, UK.

Topical antimicrobial agents for preventing and treating foot infections in people with diabetes (Protocol) 23Copyright © 2014 The Cochrane
Collaboration. Published by John Wiley & Sons, Ltd.