Topical antimicrobial agents for treating foot ulcers in people with diabetes

138 Pages·2017·1.57 MB·English

CochraneDatabaseofSystematicReviews
Topical antimicrobial agents for treating foot ulcers in people
with diabetes (Review)
DumvilleJC,LipskyBA,HoeyC,CrucianiM,FisconM,XiaJ
DumvilleJC,LipskyBA,HoeyC,CrucianiM,FisconM,XiaJ.
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes.
CochraneDatabaseofSystematicReviews2017,Issue6.Art.No.:CD011038.
DOI:10.1002/14651858.CD011038.pub2.
www.cochranelibrary.com
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review)
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Analysis1.1.Comparison 1Topical antimicrobial dressingcomparedwithnon-antimicrobial dressing, Outcome1
Proportionofwoundshealed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Analysis1.2.Comparison 1Topical antimicrobial dressingcomparedwithnon-antimicrobial dressing, Outcome2
Incidenceofinfection:mediumtermfollow-up. . . . . . . . . . . . . . . . . . . . . . . 84
Analysis1.3.Comparison1Topicalantimicrobialdressingcomparedwithnon-antimicrobialdressing,Outcome3Surgical
resection:mediumtermfollow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Analysis1.4.Comparison1Topicalantimicrobialdressingcomparedwithnon-antimicrobialdressing,Outcome4Adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Analysis2.1.Comparison2Topicalantimicrobialagent(non-dressing)comparedwithnon-antimicrobialtopicalagent
(non-dressing),Outcome1Proportionofwoundshealed:mediumtermfollow-up. . . . . . . . . . . 86
Analysis2.2.Comparison2Topicalantimicrobialagent(non-dressing)comparedwithnon-antimicrobialtopicalagent
(non-dressing),Outcome2Resolutionofinfection:mediumtermfollow-up. . . . . . . . . . . . . 87
Analysis2.3.Comparison2Topicalantimicrobialagent(non-dressing)comparedwithnon-antimicrobialtopicalagent
(non-dressing),Outcome3Surgicalresection:mediumtermfollow-up. . . . . . . . . . . . . . . 87
Analysis3.1.Comparison3Onetopicalantimicrobialagentcomparedwithanalternativetopicalantimicrobialagent,
Outcome1Proportionofwoundshealed. . . . . . . . . . . . . . . . . . . . . . . . . 88
Analysis3.2.Comparison3Onetopicalantimicrobialagentcomparedwithanalternativetopicalantimicrobialagent,
Outcome2Resolutionofinfection:mediumtermfollow-up. . . . . . . . . . . . . . . . . . 89
Analysis3.3.Comparison3Onetopicalantimicrobialagentcomparedwithanalternativetopicalantimicrobialagent,
Outcome3Surgicalresection:mediumtermfollow-up. . . . . . . . . . . . . . . . . . . . 89
Analysis4.1.Comparison 4Topical antimicrobial agentcomparedwith systemicantimicrobial agent, Outcome1
Resolutionofinfection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Analysis4.2.Comparison4Topicalantimicrobialagentcomparedwithsystemicantimicrobialagent,Outcome2Surgical
resection:mediumtermfollow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Analysis4.3.Comparison4Topicalantimicrobialagentcomparedwithsystemicantimicrobialagent,Outcome3Adverse
events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Analysis5.1.Comparison5Topicalantimicrobialagentcomparedwithgrowthfactor,Outcome1Proportionofwounds
healed:Mediumtermfollow-up. . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) i
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 134
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) ii
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Topical antimicrobial agents for treating foot ulcers in people
with diabetes
JoCDumville1,BenjaminALipsky2,ChristopherHoey3,MarioCruciani4,MartaFiscon5,JunXia6
1Division ofNursing,Midwifery&SocialWork,SchoolofHealthSciences,FacultyofBiology,Medicine &Health,Universityof
Manchester,ManchesterAcademicHealthScienceCentre,Manchester,UK.2DivisionofMedicalSciences,GreenTempletonCollege,
UniversityofOxford,Oxford,UK.3PharmacyandNutritionalCare,VAPugetSoundHealthCareSystemMedicalCenter,Seattle,
WA,USA.4Antibiotic Stewardship Programme,AziendaULSS9Scaligera,Verona,Italy.5CentroMalattie Diffusive, University of
Verona,Verona,Italy.6SystematicReviewSolutionsLtd,TheIngenuityCentre,TheUniversityofNottingham,Nottingham,UK
Contact address: Jo C Dumville, Division of Nursing, Midwifery & Social Work, School of Health Sciences, Faculty of Biol-
ogy, Medicine & Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PL, UK.
[email protected].
Editorialgroup:CochraneWoundsGroup.
Publicationstatusanddate:New,publishedinIssue6,2017.
Citation: DumvilleJC,LipskyBA,HoeyC,CrucianiM,FisconM,XiaJ.Topicalantimicrobialagentsfortreatingfootulcersinpeople
withdiabetes.CochraneDatabaseofSystematicReviews2017,Issue6.Art.No.:CD011038.DOI:10.1002/14651858.CD011038.pub2.
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Peoplewithdiabetesareathighriskfordevelopingfootulcers,whichoftenbecomeinfected.Thesewounds,especiallywheninfected,
cause substantial morbidity. Wound treatments should aim to alleviate symptoms, promote healing, and avoid adverse outcomes,
especiallylowerextremityamputation.Topicalantimicrobialtherapyhasbeenusedondiabeticfootulcers,eitherasatreatmentfor
clinicallyinfectedwounds,ortopreventinfectioninclinicallyuninfectedwounds.
Objectives
Toevaluatetheeffectsoftreatmentwithtopicalantimicrobialagentson:theresolutionofsignsandsymptomsofinfection;thehealing
ofinfecteddiabeticfootulcers;andpreventinginfectionandimprovinghealinginclinicallyuninfecteddiabeticfootulcers.
Searchmethods
WesearchedtheCochraneWoundsSpecialisedRegister,CENTRAL,OvidMEDLINE,OvidMEDLINE(In-Process&OtherNon-
IndexedCitations),OvidEmbase,andEBSCOCINAHLPlusinAugust2016.Wealsosearchedclinicaltrialsregistriesforongoing
andunpublishedstudies,andcheckedreferenceliststoidentifyadditionalstudies.Weusednorestrictionswithrespecttolanguage,
dateofpublication,orstudysetting.
Selectioncriteria
Weincludedrandomisedcontrolledtrialsconductedinanysetting(inpatientoroutpatient)thatevaluatedtopicaltreatmentwithany
typeofsolidorliquid(e.g.,cream,gel,ointment)antimicrobialagent,includingantiseptics,antibiotics,andantimicrobialdressings,in
peoplewithdiabetesmellituswhowerediagnosedwithanulceroropenwoundofthefoot,whetherclinicallyinfectedoruninfected.
Datacollectionandanalysis
Tworeviewauthorsindependentlyperformedstudyselection,’Riskofbias’assessment,anddataextraction.Initialdisagreementswere
resolvedbydiscussion,orbyincludingathirdreviewauthorwhennecessary.
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) 1
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Mainresults
Wefound22trialsthatmetourinclusioncriteriawithatotalofover2310participants(onestudydidnotreportnumberofparticipants).
Theincludedstudiesmostlyhadsmallnumbersofparticipants(from4to317)andrelativelyshortfollow-upperiods(4to24weeks).
Atbaseline,sixtrialsincludedonlypeoplewithulcersthatwereclinicallyinfected;onetrialincludedpeoplewithbothinfectedand
uninfectedulcers;twotrialsincludedpeoplewithnon-infectedulcers;andtheremaining13studiesdidnotreportinfectionstatus.
Included studies employed various topical antimicrobial treatments, including antimicrobial dressings (e.g. silver, iodides), super-
oxidised aqueous solutions, zinc hyaluronate, silver sulphadiazine, tretinoin, pexiganan cream, and chloramine. We performedthe
followingfivecomparisonsbasedontheincludedstudies:
Antimicrobialdressingscomparedwithnon-antimicrobialdressings:Pooleddatafromfivetrialswithatotalof945participants
suggest (based on the average treatment effect from a random-effects model) that more wounds may heal when treated with an
antimicrobialdressingthanwithanon-antimicrobialdressing:riskratio(RR)1.28,95%confidenceinterval(CI)1.12to1.45.These
resultscorrespondtoanadditional119healingeventsintheantimicrobial-dressingarmper1000participants(95%CI51to191more).
Weconsiderthislow-certaintyevidence(downgradedtwiceduetoriskofbias).Theevidenceonadverseeventsorotheroutcomeswas
uncertain(verylow-certaintyevidence,frequentlydowngradedduetoriskofbiasandimprecision).
Antimicrobialtopicaltreatments(nondressings)comparedwithnon-antimicrobialtopicaltreatments (nondressings):There
werefourtrialswithatotalof132participantsinthiscomparisonthatcontributedvariouslytotheestimatesofoutcomedata.Evidence
wasgenerallyofloworverylowcertainty,andthe95%CIsspannedbenefitandharm:proportionofwoundshealedRR2.82(95%
CI0.56to14.23;112participants;3trials;verylow-certaintyevidence);achievingresolutionofinfectionRR1.16(95%CI0.54to
2.51;40participants;1trial;low-certaintyevidence);undergoingsurgicalresectionRR1.67(95%CI0.47to5.90;40participants;
1trial;low-certaintyevidence);andsustaininganadverseevent(noeventsineitherarm;81participants;2trials;verylow-certainty
evidence).
Comparisonofdifferent topical antimicrobial treatments: Weincludedeightstudieswith atotalof 250 participants, butallof
thecomparisonsweredifferentandnodatacouldbeappropriatelypooled.Reportedoutcomedatawerelimitedandweareuncertain
abouttherelativeeffectsofantimicrobialtopicalagentsforeachofourreviewoutcomesforthiscomparison,thatiswoundhealing,
resolutionofinfection,surgicalresection,andadverseevents(allverylow-certaintyevidence).
Topicalantimicrobialscomparedwithsystemicantibiotics:Weincludedfourstudieswithatotalof937participants.Thesestudies
reportednowound-healingdata,andtheevidencewasuncertainfortherelativeeffectsonresolutionofinfectionininfectedulcersand
surgicalresection(verylowcertainty).Onaverage,thereisprobablylittledifferenceintheriskofadverseeventsbetweenthecompared
topicalantimicrobialandsystemicantibioticstreatments:RR0.91(95%CI0.78to1.06;moderate-certaintyevidence-downgraded
onceforinconsistency).
Topicalantimicrobialagentscomparedwithgrowthfactor:Weincludedonestudywith40participants.Theonlyreview-relevant
outcomereportedwasnumberofulcershealed,andthesedatawereuncertain(verylow-certaintyevidence).
Authors’conclusions
Therandomisedcontrolledtrialdataontheeffectivenessandsafetyoftopicalantimicrobialtreatmentsfordiabeticfootulcersislimited
bytheavailabilityofrelativelyfew,mostlysmall,andoftenpoorlydesignedtrials.Basedonoursystematicreviewandanalysisofthe
literature, wesuggest that: 1)use of anantimicrobial dressing instead of anon-antimicrobial dressing may increase thenumber of
diabeticfootulcershealedoveramedium-termfollow-upperiod(low-certaintyevidence);and2)thereisprobablylittledifferencein
theriskofadverseeventsrelatedtotreatmentbetweensystemicantibioticsandtopicalantimicrobialtreatmentsbasedontheavailable
studies(moderate-certaintyevidence).Foreachoftheotheroutcomesweexaminedtherewereeithernoreporteddataortheavailable
dataleftusuncertainastowhetherornottherewereanydifferencesbetweenthecomparedtreatments.Giventhehigh,andincreasing,
frequencyofdiabeticfootwounds,weencourageinvestigatorstoundertakeproperlydesignedrandomisedcontrolledtrialsinthisarea
toevaluatetheeffectsoftopicalantimicrobialtreatmentsforboththepreventionandthetreatmentofinfectioninthesewoundsand
ultimatelytheeffectsonwoundhealing.
PLAIN LANGUAGE SUMMARY
Topicalantimicrobialagents(antibacterialproductsapplieddirectlytowounds)fortreatingfootulcersinpeoplewithdiabetes
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) 2
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Reviewquestion
Wereviewedtheevidenceaboutwhetherornotantimicrobialagents(antibacterial products)canpreventortreatfootinfectionsin
peoplewithdiabeteswhentheyareappliedtopically(directlytotheaffectedarea).Wewantedtofindoutifantibacterialtreatments
couldhelpbothinfectedanduninfectedwoundstoheal,andpreventinfectioninuninfectedwounds.
Background
Peoplewithdiabetesareathighriskofdevelopingfootulcers.Thesewoundscancausediscomfortandoftenbecomeinfected.Diabetic
footulcersthatdonothealcanresultinamputation of partor allof thefootor eventhelowerleg.Antimicrobial agents, suchas
antisepticsandantibiotics,killorpreventbacteriafromgrowing,andaresometimesusedtotreatdiabeticfootulcers.Antimicrobials
maybeusedeithertoreduceinfectionorpromotehealingininfectedwounds,ortopreventinfectionorpromotehealinginwounds
whereinfectionhasnotbeendetected.Wewantedtofindoutwhetherantimicrobialtreatmentswereeffectiveineitherofthesecases;
whichtreatmentsweremosteffective;andifthosetreatedexperiencedanyharmfulsideeffects.
Studycharacteristics
InAugust2016wesearchedforrandomisedcontrolledtrialsinvolvingtheuseofanyantimicrobialtreatmentonfootulcersorother
openwoundsofthefootinpeoplewithdiabetes.Wefound22trialsinvolvingatotalofover2310adultparticipants(onetrialdid
notreportthenumberofparticipants).Participantnumbersineachtrialrangedfrom4to317andfollow-uptimesduringandafter
treatment ranged from4 to 24 weeks. Some trials included participants with ulcersthat were infected, while other trialsincluded
participantswithulcersthatwereuninfected.Thetrialscomparedavarietyofdifferentantimicrobialdressings,solutions,gels,creams,
orointments.
Keyresults
Manyofthetrialsdidnotreportimportantdata,whichmeansthereliabilityoftheresultsisuncertain.Theresultsoffivetrialsinvolving
945participantssuggestthatuseofsometypeofantimicrobial dressingmayincreasethenumberofulcershealedinmedium-term
follow-up(4to24weeks)whencomparedwithanon-antimicrobial dressing(lowcertaintyevidence).Duetolimitedinformation,
wewereunabletoassesstheeffectivenessoftreatmentsineitherpreventingorresolvingwoundinfection.Fourtrialsinvolving937
participantscomparedsystemicantibiotics(givenbymouthorviainjection,distributedtothewholebodybythebloodstream)with
antimicrobialtreatmentsapplieddirectlytothewound.Thesetrialsdidnotprovidedataonhealingorinfection,butitappearedthat
therewasnodifferenceinthesideeffectsexperiencedbyparticipantswhoseulcersweretreatedsystemicallyortopically(moderate
certaintyevidence).
Qualityoftheevidence
Overall, the certainty of the evidence provided by the trials was too low for us to be certain of the benefits and harms of topical
antimicrobialtreatmentsfortreatingfootulcersinpeoplewithdiabetes.More,larger,andbetter-designedrandomisedcontrolledtrials
shouldbecarriedoutinthisarea.
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) 3
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CopyTopic SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
right©alantim
20ic Antimicrobialdressingscomparedwithnon-antimicrobialdressings
17ro
Thebiala Patientorpopulation:Footulcersinpeoplewithdiabetes
Cg
ochraneCoentsfortrea ICSneottemtripvnaegrnsit:sioMonni:x:eSAdtnatnimdaicrdrodbriaeslsdirnegsssings
llaboting Outcomes Illustrativecomparativerisks* (95%CI) Relativeeffect ofparticipants Qualityoftheevidence Comments
ration.footulc (95%CI) (studies) (GRADE)
Pe
ubrs Risk with standard Riskwithantimicrobial
lisin dressings dressings
hp
ee
do
byple Proportion of wounds 425per1000 544per1000 RR1.28(1.12to1.45) 945participants ⊕⊕(cid:13)(cid:13) On average, use of an
Jow
hnith healed (476to616) (5studies) low1 antimicrobial dressing
Wiley&diabete Uuppto24weeks’follow- caonmtimpaicrreodbiwalithdraesnsoinng-
s may increase the num-
So(R
ne ber of ulcers healed
s,Ltd.view) R10is0k0d(5if1femreonreceto: 111991mmoorree)healed wounds per olovwe-ruapmpeedriioudm-termfol-
Incidenceofinfection 183per1000 62per100(7to567) RR0.34(0.04to3.10) 173 participants (2 ⊕(cid:13)(cid:13)(cid:13) Onaverage,itisunclear
Upto24weeks’follow- studies) verylow2 whetherornotuseofan
up antimicrobial dressing
compared with a non-
antimicrobial dressing
reduces the incidence
ofulcerinfectionovera
Risk difference: 121 fewer infections per 1000 medium-term follow-up
(176fewerto384more) period
Resolutioninfection Notreportedforthiscomparison N/A N/A N/A This outcome was not
reported for this com-
parison.
4
CT
opyopic
right©alantim Adverseevents 388per1000 373 per 1000 (241 to RR0.96(0.62to1.48) 134participants ⊕(cid:13)(cid:13)(cid:13) It is uncertain whether
20ic Upto24weeks’follow- 574) (1study) verylow3 use of an antimicro-
17ro up bial dressing affects
Thebiala the risk of adverse
CochraneCogentsfortrea Risk difference: 16 fewer adverse events per eucmrvseoeedbniituaosmlfdc-troaeemrsmsnpioanfnroge-ladloonvwtweim-riutpiha-
llaboting 1000(147fewerto186more) period
ration.footulc *The basis for the assumedrisk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95%confidence interval) is
Pe basedontheassumedriskinthecomparisongroupandtherelativeeffectof theintervention(andits95%CI).
ublisrsin CI:confidenceinterval;N/A:notapplicable;RR:riskratio
hp
ee
do
byple GRADEWorkingGroupgradesofevidence
Johnwith Highquality:Weareveryconfidentthatthetrueeffectliesclosetothatof theestimateof theeffect.
Wd Moderate quality: We are moderately confident in the effect estimate:the true effect is likely to be close to the estimate of the effect,but there is a possibility that it is
iley&iabete sLuobwsqtaunatliiatyll:yOduifrfecroennfti.denceintheeffectestimateislimited:thetrueeffectmaybesubstantiallydifferentfrom theestimateof theeffect.
s
So(R Verylowquality:Wehaveverylittleconfidenceintheeffectestimate:thetrueeffectislikelytobesubstantiallydifferentfrom theestimateof effect
ne
s,Ltdview) 1Downgradedtwiceforriskof biasduetoonestudy(withthehighestweightinginthemeta-analysis)beingatunclearriskof
.
selection bias and threestudies being at highrisk of performancebias (36%weighting inanalysis),although thestudies
wereatunclearorlow riskof detectionbiasforthisoutcome.
2Downgraded twice for imprecision due to sample size and low number of events. 95%CIs span both benefits and harms.
Downgradedonceduetoinconsistency:I²=60%.Downgradedonceduetoriskof performancebias.
3Downgraded twice for imprecision due to sample size and low number of events. 95%CIs span both benefits and harms.
Downgradedonceduetoriskof performancebias.
5
Descriptionofthecondition
Micro-organismsrapidlycolonisevirtuallyallopenwounds;this
BACKGROUND
usuallyhasnoapparentconsequencesintheabsenceofclinicalev-
idenceofinfection,andhealingoccursasexpected(White2006).
Worldwide,therearecurrentlyover415millionadultswithdia- However,somewoundsexhibitahostresponse(usuallymanifested
betesmellitus(5millionofwhomdieofthediseaseannually),and byinflammationortissuedamage)totheorganismstheyharbour,
theprevalenceofdiabetesisexpectedtoreachover640 million suggesting thatthey are clinically infected(Cutting 2005). The
(1in10)by2040(IDF2015).Furthermore,treatingdiabetesac- likelihoodofawoundbecominginfectedincreasesdirectlywith
countsfor12%ofglobalhealthexpenditure(USD673billion). the size of its microbial inoculum, the virulence of the specific
Skinwounds, particularly chroniculcers,commonly developin colonisingorganisms,andthelevelofdiminutionofthehost’slo-
thefeetofpeoplewithdiabetesmellitus,usuallyrelatedtoneu- calandsystemicimmunologicalresistance(Heinzelmann2002).
ropathy(nervedamage),aswellasarterial(bloodvessel)diseaseor For theclinician, characterising awound asinfectedor notis a
trauma(Davies2007;Lipsky2009).Peripheralneuropathy(dam- keyclinicalchallenge.Publishedstudiesshowthatalmosthalfof
agetothenervestothefeet),peripheralarterialdisease,orbothde- allpeoplewithadiabeticfootulcerhavenoclinicalsignsofin-
velopovertimeinmostpeoplewithdiabetes(AmericanDiabetes fection;thesepeopledonotusuallyneedtohaveculturestaken
Association 2003). Many people with diabetes also have as-yet fromtheirwound,astheygenerallydonotrequireantimicrobial
poorlydefineddefectsinimmuneresponsesthatimpairtheirabil- therapy(Lavery2006;Prompers2007).
itytoresistorovercomeinfection(Delamaire1997).Thesefactors Manyclassificationschemeshavebeenproposedfordiabeticfoot
putdiabeticpatientsathighriskofdevelopingfootulcers,most wounds,butmostcategoriseinfectiononlyasbeingeither’present’
of whichbecome infected.Theestimatedlifetimeriskof afoot or’absent’,anddonotspecifyinfectionseverityorhowtodefine
ulcer in a person with diabetes is 25%, at a cost (in Europe in itspresence.Classificationsystemsthatprovidemoreinformation
2008)ofEUR10,000foranuninfectedulcerandEUR17,000 oninfectionhavebeendevelopedbytheInternational Working
foraninfectedischaemiculcer(Markakis2016).Thesewounds, GroupontheDiabeticFoot(IWGDF)andtheInfectiousDiseases
especiallythosethatbecomeclinicallyinfected,causesubstantial Society of America (IDSA) (Table 1) (IWGDF 2015; Lipsky
morbidity. Estimates are that somewhere in the world a person 2012b).Theseclassifications,whicharenearlyidentical,havebeen
with diabetesundergoes alowerextremity amputation every20 validatedaspredictiveofthepatient’sneedforhospitalisationand
seconds.(IWGDF2016).Infectionofadiabeticfootwoundisde- for lower extremity amputation. Asthey also provide a way for
finedasthepresenceofatleasttwooftheclassicsignsorsymptoms acliniciantocommunicatekeyinformationtootherscaringfor
ofinflammation (painortenderness,warmth,redness,swelling) the wound, guidelines recommend that clinicians routinely use
orpurulentsecretions(pus).Footproblems,especiallywhencom- themtoclassifythepresenceandclinicalseverityofdiabeticfoot
plicatedbyinfection,arenowresponsibleformoredaysofhospi- infections(Lipsky2012b).
talisationthananyothercomplicationofdiabetes(Pecoraro1990; In light of the high prevalence of infection in foot wounds in
Singh2005).Diabeticfootinfections,inparticularthosethatcon- people with diabetes, it is important for clinicians to consider
tiguouslyspreadtounderlyingbone,arealsothemainprecipitat- this possibility when such patients present for care. Clinicians
ingfactorforlowerextremityamputation,whichisassociatedwith shouldgenerallydefineinfectionbythepresenceofatleasttwoof
substantialfinancialcost,reducedqualityoflife,andearlymortal- theclassicsymptomsorsignsofinflammation, thatiserythema
ity(Lipsky2012b;Lipsky2016).Toavoidtheseadverseoutcomes (redness),calor(warmth),tumour(swellingorinduration),dolour
itiscrucialtopreventfootinfections,orfailingthat,tooptimally (painortenderness),orpurulentsecretions(pus).Asthepresence
treattheinfectedwounds. Treatmentofinfectionalmostalways ofneuropathyorarterialorimmunologicaldiseasesmayobscure
requiresantimicrobial therapy,which maybegivensystemically thesefindings,someauthoritiesacceptadditional“secondary”or
(tothewholebodyviatheoralorparenteral(i.e.intravenousor “intermediate”signsofinfection(Cutting2005;Gardner2001;
intramuscular)route)ortopically(i.e.locally,throughapplication Lipsky2012b).
ofantiseptic,antibiotic,orotherantimicrobialpreparations(e.g. Cultures of specimens fromacutely infectedwounds (especially
solutions,creams,gels,ointments)).Sometimesitisdifficultfor inpatientsfromhigh-incomeWesterncountrieswhohavenotre-
thecliniciantotellifadiabeticfootwoundisinfected,especially centlybeenonantibiotictherapy)usuallygrowbacteriaclassified
if thepatient hasperipheralneuropathyor arterialdisease. Fur- asaerobicgram-positive cocci. Inthissituation theseare gener-
thermore,themerepresenceofmicro-organisms,especiallyifthey ally the only bacteria against which clinicians need target their
arevirulentorpresentinhighnumbers,mayalsoimpairwound antimicrobial therapy. However, in chronic wounds, or when a
healinginclinicallyuninfectedwounds.Thussomeadvocatepre- patienthasrecentlybeentreatedwithantibiotics, otherbacteria
scribingantimicrobialtherapy(especiallytopically)forhigh-risk (especiallyaerobicgram-negativerodsandobligateanaerobes)of-
clinically uninfected wounds to reduce the bacteria ’bioburden’ tenaccompany thesegram-positive cocci, necessitatingbroader-
andpotentiallyacceleratehealingoravoidovertinfection. spectrumantibiotictherapy.Recently,moleculardiagnosticstud-
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) 6
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
iesofwoundshaveshownthattheyharbouranevengreaterva- activity.Unfortunately,theymaybetoxictooneormoretypesof
riety of organisms than had previously been recognised (Davies hostcellsortissues(e.g.fibroblasts,keratinocytes,andpossibly
2004; James 2008), but the clinical importance of this finding leukocytes).Topicalantisepticagentsusedinthepast(e.g.
is as yet unclear (Lipsky 2013). Furthermore, in many chronic hexachloropheneandiodines)areusedlessfrequentlytoday
woundsbacteriapersistasso-called“smallcolonyvariants”(von becauseofconcernsabouttoxicitytohostcellsandthe
Eiff2006),whicharebothmoredifficulttocultureandtoerad- availabilityofsaferagents.Chlorhexidineandpovidoneiodine
icate.Finally,micro-organisms inchronicwounds oftenexistin areolderagentsthathavebeen(andcontinuetobe)widelyused
statesorcommunitiesthatareparticularlydifficulttotreat,such aswoundantiseptics.Recently,avarietyofproductsthatrelease
asinanadhesive,polymericmatrixcalledbiofilm,whichinduces silverionshavebeenapprovedandarebeingpromotedfor
chronicinflammation,delayshealing,andprotectstheorganism managementofwoundmicro-organisms.
fromtheeffectsofantimicrobialtherapy(Rhoads2008). • Antibiotics:Thesearechemicalsproducedeithernaturally
Giventheproblemsassociated withtreating diabeticfootinfec- (byamicro-organism)orsyntheticallythat,indilutesolution,
tions, treatment with topical antimicrobials has potential bene- inhibitorkillothermicro-organisms.Theyusuallyactonone
fits,forexampleitcouldresultinveryhighdruglevelsatthein- specificcelltarget,haveanarrowerspectrumofactivitythan
fectedsite (withlittleornone atothersites)andmayallowthe antiseptics,arerelativelynon-toxic,andaremoresusceptibleto
use of agents that cannot be given systemically (Lipsky 2009). losingtheireffectivenessasbacteriadevelopresistance.Most
Thesefindings,combinedwithawishtoavoidsystemicantibiotic agentsthatareusedexclusivelyastopicalantibioticshaveefficacy
therapywherepossible,haveledmanyclinicianstoconsiderusing againstgram-positivebacteria(e.g.bacitracin,mupirocin,
topicalantimicrobialtherapyforopeninfectedwounds,especially retapamulin),withasmallernumberdemonstratingefficacy
thosethatfailtohealdespiteapparentlyappropriatetreatment.It againstgram-negativebacteria(e.g.neomycin,silver
was thus important to determine if thisroute of therapyis safe sulphadiazine).Someantibioticsthatareusedsystemically(e.g.
andeffective. gentamicin,metronidazole,clindamycin)havealsobeen
formulatedfortopicaluse.
Below,wehaveprovidedasummaryoftheprincipalcharacteristics
Descriptionoftheintervention
ofcurrentlyavailableantiseptics(Table2)andtopicalantibiotics
Clinicallyinfectedwoundsvirtuallyalwaysrequireantibioticther- (Table3).
apy, whereas clinically uninfected wounds that are healing nor-
mallydonot(Lipsky2009).Ofnote,somesuperficialinfections
(e.g.impetigo,fungaldermatitis)mayrespondtofirst-linetopical Howtheinterventionmightwork
antimicrobial therapy alone, without recourse to systemic ther-
Formillenniahealershaveappliedvariouscompoundstoinfected
apy.However,controversyexistsoverhowtotreatpoorlyhealing
wounds,someofwhich(e.g.silver,honey)arestillinusetoday.
woundsthatdisplay’secondary’signssuggestiveofinfectionand
Useofatopicalapplicationhasmanypotentialadvantagescom-
thatmaybenefitfromtopicalantimicrobialagents.Therationale
pared with giving systemic antibiotic therapy,including: a high
forusingatopicalantimicrobialistokill,oratleasthalt,therepli-
andsustainedconcentrationoftheantimicrobialagentatthesite
cation of pathogenic micro-organisms on theskin, mucosae, or
of infection; the need to use only a limited amount of the an-
inawound,withoutcausingclinicallysignificantdamagetothe
timicrobialattheselectedsite;avoidanceofpotentialtoxicityas-
hostcells.Topicalantimicrobialsmaybeusedontheirownorin
sociatedwithsystemictreatment;abilitytousenovelagentsnot
combinationwithothertopicalorsystemicantimicrobialagents.
availableforsystemicuse;easyapplicationintheoutpatientset-
Thereareseveralclassesoftopicalagentsthatinhibitorkillmicro-
ting;andpotentiallybetterpatientadherencetotreatment.Top-
organisms(Lipsky2009).
icaltreatmentsmayalsoprovehelpfulinaddressingtheglobally
• Disinfectantsarenon-specificagentswithactivityagainst
increasingproblemofmultidrug-resistantorganismsthatarenow
virtuallyalldisease-causingmicro-organisms,includingthosein
untreatable with most systemic agents. For example, a study of
asporestate.Sincethesemaybetoxictohosttissues,theyare
47organismsfromburnwoundsthatweremultidrug-resistantto
usedprimarilyforsterilisinginanimatesurfacesandnotfor
systemicantibioticsweresusceptibleto11commonlyusedtopical
topicaltreatmentofwounds.
antibiotics and antiseptics, although the ratesof resistance were
Mosttopicalantimicrobialsforclinicalusebelongtooneoftwo higherthaninnon-multidrug-resistantorganisms(Neely2009).
majorgroups: Topical antimicrobial therapyalsohassome potential disadvan-
• Antiseptics:Theseareusuallyatypeofdisinfectantthatcan tages:fewagentshavebeenproventobeeffectiveinclinicaltrials;
beusedonintactskinandsomeopenwoundstokillorinhibit almostallhaveminimalpenetrationofintactskinorsofttissue,
micro-organisms.Theyoftenhavemultiplemicrobialtargets,a limitingusetoopenwoundsthatdonothaveeithercellulitisor
broadantimicrobialspectrum,andresidualanti-infective deepsoft-tissueinfection;systemicabsorptionofsomeagentsmay
Topicalantimicrobialagentsfortreatingfootulcersinpeoplewithdiabetes(Review) 7
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.