antimicrobials and non-healing wounds

EWMA Document:Antimicrobials and Non-healing WoundsEvidence,controversiesandsuggestions

A EWMA Document

S2 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3

EWMA2013

Allrightsreserved.Noreproduction,transmissionorcopyingofthispublicationisallowedwithoutwritten

permission.Nopartofthispublicationmaybereproduced,storedinaretrievalsystem,ortransmittedinanyformor

byanymeans,mechanical,electronic,photocopying,recording,orotherwise,withoutthepriorwrittenpermission

oftheEuropeanWoundManagementAssociation(EWMA)orinaccordancewiththerelevantcopyrightlegislation.

Althoughtheeditor,MAHealthcareLtd.andEWMAhavetakengreatcaretoensureaccuracy,neither

MAHealthcareLtd.norEWMAwillbeliableforanyerrorsofomissionorinaccuraciesinthispublication.

PublishedonbehalfofEWMAbyMAHealthcareLtd.

Publisher:AnthonyKerr

Editor:DanielShanahan

Designer:AlisonCutler

Publishedby:MAHealthcareLtd,StJudesChurch,DulwichRoad,London,SE240PB,UK

Tel:+44(0)2077385454Email:[email protected]:www.markallengroup.com

F. Gottrup,1(Editor)MD,DMSci,ProfessorofSurgery,ChairofAntimicrobialDocumentauthorgroup;

J. Apelqvist,2(Co-editor)MD,PhD,SeniorConsultant,AssociateProfessor;

T. Bjansholt,3MSc,PhD,AssociateProfessor;

R. Cooper,4BSc,PhD,PGCE,CBIOL,MSB,FRSA,ProfessorofMicrobiology;

Z. Moore,5PhD,MSc,FFNMRCSI,PGDip,DipManagement,RGN,LecturerinWoundHealing&TissueRepair;

E.J.G. Peters,6M.D.,PhD,Internist-InfectiousDiseasesSpecialist;

S. Probst,7DClinPrac,RN,Lecturer;

1BispebjergUniversityHospital,Copenhagen,Denmark;

2SkneUniversityHospital,Malmoe,Sweden;

3UniversityofCopenhagenandCopenhagenUniversityHospital,Copenhagen,Denmark;

4CardiffMetropolitanUniversity,Cardiff,Wales,UK;

5RoyalCollegeofSurgeonsinIreland,Dublin,Ireland;

6VUUniversityMedicalCenter,Amsterdam,theNetherlands;

7ZurichUniversityofAppliedSciences,Winterthur,Switzerland.

Editorialsupportandcoordination:EWMASecretatiat

[email protected]:www.Ewma.org

ThedocumentissupportedbyanunrestrictedgrantfromB.BraunMedical,BSNMedical,ConvaTec,PolyMem,Flen

Pharma,Lohmann&Rauscher,MlnlyckeHealthCare,Schlke&Mayr,Smith&Nephewandsorbion.

EucomedAdvancedWoundCareSectorGroupprovidedinitialfundingforthedocument.

Thisarticlehasnotundergonedouble-blindpeerreview.

Thisarticleshouldbereferencedas:Gottrup, F., Apelqvist, J., Bjansholt, T. et al. EWMA Document: Antimicrobials and

Non-healing WoundsEvidence, Controversies and Suggestions. J Wound Care. 2013; 22 (5 Suppl.): S1S92.

JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S3

ContentsIntroduction 4Aim 5Objectives 5Structureandcontentofthedocument 5

Method and terminology 8

the principal role of 10 bioburden in woundsWherearewetoday? 10Host-pathogeninteractions 11andoutcomesinwoundhealingMicrobiology 12Biofilm 13Resistanceandtolerance 13toantimicrobialinterventions

Controversies 14Host-pathogeninteractions 14andoutcomesinwoundhealingMicrobiology 15Biofilm 19Resistanceandtolerance 21toantimicrobialinterventions

treatment 27Wherearewetoday? 27Active/passivecontrol 27Featuresofdifferentcategories 28ofantimicrobialagentsTopicalantibiotics 28Antiseptics 30

Indicationsfortreatment 30PreventInfection 30Resolutionofinfection 32

Strengthsandlimitations 32ofthecurrentevidencebase

Controversies 35Recurrenceofinfection 35Whattypeofevidenceshouldwebelookingfor? 35Infectionasanendpoint 37Strengthsandlimitations 38ofthecurrentevidencebase

Patients perspective 41Wherearewetoday? 41Meetingtheclinicalneedsofpatients 41Patientsafety 41Overtreatment 42

Theimpactofwoundinfectiononqualityoflife 42Controversies 43Patientsafety 43Insufficienttreatment 44Overtreatment 45

Patientinvolvement 45

organisation 47Wherearewetoday? 47Accesstotreatment 47Education 48Whichmodeltousewhenorganisingand 48educatingaboutantimicrobials?Presently-usedmodels 49Generalwoundmanagement 49Diabeticfootulcerpatients 49

Controversies 50Organisationinwoundmanagement 50AccesstoTreatment 52Competencies 53Otherinfluences 54

Economics 55Wherearewetoday? 55Risktopatientsandincreasedburden 55healthcareprovisionDiabeticfootulcers 55Pressureulcers 56Legulcers 57

UseofHealthEconomicstoimprovethe 57managementofnon-healingulcersHealthEconomicsandorganisationofcare 58andfactorsrelatedtohealingof 58non-healingwoundstocomparetreatmentinterventions 59innon-healingulcersandreimbursement 59

Summary 61Controversies 61

Future perspectives 64Potentialconsequencesifwedonothing 64Withregardtobioburdeninnon-healingwounds 65Withregardtotreatmentofnon-healingwounds 66Fromthepatientperspective 67Fromtheorganisationperspective 67Fromtheeconomicperspective 68

References 69


Non-healingwoundsareasignificantproblemforhealth-caresystemsworldwide.Intheindustrialisedworld,almost11.5%ofthepopulationwillhavea

problemwoundatanyonetime.Furthermore,

woundmanagementisexpensive;inEurope,

theaveragecostperepisodeis6650forleg

ulcersand10000forfootulcers,andwound

managementaccountsfor24%ofhealth-care

budgets.Thesefiguresareexpectedto

risealongwithanincreasedelderlyand

diabeticpopulation.14

Infectionisoneofthemostfrequent

complicationsofnon-healingwounds.Itcan

jeopardisetheprogressiontowardshealing,

resultinlongertreatmenttimesandincreasethe

resourceuse.Intheworstcases,itcanresultina

majoramputationoralife-threateningcondition.

Woundsaredisposedtoinfection,asthe

exposureofsubcutaneoustissuefollowingaloss

ofskinintegrityprovidesamoist,warm,and

nutrient-richenvironment,whichisconducive

tomicrobialcolonisationandproliferation.

Consequently,useofantimicrobialagentsis

importantinwoundmanagement.

Inappropriateuseofantimicrobials(especially

antibiotics)createsanenvironmentforthe

selectionofresistanceagainstthecurrently

availableantimicrobialproducts,withthepotential

consequenceofsignificantlyjeopardisingpatients

healthstatus.Thedevelopmentofsocalled

superbugsisforeseeableandisthebackgroundfor

increasedpoliticalinvolvement.57

In2009,theEUmemberstatesadoptedcouncil

conclusionsconcerninginnovativeincentivesfor

effectiveantibiotics.Thisisoneofthesingle

mostpowerful,concertedpoliticalstanceson

antibioticresistanceever.Hereitisrecognised

thatthespreadofantibioticresistanceisamajor

threattopublichealthsecurityworldwideand

requiresactionatalllevels.Hence,theycallupon

thememberstatestodevelopandimplement

strategiestoensureawarenessamongthepublic

andhealthprofessionalsofthethreatofantibiotic

resistanceandofthemeasuresavailableto

countertheproblem.

Thishasbeenfollowedbyseveralpan-European

initiatives,suchastheconferenceCombating

AntimicrobialresistanceTimeforJointAction

inMarch2012,7inwhichtheEuropeanWound

ManagementOrganisation(EWMA)participated.

Theconferenceconclusionswerethattherewasa

substantialgapintheknowledgeinthisarea.

Furthermore,theEuropeanCommissionhas

followedthisbyareportonimplementationof

thecouncilrecommendationsonpatientsafety,in

whichtheyconcludethatevenifmanymember

stateshavetakenavarietyofactions,thereisstill

considerableroomforimprovement.8,9

Resistancetoantibioticsresultsinaconsiderable

decreaseinthepossibilityofeffectivelytreating

infections,andincreasestheriskofcomplications

anddeath.10IntheEuropeanUnion(EU)alone,

itisestimatedthat2millionpatientsacquire

nosocomial(hospital-acquired)infectionseach

Introduction


year,11ofwhichmorethanhalfaredrug-resistant.12

Infectionsbasedonresistantbacteriaareassociated

withuptotwo-foldincreaseinmortalitycompared

withinfectionwithsusceptiblemicrobes.13

Coupledwithinsufficientinvestmentinthe

developmentofnewantibiotictreatments,the

issueofdrug-resistantbacteriaisbecominga

pressingpublic-healthconcern.In2007,the

EuropeanAntimicrobialResistanceSurveillance

System(EARSS)reportedthatStaphylococcus aureus

hadbecomeresistanttotheantibioticmeticillin

(MRSA),indicatingthatbeta-lactamantibiotics

arenotsuitableforempirictreatmentofwound

infectionsinEurope.14Todate,thereisno

collectionofdataforbacterialresistanceinwounds.

Despiteatremendousamountofliterature

coveringtheeffectsanduseofantimicrobials,and

thedevelopmentofresistanceinthewoundarea,

thereisalackofaconsistentandreproducible

approachtodefining,evaluatingandmeasuring

theappropriateandadequateuseofantimicrobials

locally/topicallyinwoundmanagement,froma

clinicalandindustryperspective.

Thislackofinformationcanbestbeillustrated

bythefactthat,despitetheextensiveuseof

antimicrobialsinwounds,theiruseremains

controversialforwoundmanagement.These

controversieshaveneverbeendiscussedand

evaluatedindetail,whichisamajorreasonfor

woundinfectionpersistingasoneofthemost

seriousinfluencingfactorsfortheexistenceof

non-healingwounds.

Thisdocumentdescribesthesecontroversies

andhopestoraiseinterestinhowtosolvethese

problemsforthefutureuseofantimicrobials.For

thisreason,EWMAestablishedthegroup,which

producedthisdocument.

Bydiscussionandclarification,wehopeto

contributetoareductionintheburdenofcare,in

anefficientandcost-effectiveway.

StatementTherearealargenumberofantimicrobialwound

careproductsavailable,butweneedtobebetter

preparedforselectingtherightproductforthe

rightpatient,fortherightwound,attheright

time.Thereisconfusionamongpolicymakers,

patients,cliniciansandresearchersastothe

controversiesfortheuseofantimicrobialsin

wounds.Mostdiscussionsandrecommendations

donotdifferentiatebetweendifferenttypesof

antimicrobials,especiallywithregardtoantibiotics

andantiseptics.5

Thisdocumentdescribesthecontroversiessurroundinguseofantimicrobialsinwoundmanagement,andhopestoraiseinterestinhowtosolvethese

problemsforthefutureuse

ofantimicrobials


Aim Theintentionofthisdocumentistofocuson

theresponsibledesignanduseofantimicrobial

strategiesinwoundsthatfailtoprogressthrough

anorderlyandtimelysequenceofrepair.Inthis

document,thesetypesofwoundsaredefinedas

non-healing.15Thefocusisnotonaspecifictype

ofnon-healingwound,buttoprovidemoregeneral

recommendationsforthesetypesofwounds.

Animalandcellularmodels,acutewound(surgical/

traumawounds)andburnsareexcludedfrom

thisdocument.Systemicinfections,debridement

asabioburdencontrolandothertypesofwound

managementstrategieswillnotbecoveredindetail.

Thedocumentstructureisinspiredfromthe

differentelementsthatarenormallyincludedin

thehealthtechnologyassessment(HTA)approach.

Itisnotatraditionalpositiondocumentthat

discussesdifferenttreatmentstrategies,when

tousewhichproduct,oranassessmentofone

productoveranother.

Theoverallaimofthisdocumentistohighlight

currentknowledgeregardinguseofantimicrobials,

particularlyinnon-healingwounds,todiscuss

whatstilliscontroversialandgivesuggestionsfor

futureactions.

ObjectivesThesegoalswillbeachievedbythefollowing:

1Producinganupdateofeachtopicmentioned,includingstatementsonwhichitemshavebeen

showntobebasedonevidenceatthehighestlevel.

2Uncoveringcontroversiesandissuesrelatedtouseofantimicrobialsinwoundmanagement;describe

possiblesolutionsandtheprosandconsofeach

3Summarisingtheinformationpresentedandofferperspectivesforfurtherwork.

Theintentionsofthedocumentaretopresenta

platformofviewpointsfromwhichwecanbuild

messagesforthedifferentstakeholders,including

patients,healthprofessionals,policymakers,

politicians,industryandhospitaladministrators.

StructureandcontentofthedocumentThedocumentincludesthedifferentaspectsof

health-careperspectivessurroundingthecentral

themeofantimicrobialsinwounds.Eachchapter

beginswithanintroductiontothecurrentknowledge

andstatusofthespecifictopic;wehavecalled

thiswherearewetoday.Thissectionalsocovers

anassessmentofthecurrentliteratureandwhat

evidencethereisfortheexistingconsensus.

Themethodfortheevidenceassessmentbuilds

uponEWMAspreviousworkwithoutcomes15and

Theintentionofthisdocumentistofocusontheresponsibledesignanduseofantimicrobialstrategiesinwoundsthatfailtoprogressthroughanorderly

andtimelysequenceofrepair


isthefoundationfortherecommendationsmade

inthisdocument.

Thesecondsectionofeachchapterwilladdressthe

relevantcontroversies.Eachcontroversyhasitsown

subtitle,whichisstatedbelowthetheauthorgroups

statement.Followingthestatement,thecontroversy

isdiscussedandashortconclusionisgiven.

Thepresentdocumenttriestouncover

thecontroversieswithregardtotheuseof

antimicrobialsinwoundcare,withafocuson

non-healingwounds.Mostresearchwithregard

toinfectionandwoundhealingisrelatedtoacute

woundsandaminorpartisrelatedtonon-healing

wounds;however,someevidencefromacute

woundswillbepresentedwhenapplicable.

Thedocumentwillfocusonlocal(topical)

treatmentwithantimicrobials,suchasantibiotics

andantiseptics.Treatmentwithsystemicantibiotics

isnotwithinthescopeofthepresentdocument,

butresultsmaybeusedincaseoflackingevidence

forlocaltreatment.Thedocumentwillconsider

infectionrateasacontinuum(forthedocuments

definitionofinfectionpleaserefertoTable2-1).We

willpresentoveralltreatmentstrategies,butnot

judgewhetheronetreatmentisbetterthananother

orcomparetreatmentstrategies(orproducts).

Therefore,therewillbenodiscussionofpractical

treatmentsordescriptionsofclinicalguidelines;

however,theorganisationalaspectsoftreatment

willbeexplored.Sincetheauthorsareresidentsof

EuropeandEWMAisaEuropeanassociation,the

documentwillonlytakeEuropeanpatientsand

health-caresystemsintoconsideration.

Theopinionsstatedinthisdocumenthavebeen

reachedbyaconsensusoftheauthorsinvolved,

weighingtheirprofessionalopinionsbasedon

theirindividualresearchandthatoftheirpeersas

wellastheirownclinicalexperience.


Search history and development of the documentEachchapterofthedocumenthasbeendivided

betweentheauthorsandtheeditor,andtheco-

editorhasprovidedfeedbackinanediteddraft.This

processhasbeenrepeatedseveraltimes;thegroup

editedthefinaldocumentandallauthorsagreedon

allcontroversies,statementsanddiscussions.The

finaldraftwassenttoareviewprocessduringwhich

resourcepersons,EWMACouncilmembersand

supporterswereaskedtocommentonthedraftin

aninternalvalidationprocess.

Methodandterminology

term DefinitionAntibiotics Achemicalsubstancethateitherkillsorinhibitsthegrowthofamicroorganism,suchasbacteria,fungior

protozoa.Antibioticshavethreemajorsourcesoforigin:(i)naturallyisolated,(ii)chemicallysynthesised,or(iii)semi-syntheticallyderived.Theycanbeclassifiedaccordingtotheireffectonbacteriathosethatkillbacteriaarebactericidal,whilethosethatinhibitthegrowthofbacteriaarebacteriostatic.Antibioticsaredefinedaccordingtotheirmechanismfortargetingandidentifyingmicroorganismsbroad-spectrumantibioticsareactiveagainstawiderangeofmicroorganisms;narrow-spectrumantibioticstargetaspecificgroupofmicroorganismsbyinterferingwithametabolicprocessspecifictothoseparticularorganisms.6

Antimicrobialagents Anysubstancewiththeabilitytoinhibitamicroorganism,whichmeansthatthedefinitioninludesbothantibioticsandantiseptics,irrespectiveofbeingintheformofadressing,solution,gelordrug.

Antimicrobialresistance Theabilityofamicroorganismtosurviveandevenreplicateduringacourseoftreatmentwithaspecificantibioticorantiseptic.Itcanarisefromgeneacquisitionand/ormutation.Failuretoresolveaninfectionwiththefirstcourseofanantibioticorantiseptictreatmentmaymeanthattheinfectionspreadsorbecomesmoresevere.Intrinsic resistance BacteriahaveneverbeenshowntobesusceptibleAcquired resistance Previouslysusceptiblebacteriahavebecomeresistantasaresultofadaptationthrough

geneticchangeMultidrug resistance Correspondstoresistanceofabacteriumtomultipleantibiotics.6

Antimicrobialtolerance Theabilityofamicroorganismtosurviveandevenreplicateduringacourseoftreatmentwithaspecificantibioticorantiseptic.Toleranceisdistinctfromresistance,sinceresistanceiscausedbytheacquisitionofdeterminantsthatregulateactivemechanisms,whichdirectlydiminishtheactionoftheantimicrobialagentandallowcelldivisionandmicrobialgrowth,whereastoleranceenablesthecellsinbiofilmstosustainlong-termexposuretotheantimicrobialagentswithoutlossofviabilityorgeneticchange.Antimicrobialtoleranceisnotduetoapermanentgeneticchange.16

Table2-1.Definitionsusedinthedocument

Besidesaninitialliteraturesearch,aspecific

literaturesearchwasmadewithregardtothe

studydesign,endpointsandoutcomesin

comparative/randomisedcontrolledtrials(RCTs)

ontheantimicrobialtreatmentofwounds.This

systematicreviewwasmadetosupplementan

earlierliteraturesearchconductedin2009.

DefinitionsForthefulllistofdefinitionsusedinthedocument,

pleaserefertoTable2-1.


term DefinitionAntiseptic Agentsinhibitingthegrowthanddevelopmentofmicroorganisms.Anantisepticisa

non-specificchemicalpossessingantimicrobialpropertiesthatcanbeusedonskin,woundsandmucousmembranes.17

Bacteria Prokaryotescanbedividedintocategories,accordingtoseveralcriteria.Onemeansofclassifyingbacteriausesstainingtodividemostbacteriaintotwogroups(Gram-positive,Gram-negative),accordingtothepropertiesoftheircellwalls.6

Bioburden Bioburdenisthepopulationofviablemicroorganismson/inaproduct,oronasurface.17

Biofilm Acoherentclusterofbacterialcellsimbeddedinabiopolymermatrix,which,comparedwithplanktoniccells,showsincreasedtolerancetoantimicrobialsandresiststheantimicrobialpropertiesofhostdefence.16

Colonisation Microbialmultiplicationinoronthewoundwithoutanovertimmunologicalhostreaction.16

Contamination Microbialingressintothewoundwithoutgrowthanddivision.17

Empiricalantibiotictherapy

Antibiotictherapycoveringatthemostprobableorimportantmicroorganismwiththemostprobableresistancepattern.17

Endpoints Theoccurrenceofadisease,symptom,sign,orlaboratoryabnormalitythatconstitutesoneofthetargetoutcomesofaclinicaltrial.18

Hostdefence Thecapacityofanorganismoratissuetowithstandtheeffectsofaharmfulenvironmentalagent.16

Infection Invasionandmultiplicationofmicroorganismsinbodytissues,evokinganinflammatoryresponse(systemicand/orlocal)andcausinglocalsignsofinflammation,tissuedestruction,andfever.6Itisperhapsworthnotingthatdefinitionsofwoundinfectionvary,19butthatdiagnosisisbasedonclinicalsignsandsymptoms.16

Outcome Documentationoftheeffectivenessofhealthcareservicesandtheendresultsofpatientcare.15

Recurrenceofinfection Areoccurrenceofthesameillnessfromwhichanindividualhaspreviouslyrecovered.17

Reductionofbioburden Reductionofthesizeanddiversityofamicrobialpopulation.17

Resourceutilisation Thetotalamountofresourcesactuallyconsumed,comparedagainsttheamountofresourcesplannedforaspecificprocess.6

Woundcleansing Removingharmfulsubstances(forexample,microorganisms,celldebrisandsoiling)fromthewound,sothatthehealingprocessisnotdelayed/hindered,ortoreducetheriskofinfection.17

Table2-1.Definitionsusedinthedocumentcontinued


Thischapterwilldescribethecontroversiessurroundingthesignificanceofbioburdeninwoundsfromascientificpointofview:Host-pathogeninteractionsandoutcomesinwoundhealing

QDoesinfectionimpairwoundhealing?

QDobacteriaimpairwoundhealinginanon-infected,non-healingwound?

Microbiology

Q Isthenumberofaspecificbacteriumpergramme/cm3oftissueanadequateindicatorof

infectioninalltypesofwounds?

Q Shouldmicrobialorganismsalwaysbeeliminatedfromawound?

QDoweknowenoughtosetanindicationfortopicalantimicrobialinterventionfroma

microbiologicalperspective?

Q Isthetypeorvirulenceofbacteriaimportant?

QWhatiscriticalcolonisation?

Q Isremovalofmicroorganismsfromwoundsasufficientendpointfortheefficacyoftheuseof

antimicrobialsinwounds?

Theprincipalroleofbioburdeninwounds

Biofilm

QDoesthepresenceofabiofilmitselfinfluencewoundhealing?

Q Isthepresenceofabiofilminawoundalwaysundesirable?

QHowcanbacteriainbiofilmsberemovedfromwounds?

Resistanceandtolerancetoantimicrobialinterventions

Q Isthereanyantimicrobialagentthatisnotexpectedtoselectforresistanceortolerance

inbacteriainthewound?

Where are we today?HistoricalbackgroundTheformulationofthegermtheoryofdiseaseby

Kochin1876establishedtheroleofinfectious

agentsinthecausationofinfection;fromthis,

therelevanceofantimicrobialagentsintreating

andpreventinginfectionsbecameevident.The

useofantimicrobialinterventionsintreating

woundshasalonghistoryandevenancient

civilisationsareknowntohavedevisedcrude

antimicrobialtopicalwoundremediesfromlocal

materials,suchaswine,vinegar,honey,plant

extractsandminerals.Withthedevelopmentof


thechemicalindustryduringthe19thcentury,

antisepticsbecameavailablefortreatingwounds.

Surgicalprocedureswerefearedastheyoften

resultedinlife-threateninginfections,known

ashospitalgangrene,andmortalityrateswere

7080%.20Theneedforhandwashingwasfirst

recognisedbyIgnazSemmelweisand,inthelate

19thcentury,JosephListerdevelopedaconcept

ofasepticsurgeryinwhichcarbolicacidwasused

toreducethemicrobialcontaminationofsurgical

instruments,theoperatingtheatreenvironment,

incisionsitesandthesurroundings.

Thesystemicuseofchemicalagentsasmagic

bulletstotreatinfectionwaspioneeredbyPaul

Ehrlichatthebeginningofthe20thcentury.

Later,thediscoveryofantibiotics(Alexander

Fleming)providedavarietyofnaturaland

semi-syntheticantimicrobialagentsthatwereable

tolimitthegrowthofspecificinfectiousagents,

bytargetingapreciseintracellularsiteorpathway.

Cliniciansbegantorelyonantibioticsinsteadof

antisepticsforpreventingandtreatingsystemic

andlocalisedwoundinfections,duetotheir

rapidmodeofactionandeffectiveness.

Additionally,reportsofcytotoxicityobtained

fromanimalmodels21,22discourageduseof

antisepticsinwoundcare.

Antibioticshavebeenusedextensivelyinmedicine

andagriculture.Duringthe1950s,antibiotic-

resistantbacteriawerefirstreported;morerecently,

antiseptic-resistantbacteriahavebeendetected.

Continualmicrobialevolutionandthespreadof

resistantstrainshaveledtoincreasedprevalence

andemergenceofmultidrug-resistantstrains.

Thishasreducedtheefficacyofantimicrobial

agentsincontemporarypracticeandthedilemma

ofmanagingwoundinfectioneffectivelyinthe

futuremustbecarefullyconsidered.Althougha

widerangeofantimicrobialproductsareavailable

fortreatingwounds,fewarewithoutlimitations

(Table3-1andTable3-2).

Host-pathogeninteractionsandoutcomesinwoundhealingLossofintegrityoftheskinprovidesanopportunity

fortheingressofmicrobialcells,andthepresence

ofmicroorganismsinwoundsisnotuncommon.

Theoutcomeofcomplexinteractionsbetweenthe

TheformulationofthegermtheoryofdiseasebyKochin1876establishedtheroleofinfectiousagentsinthecausationofinfection;fromthis,

therelevanceofantimicrobial

agentsintreatingandpreventing

infectionsbecameevident


humanhostandwoundbioburdenisnotreadily

predictable,butthreeconditionsarerecognisable:

1Whenconditionswithinawounddonotfavourthemultiplicationofanyofthecontaminating

microbespresent,theirpersistenceisshort-

termandwoundhealingmaynotbeaffected

(contamination)17

2Colonisationoccurswhenastableequilibriumisreachedbymicrobesthatsuccessfullyevadehost

defencesandgrowwithoutelicitingasystemic

immuneresponsesorovertclinicalsymptoms.23

Thereisevidencethatcolonisationdoesnot

impairwoundhealinginvenouslegulcers24

3Whenanimbalancearisesbecausehostimmunologicalcompetenceiscompromised

and/ormicrobesmanifestvirulencefactors,overt

woundinfectionresultsandmicrobialinvasion

intohosttissuesleadstocellulardamage,

immunologicalresponses,andthedevelopment

ofclinicalsignsandsymptoms.25

Thefactorsthatdeterminetheoutcomeof

host-pathogeninteractionsarenotcompletely

understood,26,27andtheimpactofmicrobialcells

andtheirproductsonhealingarealsonotyet

fullyelucidated.Furthermore,thereasonsforthe

transitionofanacutewoundtoachronicwound

are,atpresent,onlypartiallyexplained.

MicrobiologyThebacterialdiversityinnon-healingwounds

ishigh.28,29Ininvestigatingthebacterialfloraby

conventionalculturing,itwasobservedthatchronic

venouslegulcersharbourS. aureus(in93.5%of

theulcersexamined),Enterococcus faecalis (71.7%),

Pseudomonas aeruginosa(52.2%),coagulase-negative

staphylococci(45.7%),Proteus spp.(41.3%)and

anaerobicbacteria(39.1%).30Anotherstudyof

chronicvenouslegulcersfoundthemostcommon

bacteriatobeS. aureus(65%),Enterococcus(62%)

andPseudomonas(35%).31Allofthestudies

characterisingthemicrobialfloraofnon-healing

woundsagreeonthenearlyuniversalpresenceof

S. aureus.3134Inaddition,moststudiesrecoveredP.

aeruginosainapproximatelyhalfoftheinvestigated

venouslegulcersandshowedthatthedeepdermal

tissuesofallnon-healingwoundsharbourmultiple

bacterialspecies.30,33,35Theorganisationand

distributionoftwobacterialspeciesinthechronic

woundbedhasbeenexploredintwostudies.35,36

Twospecificpeptidenucleicacid(PNA)probesfor

fluorescentin situhybridisation(FISH)analysis,

oneforS. aureusandoneforP. aeruginosa,in

combinationwithauniversalbacterialprobewere

usedinbothstudies.Theobservationsrevealedthat

bothbacteriamightbepresentinthesamewound

butatdistinctlocations,andthatveryfewbacteria

ofdifferentspecieswereobservedincloseproximity

toeachother.31

Indiabeticfootwounds,Gram-positiveaerobic

cocciwerefoundin59%ofcultures(ofwhich24%

wereS. aureus),andGram-negativeaerobeswere

foundin35%ofcultures(23%Enterobacteriaceae,

ofwhich29%wereEscherichia coliand28%were

Proteus mirabilis).P. aeruginosawaspresentin8%

ofallisolatesandanaerobesaccountedforfewer

than5%ofallisolates.37Othergroupshaveused

moleculartechniques,suchas16Ssequencingand

denaturinggradientgelelectrophoresis(DGGE),

toelucidatethemicrobiotaofnon-healing

wounds,23,3840andfoundmorediversemicrobial

communities,includinganaerobicbacteria,in

manywounds.Indiabeticfootulcers,DeSottoand

coworkers37foundthattakingdeeptissuecultures,

asopposedtosuperficialwoundswabs,ledtoa

substantialreductioninthenumberofcultured

species,andareductionintheprevalenceof

multidrug-resistantorganismsandthenumberof

organismsconsideredmerecolonisers.Therefore,

itcanbeconcludedthatthereissubstantial

evidenceforthepresenceofconsiderableamounts

ofbacteriainalltypesofnon-healingwounds.


Traditionalculturingtechniquesarenormally

usedtoprovidequalitativeinformationon

thepresenceofpotentialpathogensandtheir

antibioticsensitivities.However,antimicrobial

interventionswillbechosenonempiricalcriteria

whenpatientspresentwithspreadingwound

infections.Rapidmolecularcharacterisationof

woundmicrobialfloraisnotroutinelyavailable

anddoesnotyetprovideadequateinformation

onantimicrobialsusceptibility.

BiofilmsUntil40yearsago,medicalscientiststhought

bacteriatoexistsolelyasfree-livingorganisms

and,assuch,werestudiedinlaboratory

experimentsinshakencultures.Thisformisnow

describedastheplanktonicphenotype.Inthelate

1970s,itwasrealisedthatbacteriamayoccurin

aggregatesinnatureandinchronicinfections.41,42

Thisaggregatingprocesswaslatertermedthe

biofilmgrowthphenotype.43Theplanktonic

andbiofilmgrowthphenotypesaredistinctnot

onlybecausebacteriainbiofilmsaresessile,but

becausetheyexhibitextremeresistance/tolerance

toantibioticsandmanyotherconventional

antimicrobialagents,aswellasanextreme

capacitytoevadehostdefences.33,34,4446

BiofilminwoundsBiofilmwerefirstassociatedwithhealedwounds

whentheyweredetectedonsuturesandstaples

thathadbeenremovedfromsurgicalincision

sites.47Murinemodelswereusedtoinvestigate

theabilityofstaphylococcitoformbiofilmin

acutewounds4850andtodelayhealing.51Thefirst

directevidenceofthepresenceofbiofilminnon-

healingwoundswasbasedonthemicroscopic

observationofbacterialaggregates.5254The

biofilmgrowthphenotypeprotectsthebacteria

fromantibioticsandotherantimicrobialagents,

suchassilver,andhostdefencemechanisms(such

astheimmunesystem).Thephenotypehasbeen

definedas:

A coherent cluster of bacterial cells imbedded

in a matrix, which are more tolerant to most

antimicrobials and the host defence, than

planktonic bacterial cells.55

Thissuggeststhatifthebacteriasucceedin

formingabiofilmwithinthewoundbed,they

willbeextremelydifficulttoeradicate,otherthan

bysurgicalormechanicalwounddebridement.

Essentially,biofilmconsistofaggregatedbacteria

inmultiplelayers.Itisnotknowhowmany

bacteriallayersittakesfortheaggregatetoreach

thebiofilm-tolerantphenotype.Mostofour

knowledgeisderivedfromin vitro studieswhere

tolerantbacteriaaredormantandcloselyresemble

thestationarygrowthofplanktonicbacteria.

Thisdormancyisthoughttobeestablishedby

increasinggradientsofnutrientsandoxygen,as

thelayersofbacteriaincrease.56

Thematrixofthebiofilmalsoplaysarole.Itis

notabullet-proofphysicalshellsurroundingthe

bacteria;instead,thematrixcomponentschelate

and/orneutralisedifferentantimicrobialagents,

whereasothersfreelypenetrate.Asecondaryeffect

ofmanybacterialaggregatesistheinitiationof

cell-to-cellsignalling,alsotermedquorumsensing,

whichinitiatesvirulencefactorsandincreased

antimicrobialandhosttolerance.

ResistanceandtolerancetoantimicrobialinterventionsResistancetoanantimicrobialagentcanariseby

mutationand/orgeneacquisition.

Reducedsusceptibilityofbiofilmtoantimicrobial

agentsandhostdefencemechanismsiscorrelated

tothedevelopmentofbacterialaggregationand

isreferredtoastolerance.Toleranceisdistinct

fromresistance,sinceresistanceiscausedbythe

acquisitionofdeterminantsthatregulateactive

mechanisms,whichdirectlydiminishtheactionof

theantimicrobialagentandallowcelldivisionand


microbialgrowth.Conversely,toleranceenablesthe

cellsinbiofilmtosustainlong-termexposuretothe

antimicrobialagentswithoutlossofviability.

Biofilmdisruptionanddispersalexperiments

suggestthattoleranceisreadilyreversible,whereas

resistanceduetomutationaleventsisnot.57The

manycelllayersinbiofilmcausemetabolicactivity

gradientsthatmediateslowergrowthrateofthe

innerpartofthebiofilmanddecreaseaccessto

nutrientsandoxygen.Thematrixofthebiofilm

alsocontributestotolerance,assomeofthe

matrixcomponents,suchasextracellularDNA

andalginate,areknowntochelateantibiotics.58

Manyantibioticsshowhighlevelsofantimicrobial

activityonlyonmetabolicallyactivebacteria.

controversiesHost-pathogeninteractionsandoutcomesinwounds

QDoesinfectionimpairwoundhealing?

StatementWoundinfectionmayinterruptthewound

healingprocess.

DiscussionWoundhealingisnormallyexpectedtoproceed

accordingtoexpectedtimeframes,59butcanbe

prolongedbyvariousintrinsicand/orextrinsic

factors.Atpresent,thereisinsufficientinformation

onthewayinwhicheitheracuteorchronic

infectionimpactstheeventsofhealing.

ConclusionMoreresearchintotheeffectsofmicrobialcells

andtheirproductsonthecellsandcomponents

involvedinwoundrepairisindicated.

(Forfurtherdiscussion,lookattheinfluence

ofbacteriaonwoundhealingbelow).

QDobacteriaimpairwoundhealinginanon-infected,non-healingwound?

StatementSomebacteriahavethepotentialtoimpairwound

healingintheabsenceofinfection,butthereis

insufficientevidencefromaclinicalperspective.

However,therearein vitrodatathathaveshownthat

somebacteriacanimpairwoundhealing.

DiscussionEventhoughnodefiniteconclusionscanbedrawn

atthemoment,astudybyJamesetal.54established

anelevatedpresenceofmicrobialaggregatesin

non-healingwoundscomparedwithacutewounds,

usingscanningelectronmicroscopy(SEM).In

addition,ithasbeenreportedthatP. aeruginosa-

infectedwoundsappearsignificantlylargerinsize

thanwoundsthatdonotcontainP. aeruginosa.6062

Bothcellularandhumoralresponsestakepartin

theinflammatoryprocessofnon-healingwounds.

Somebacteriahavethepotentialtoimpairwoundhealingintheabsenceofinfection,butthereisinsufficientclinicalevidence


Similartoanyotherinfection,polymorphonuclear

leucocytes(PMNs;themajorityofwhiteblood

cells)aredetectedinhighamountsinnon-

healingwounds,especiallywheninfectedwith

P.aeruginosa.63ButwhatroledoesP.aeruginosa

possiblyplay?ItwasdemonstratedbyJensen

etal.64thatP.aeruginosabiofilmsarecapable

ofeliminatinghumanneutrophilsbyexcreted

rhamnolipids.Bjarnsholtetal.52proposedthat

thiseliminationalsooccursininfectedwounds.

Theconsequencesareachronicinflammatory

condition,acontinuousinfluxofneutrophilsand

aneffluxofintracellulardegradationenzymesfrom

deadneutrophils,suchasreactiveoxygenspecies

(ROS)andmatrixmetalloproteinases(MMPs).

P.aeruginosaalsoseemstoplayaroleinthesuccess

rateofsplit-thicknessskingrafting,substantiating

thenegativeroleofbacteriainwoundhealing.65

Inarecentstudy,66thebioburdenof52non-

healing,neuropathic,non-ischaemic,diabeticfoot

ulcers,withoutclinicalevidenceofinfection,was

investigated.Itwasfoundthatmicrobialload,

diversityandthepresenceofpotentialpathogens

wasgrosslyunderrepresentedbyswabsprocessed

byconventionalbacterialculturecomparedwith

thosewhoseDNAwascharacterisedbysequencing

bacterialribosomalgenes.Ulcerdepthwas

positivelycorrelatedwithabundanceofanaerobes

andnegativelycorrelatedwithabundanceof

Staphylococcus.Ulcerdurationwaspositively

correlatedwithbacterialdiversityandhigherlevels

ofGram-negativebacteria,butnotStaphylococcus.

Ulcersinpatientswithpoorglycaemiccontrolhad

higherlevelsofStaphylococcusandStreptococcus.

ConclusionInlaboratorystudies,ithasbeenshownthat

somebacteriahavethepotentialtoimpairwound

healingintheabsenceofinfection,butthereis

insufficientclinicalevidencetodrawdefinitive

conclusions.Furtherstudieselucidatingtheprecise

roleofbacteriaareurgentlyneeded.

MicrobiologyQ Isthenumberofaspecificbacteriumper

gramme/cm3tissueanadequateindicatorof

infectioninalltypesofwounds?

StatementWebelievethatthedefinitionofinfectionforacute

wounds(105bacteria/cm3tissue67)maynotbe

appropriatefornon-healingwounds.

DiscussionArelationshipbetweenskingraftsurvivalin

animalwoundsandthepresenceofbacteriawas

demonstratedbyLiedburg,ReissandArtz,68and

confirmedinhumansbyKrizek,Robsonand

Kho.67Krizeketal.67showedthat,onaverage,

94%ofgraftssurvivedwhen105cfu/gbacteria

werepresentinbiopsiesandonly19%survived

whenthecountexceeded105cfu/g.Quantitative

bacteriologywasperformedonwoundsundergoing

delayedclosureandthosewith105cfu/gbacteria

atclosurehealedsuccessfully,butthosewith

>105cfu/gbacteriadidnot.69Similarly,bacterial

numberswereshowntoinfluenceinfection70and

thesuccessfulclosureofpedicledflaps.71

In1969,arapidmeansofestimatingbacterial

numbersusingastainedslidepreparedimmediately

frombiopsymaterialwasdeveloped.72Hence,the

105cfu/gthresholdbecamethegenerallyaccepted

definitionofinfection.73,74However,multiple

samplingofsevendecubitusulcersandtwo

postoperativesamplesshowedthelimitedvalueof

asingletissuesample;75also,estimatingbacterial

numbersintissuecollectedfromburnpatients

failedtodistinguishbetweencolonisedandinfected

patients.76Therefore,relevanceofdetermining

bioburdensizeinnon-healingwoundsandthe105

guidelinehasbeenchallenged.77

Laboratoryprotocolsfortheroutineprocessingof

woundswabsusuallyaimtoisolateandidentify

potentiallypathogenicorganisms.Theydonot


normallyincludethequantitativeassessmentof

bacterialcells,whereasthoseforbiopsiesmay.

However,biopsiesarenotoftenemployedinthe

diagnosisofinfection.Inenumeratingbacterial

numbers,methodsaregenerallydesignedtoestimate

thetotalviablenumberofaerobicbacteria,even

thoughnosinglemethodcanprovidesuitable

laboratoryconditionstosupportthecultivationof

allaerobicbacteria.Numbersofaspecificbacterium

couldbereasonablyandaccuratelyestimated,but

thiswouldnotnecessarilyreflectthetotalviable

countofallbacteria.Moreover,comparedwitha

quantitativemoleculartechnique,conventional

bacterialcountinggaveanunderestimateonaverage

of2.34logandamaximumdifferenceofmorethan

6log.66Itisimportanttonotethatswabsareusedto

recoverbacteriafromthewoundsurface,whereas

biopsiessampledeepertissue.Sincevaryingprotocols

mayhavebeenusedindifferentlaboratories,

comparisonofbacterialnumbersindifferentstudies

isunwise.Furthermore,methodstodetectbiofilm

duringtheroutineprocessingofclinicalspecimens

derivedfromwoundsarenotyetavailable.

Manydifferentbacterialandfungalspecieshave

beenidentifiedinnon-healingwounds.The

quantityofeachspeciesmayvaryandwhether

smallamountsofonebacteriummightboostone

ofthemajorinhabitantsofawoundisnotknown.

Frommicroscopicinvestigations,weknowthat

thebacteriainnon-healingwoundsareprimarily

foundinsmall,localandveryheterogeneously

distributedbiofilmaggregates;7880however,some

ofthesesmallaggregateselicitamassiveneutrophil

infiltrationandadelayinhealing,whereasothers

donot.Thisindicatesthatthenumberofbacteria

percm3tissuemaynotberelevant,whilewhich

speciesarepresentmay.

ConclusionThereisaneedtoinvestigatetherelationship

betweenmicrobialpopulationsizesinnon-healing

woundsandclinicalindicatorsofinfection.

Q-i Shouldmicrobialorganismsalwaysbeeliminatedfromawound?

StatementThecausalrelationshipbetweenthepresenceof

microorganismsinawoundandtheprogressof

woundhealingisnotentirelyunderstood,butwe

believethatnotallmicrobialorganismsmustbe

eliminatedfromthewound.

Q-ii Doweknowenoughtoagreeonanindicationforuseoftopicalantimicrobialintervention

fromamicrobiologicalperspective?

StatementUnlikeindicationsforinitiatingsystemicantibiotic

therapyforwoundinfections,indicationsfor

initiatingtopicalantimicrobialagentsareless

well-defined.Webelievethatitislikelythatboth

indicationsforsystemicandtopicalantimicrobial

agentsareequal.

DiscussionThehumanbodyisnotgermfree,butsupportsa

diversenaturalfloraofmicrobialspecieswithout

detriment.Someevidencedemonstratesthathealing

inasterilewoundproceedsatslowerratesthanin

non-sterilewounds.Animalmodelshavebeenused

toexploretheeffectsofbacteriaonhealingrates.

Fasterhealinginwoundsthathadbeeninoculated

withstaphylococcicomparedwithsimilarwounds

protectedfromenvironmentalcontaminationby

dressingswasreportedbyCarrelin1921,81and

woundsinoculatedwitheitherS.aureusorBacillus

subtilisshowedarapidgainintensilestrength.82

Acceleratedhealinghasalsobeenreportedin

woundsinfectedwithGram-negativebacteria

wherethepresenceofProteusorE. coli,orboth

evokedagreaterinflammatoryresponseand

increasedwoundstrengthduetoincreased

collagencontent.83Someevidencesuggeststhat

thiseffectwasrelatedtoinoculumsize.Wounds


thatreceived107cfuormoreE. coliexhibitedsigns

ofinfectionbygrossappearanceandhighertensile

strength,thosewith103106cfuE. coli hadahigh

tensilestrengthbutvariablesignsofinfection,and

thosewith102cfuE. coliwereweakerthancontrol

woundsandwithoutinfection.84

Theinvolvementofdifferentmicrobialspeciesin

delayedhealinghasbeenextensivelyinvestigated;

however,conflictingevidencelinkingbioburden

tohealingprogressexists.AlthoughS. aureusis

commonlyisolatedfromwounds,ithasnotalways

beenlinkedtoinfection.85P. aeruginosawasassociated

withenlargedulcers61andenlargedpressuresores,86

butwasnotthoughttocausedelayedhealing.

Thispathogenproducesarangeofvirulence

determinants,ofwhichexpressionisinfluenced

bybacterialnumbersviachemicalsignallingor

quorumsensing.Forexample,rhamnolipidsfrom

P. aeruginosaimpairneutrophilfunctionandimpact

healing.52Incidenceofanaerobesandchronic

woundinfectionhasbeenlinked,85andsynergistic

relationshipsbetweenanaerobesandcoliforms

facilitateinfectionsatlowpopulationdensities.87

Hence,determiningthenumberofspecificbacteria

maybemoreinformativethandeterminingtotal

bacterialnumbersinthefuture.

Longitudinalstudieshaveindicatedthatthe

presenceofadiverseflora,ratherthanany

particularspecies,islinkedtorecalcitrant

wounds.88,89Sincetheimpactofmicrobialflora

onwoundsdoesnotyetseemtobeadequately

explained,itisdifficulttopredicthowantimicrobial

interventionswillaffectratesofhealing.However,it

shouldbecautionedagainstdismissingthepresence

ofcertaincombinationsofbacteriadetectedin

wounds,suchascoliformsandanaerobes,since

theycanactsynergisticallytofacilitateinfection.

Acorrelationbetweendecreasingbacterialload

andtherateofwoundhealingwasdemonstrated

byLymanetal.in1970,45andtheneedtoreduce

microbialpopulationstolessthan106cfu/ml

woundexudatetoabolishdelayedhealingin

pressureulcerswasdemonstrated.46

Inarecentretrospectivecohortstudy,90itwas

demonstratedthatindividualisedtopicaltreatment

regimens,includingtopicalantibiotictherapy

aimedatspecificbacterialspeciesidentifiedwith

moleculardiagnostics,resultedinsignificantly

improvedhealingoutcomescomparedwith

eithertheuseofsystemicantibioticsindicatedby

moleculardiagnosticsortostandardcare.

MolecularcharacterisationofstrainsofS. aureus

isolatedfromdiabeticfootulcerssuggestedthat

strainsisolatedfromuninfectedulcersthathealed

orhadafavourableoutcomedifferedfromthose

derivedfrominfectedulcers.91

ConclusionAtpresent,theevidencetoshowthatcontrolling

woundbioburdenimproveshealingoutcomesis

limited.Thereisaneedtodeterminetheeffects

ofeachindividualspeciesaswellastheeffectsof

combinationsofspeciesonhealingoutcomes.

Q Isthetypeorvirulenceofbacteriaimportant?

StatementSomebacteriaaremoreaggressivethanothersin

causinginfectioninawound.

DiscussionIdentificationofseriouspathogens,suchasbeta-

haemolytic(GroupAandG)Streptococcus,isalways

ofclinicalsignificanceinanon-healingwound.

However,studiescorrelatingspecificbacterialspecies

towoundhealingindicatethatthepresenceofP.

aeruginosaplaysanimportantroleinwoundhealing

andthesuccessrateofskingrafting.65Additionally,it

hasbeenreportedthatP. aeruginosa-infectedwounds

appearsignificantlylargerintermsofareathan

woundsthatdonotcontainP. aeruginosa.6062


Theexpressionofvirulencedeterminantsin

bacteriaisofteninfluencedbythenumbersof

individualspresentinthepopulationofaspecies.

Thisisknownasquorumsensingandexplainswhy

bacteriapresentinhighnumbersmaybevirulent,

butthesameorganismatlownumbersisnot.Italso

indicatesthatenumeratingspecificbacteriarather

thanwholecommunitiesmaybemoreinformative

forinitiatingantimicrobialinterventions.

ConclusionGroupAandGbeta-haemolyticstreptococciare

clinicallysignificantinwounds.Insomestudies

andincertainwounds,P. aeruginosaseemstoplay

animportantrole.

QWhatiscriticalcolonisation?

StatementCriticalcolonisationisatermusedtodescribe

woundsthatfailtohealduetomicrobial

multiplication,withouttissueinvasionoranovert

hostimmunologicalresponse.

DiscussionThetermcriticalcolonisationwasfirstusedin

1996toexplaindelayedwoundhealingthatwas

amelioratedbytopicalantimicrobialtreatment.92,93

Itwasusedtomodifytheconventionalmodel

ofwoundinfection(wherecontamination,

colonisationandinfectionweredistinct

outcomes),toexplainthewidespectrumof

conditionsbetweenwoundsterilityandinfection.

Thismodellaterbecameknownasthewound

infectioncontinuum,whereincreasingbioburden

wasrelatedtoclinicalcircumstancesandcritical

colonisationwasintermediatetocolonisationand

infection.94Hencecriticalcolonisationmightbe

consideredtobesynonymouswithlocalinfection,

orcovertinfection.

Traditionally,indicatorsofwoundinfection

wereconsideredtobeswelling,erythema,pain,

increasedtemperatureandlossoffunction.

Additionalindicatorshavebeenidentified,95,96

buttheirimportancedependsonwoundtype.

Sometimes,criticalcolonisationisdefinedas

105or106organismspergrammeoftissue.9799

Mnemonictermshavebeensuggestedtoevaluate

clinicalsignsandsymptomsthatdistinguish

betweencriticalcolonisationandinfection;100

indicatorsofcriticalcolonisationwereanon-

healingwound,increasedexudation,redfriable

tissue,thepresenceofdebrisandmalodour.

Indicatorsofinfectionweredefinedasincreasing

woundsizeandtemperature,abilitytoprobe

tobone,newbreakdown,oedema,erythema,

increasedexudationandmalodour.Inastudyto

evaluatetheabilityoftheseclinicalindicators

todiscriminatebetweencriticalcolonisation

andinfection,withrespecttobacterialburden

accordingtosemi-quantitativeswabculture,

combininganythreesignsgavesensitivity

andspecificityof73.3%and80.5%forcritical

colonisation,and90%and69.4%forinfection,

respectively.101Whilewoundscontaining

debris,friabletissueandexhibitingincreased

exudate(criticallycolonised)werefoundtobe

fivetimesmorelikelytoyieldscantorlight

bacterialgrowth,thosewithelevatedtemperature

(infected)wereeighttimesmorelikelytogive

moderateorheavygrowth.Thussomeindicators

hadgreaterweightthanothers.101

Inaclinicalstudy,inclusioncriteriaforpatients

withchronicvenouslegulcerswithsignsof

criticalcolonisationstipulatedthatonlyoneof

fourclinicalsignswasrequired,102suggestingthat

differentwaysofdefiningcriticalcolonisation

exist.Recently,theextentofcriticalcolonisation

incombatwoundswasthoughttobeassociated

withinflammatoryresponse.103Oneofthe

importantargumentsagainstusingtheterm

criticalcolonisationandagainstitsimportance

inwoundhealingisthatevidencedoesnot

supportusingsystemicantibiotictherapyfor


treatingclinicallyuninfectedwounds,either

toenhancehealingorasprophylaxisagainst

clinicallyovertinfection.34,36Asmentionedearlier,

therelationshipbetweenhighbacterialloadand

clinicaloutcomeisuncertain.

Withthisinmind,itdoesnotseemappropriate

tousebacterialload,criticalcolonisationor

bioburdenasoutcomesforstudiesontopical

antimicrobialagents,untilfurtherstudiesclarify

howtheseoutcomesshouldbedefined.

ConclusionAtpresent,aconsensusonhowtodefineand

identifycriticalcolonisationhasnotbeenreached.

Webelievethetermisconfusingandneedsa

stricterdefinitionbeforeitcanbeusedinclinical

practiceorasanendpointinresearch.Further

investigationintotherelationshipbetween

bioburden,inflammatoryresponseandclinical

outcomeisneeded.Itdoesnotseemappropriate

tousebacterialload,criticalcolonisationor

bioburdenasoutcomesinstudiesoftopical

antimicrobialagents.

Q Isremovalofmicroorganismsfromwoundsasufficientendpointfordemonstratingthe

efficacyoftheuseofatopicalantimicrobial

agentinwounds?

StatementRemovalofmicroorganismsisnotasufficient

endpointfortheefficacyofatopicalantimicrobial

agent.Itisnotaverygoodsurrogateparameter

todemonstratetheclinicalsignificanteffectofan

antimicrobialproduct.

DiscussionTheefficacyofsystemicantimicrobialagents,

aswellastopicalantimicrobialagents,has

traditionallybeenevaluatedusingacombination

ofin vitrotests,in vivo modelsandclinicalstudies.

Fewclinicalstudieshavemonitoredwoundsfor

theeradicationofmicroorganisms.Clinicalstudies

designedtoevaluatetopicalantimicrobialagents

oftenuseinfectionortimetohealingasendpoints,

ratherthantheeradicationofmicrobialspecies

fromwounds.Asmentionedearlier,manydifferent

microbialspecieshavebeenidentifiedinnon-

healingwounds.Thequantityofeachspeciesmay

varyandwhethersmallamountsofonebacterium

mightboostoneofthemajorinhabitantsofa

woundisnotknown.Microscopicinvestigations

showedthatthebacteriainnon-healingwounds

areprimarilyfoundinsmallbiofilmaggregates;7880

however,whilesomeofthesesmallaggregates

elicitamassiveneutrophilinfiltrationanddelay

inhealing,othersdonot.65,104Thismightindicate

thatthenumberofbacteriamaybelessrelevant

thanwhichspeciesarepresent.

ConclusionIfanantimicrobialagentisintendedtoeradicate

aspecificorganismfromawound,then

monitoringitspersistenceduringaclinicaltrial

isjustified.Otherwise,untiltheimpactofagiven

speciesormixedcommunityonwoundhealingis

understood,monitoringbioburdenmaynotyield

meaningfulinformation.

Removalofmicroorganismsisnotasufficientendpointfortheefficacyofatopicalantimicrobialagent


BiofilmQDoesthepresenceofabiofilmitselfinfluence

woundhealing?

StatementBiofilmmaybepresentinnon-healingwounds,

buttheirinfluenceonwoundhealinginthe

clinicalsettingisuncertain.Themajorissueisthe

lackofaclinicaldefinition.

DiscussionThefirstdirectevidenceofbiofilminvolvementin

non-healingwoundswasbasedonthedetection

ofbacterialaggregates.5254Thesethreepublications

wereprecededbyanumberofreportssuggestingthe

presenceofbiofilmsinwoundsandwerefollowed

byarticleselaboratingonandexpandingthe

observationsofbiofilminnon-healingwounds.105,106

Inapreviousstudy,80Kirketerp-Mlleretal.

collectedandexaminedchronicwoundsamples

obtainedfrom22differentpatients,allclinically

suspectedtobeinfectedbyP. aeruginosa.Using

classicculturingmethods,S. aureuswasdetectedin

themajorityofthewounds,whereasP.aeruginosa

wasobservedlessfrequently.Incontrast,usingPNA

FISH,theauthorsfoundthatalargefractionofthe

woundsthatharbouredP.aeruginosa aggregated

asmicrocoloniesimbeddedinabiofilm.These

microcoloniesweredetectedinsidethewoundbed,

whereasS.aureus,whenpresent,wasdetectedon

thesurfaceofthewounds.Thisfindingissupported

byotherobservations,53demonstratingthatS.aureus

formsmicrocoloniesencasedinanextracellular

matrixonthesurfaceofthewoundbed.

Inonestudy,54astatisticallysignificantassociation

betweenthepresenceofmicrobialaggregates

innon-healingwoundscomparedwithacute

woundswasestablishedbySEM.However,notall

non-healingwoundscontainbiofilms;thus,the

presenceofbiofilmsinnon-healingwoundsdoes

notbyitselfaccountforfailuretoheal.

ConclusionBiofilmhavebeendemonstratedtobepresentin

non-healingwoundsandseemtointeractwith

thewoundbed.However,theclinicalinfluence

ofbiofilmonwoundhealingisnotyetfully

elucidated.Evidencethatbiofilmcontributeto

chronicinflammationinawoundexists,buthow

thatinfluenceswoundhealingremainsunclear.

Q Isthepresenceofbiofilminawoundalwaysundesirable?

StatementThepresenceofabiofilminawounddoesnot

alwaysleadtotreatmentfailureand/ordelayed

healing.

DiscussionAlthoughwoundchronicitywasassociatedwith

thepresenceofbiofilm,54notallnon-healing

woundscanbeassumedtocontainbiofilm.The

discoveryofbiofilmontheintradermalsurfaces

ofclosuresinhealedwounds,47forexample,

demonstratesthatthepresenceofbiofilmdoesnot

alwaysresultinadverseeffectsinsurgicalwounds.

ConclusionItispresentlynotknownwhethertheeffectsof

biofilminanywoundalwaysleadtoproblems.No

specificindicationsfortreatmentofbiofilmshave

beenestablishedfornon-healingwoundsandmay

havedifferingoutcomesindifferingcircumstances.

Thisisanemergingareaofresearch.

QHowcanbacteriainbiofilmsberemovedfromwounds?

StatementBacteriainbiofilmswillbedifficulttoremove,other

thanbymechanicalorsurgicalmeans.

DiscussionItiswellestablishedfromin vitro,in vivoandpatient


studiesthatbacteriagrowinginbiofilms

arealmostimpossibletoeradicatewithantibiotics.107

Ontheotherhand,bacteriainacuteinfections

thatarenotinthebiofilmmodeofgrowtharestill

susceptibletoappropriateantibiotics.Oneapproach

tomanagingbiofilminnon-healingwoundshas

beensuggested,wherebyphysicalremovalofthe

biofilmbysharpdebridementisimmediately

followedbyantimicrobialstrategiestargetedat

planktonicbacteriatopreventthere-establishment

ofthebiofilm.54,108

Treatingnon-healingwoundscontainingbiofilm

withantibioticsaloneisunlikelytoleadto

bacterialeradication,butcouldselectantibiotic-

resistantbacteria.Evasionofimmunedefence

issupportedbyobservationsthatP. aeruginosa

biofilmsaresurroundedbyneutrophils,butare

notpenetrated.52,63Thisisverysimilartowhat

hasbeenobservedwithin vitro biofilmsoverlaid

withfreshly-isolatedhumanPMNs.56Thereseem

tobesimilaritiesbetweenpatientswithcystic

fibrosis(CF)andthosewithachronicwound.Both

patientgroupssufferfromdefectsintheprimary

lineofdefence.CFpatientsexperienceabuild-up

ofthickenedmucusthathampersthemechanical

processofclearingbacteria.Non-healingwounds

consistprimarilyofgranulationtissuecomposed

ofanetworkofcollagenfibres,newcapillaries,

andextracellularmatrixtogetherwithPMNs,

macrophages,andfibroblasts.Embeddedin

thisenvironmentarebiofilm,butthesearenot

eradicatedbyPMNs.Thebiofilmseemtosuppress

theactivityofthecellulardefencesystem,which

mightexplainthelackofwoundhealingwiththe

presenceofbiofilmorviceversa.

Severalantimicrobialagentshavebeenshown

toinhibitbiofilmsin vitro (Table3-1).Inone

model,109iodinewasshowntobemoreeffective

atdisruptingmixedbiofilmsofPseudomonas and

Staphylococcus thaneitherantibioticsorsilver-

containingdressings.

Theresistanceortolerancetoantibioticsand

antiseptics,andtheevasionofthehostsimmune

systemwouldimplythatifbacteriasucceedin

formingabiofilminthewoundbed,theywould

beextremelydifficulttoeradicateotherthan

bysurgicalormechanicalwounddebridement.

There-establishmentofabiofilmreliesinitially

onplanktoniccells,whichmaybesusceptible

toantimicrobialagents;thus,biofilmremoval

coupledwithmethodstopreventnewbiofilm

formationmayofferafuturemanagementstrategy.

ConclusionBacteriainbiofilmaretoleranttoantibiotics,

someantisepticsandthehostimmunedefence

mechanisms;theyseemtobemosteffectively

removedbymechanicalorsurgicalmeans.The

re-establishmentofabiofilmreliesinitiallyon

planktoniccells,whichmaybesusceptibleto

antimicrobialagents,sobiofilmremovalcoupled

withmethodstopreventnewbiofilmformation

mayofferafuturemanagementstrategy.Additional

innovativeanti-biofilmagentsalsoneedtobefound.

ResistanceandtolerancetoantimicrobialinterventionsQ Isthereanyantimicrobialagentthatisnot

expectedtoselectforresistanceortolerancein

bacteriainthewound?

StatementEventually,itislikelythatresistancewilldevelop

againstanytopicalantimicrobial.Inexperiments,

bacteriatreatedwithhoney,povidoneiodine,

octenidine,polyhexanideandchlorhexidinein

vitrohavenotbeenshowntodevelopresistance.

Resistanceagainstsilverhasbeendescribed;

however,itsconsequencesandclinicalimpactis

controversialornotknown.

DiscussionThemorefrequentlyanagentisutilised,thegreater

theopportunitytoselectforresistantmutants


andfortransmissiontosusceptibleindividuals.

Resistancetoanantimicrobialagentcanariseby

spontaneousmutation,bychemicallyorphysically

inducedmutation,andbygeneacquisition.

Genetransferbetweenbacterialspeciesisachieved

bythreedistinctprocesses:transformation,

transductionandconjugation.Resistance

determinantsaretransferredbetweenstrainson

plasmids,transposonsandintegrons.Possession

ofaresistancedeterminantmaygoundetected

untilselectionpressureisapplied.Inthepresence

ofaninhibitor,suchasanantibioticorantiseptic,

susceptiblemicrobialcellswillbeinhibited,leaving

resistantstrainsunaffectedandabletoflourish

withoutcompetition.

Antibioticresistanceiswelldocumented.110

Resistancetosometopicalagentsusedinwound

carehasalsobeenreported(Table3-1andTable3-2)

andinstancesofresistancetobothantibiotics

andantisepticsareknown.111Atpresent,most

informationisobtainedfromin vitro data,whichis

outofthescopeofthepresentdocument.However,

resistancetobacteriacanonlybetestedin vitro.

Theintervalbetweentheintroductionofan

antimicrobialagentandtheemergenceofresistant

strainsisunpredictable.Thelikelihoodthat

resistantstrainswillarisecanbeestimatedin

trainingexperimentswhereculturesarerepeatedly

subculturedinlowconcentrationsofaninhibitor.

Todatehoney,povidoneiodine,octenidineand

polyhexaninde(PHMB)failedtoselectforresistant

organismsusingthisapproach(Table3-3).A

caveattothisremarkisthatthesementioned

substanceshavenotbeenasthoroughlystudied

asotherproducts,suchaschlorhexidineand

silver.Resistanceagainstsilverhasbeendescribed;

however,itsconsequencesandclinicalimpact

arecontroversial,ornotknown.Morestudies

performedtoresistanceincreasethechancethat

resistanceagainstthesubstancewillbefound.

Biofilmdisruptionanddispersalexperiments

suggestthattoleranceisreadilyreversible,but

resistanceduetomutationaleventsisnot.57

Toleranceiscorrelatedtotheaggregationof

bacteria.Themanycelllayersintheaggregates

causemetabolicactivitygradients.Thismediatesa

slowergrowthrateoftheinnerpartofthebiofilm

anddecreasesaccesstonutrientsandoxygen.Many

antibioticsshowonlyhighlevelsofantimicrobial

propertiesonbacteriawithmetabolicactivityor

bacteriathatmultiply.Thematrixofthebiofilms

alsocontributestotolerance,assomeofthematrix

componentsareknowntochelateantibioticssuch

asextracellularDNAandalginate.49

Sincechronicinfections,bydefinition,lastfor

longperiods,thedevelopmentofgeneticand

inducedresistancealsoplaysamajorrolein

treatmentfailure.Exposureofmicrobialcultures

toantimicrobialagentsincreasestheselection

pressureforresistantvariantstogrowandmultiply.

ConclusionResistancetoantimicrobialagentsseemsto

bepossiblewithmostantimicrobials,even

thoughbacteriatreatedwithhoney,povidone

iodine,octenidineandpolyhexanideinin vitro

experimentsthusfardidnotdevelopresistance.

Themorefrequentlyanagentisused,the

greateristheopportunitytoselectforresistant

mutantsandfortransmissiontosusceptible

individuals.Wehavetorecognisethatresistance

ofwoundpathogensagainstthewiderangeof

antimicrobialagentsusedinwoundcareisnot

routinelymeasured,eitherduetolackofavailable

technologyorresources.Theremaycomeatime

whenthisisnecessaryandsuitablemethodswill

havetobeintroduced.


clinical

use

Antibiotic

target site

/ mod

e of action

Resistant bacteria

isolated

and citatio

n

Antibiofilm

activity

local

cytotoxicity

System

ic

toxic effects

Allergenicity

1948

Bacitracin

Interfe

reswith

bacteria

lcell-wallsynthesis

S. au

reus

112

Beta-haemolytic

streptococci(2)

113

N/A

+

+++

1948

Mafen

ide

Inhibitsfo

licacidbiosynthesis

N/A

++

++

++

1950

sPo

lymyxinE

(colistin)

Disrup

tsbacteria

lcellm

embranes

bybindingtoph

osph

olipids

P. ae

rugino

sa11

4

Acinetob

acter b

auman

nii

Kleb

siella

spp

.

++

++

+

1960

sNeo

mycin

Inhibitsbacteria

lproteinsynthesis

S. au

reus

115

E. coli11

6

P. ae

rugino

sa11

7

N/A

++

++

+++

1967

Silver

sulphadiazine

Preven

tsfo

licacidbiosynthesis

Gram-negativebacilli1

18N/A

++

++++

1971

Gen

tamicin

Interrup

tsbacteria

lproteinsynthesis

bybindingto30

srib

osom

alsub

unit

Gram-negativebacilli1

19

S. au

reus

118

Highlevelresistancein

enterococci11

9

++

+++

+

1985

Mup

irocin

Inhibitsbacteria

lproteinsynthesisand

RNAsynthesis

S. au

reus

119

++

+

1987

Amph

otericin

Disrup

tscellm

embranes

Cand

ida albica

ns12

0N/A

++

+++

+

Table3-1.Activebioburdencontrol:Propertiesoftopicalantibioticsutilisedinwoundcare

Notdetected +Weakeffects ++Significanteffects +++Severeeffects


clinical

use

topical antimicrobial

agent

target site

/ mod

e of action

Resistant

bacteria first

isolated

Exam

ples of

antib

iofilm activity Ex

amples of

cytotoxicity

(in vitr

o tests)

Exam

ples of

system

ic tox

icity

and allergenicity

Antiquity

Silver

Interactswith

thiolgroup

sin

mem

brane-bo

unden

zymes

andbind

stoD

NAtocause

strand

breakage

E. coli12

3

Enteroba

cter

cloac

ae12

2

P. ae

rugino

sa12

3

A. bau

man

nii12

4

P. ae

rugino

sa12

5

10m

ultid

rugresistant

bacteria

126

P. ae

rugino

saand

S. au

reus

109

Hum

ankeratinocytes

127

Mon

olayers,explants

andmurinemod

el12

8

Hum

andiabe

tic

fibroblasts

129

Murinefib

roblasts

130

Argyriaand

argyrosis1

31

Antiquity

Hon

eyPreven

tscelld

ivision

in

staphylococciand

disrup

ts

outermem

branesof

Pseu

domon

as

P. ae

rugino

sa,S. a

ureu

s132

MRS

A13

3

1827

Hypochlorite

(alsokno

wnas

Eaude

Javel,E

USO

L,Dakins

solutio

nandbleach)

Supe

roxidisin

gagent

inhibitio

nofglucose

oxidationandDNA

replication,de

pletionof

adeninenucleo

tides,protein

denaturatio

n

E. coli,S

. aureu

s134

MRS

A13

5

P. ae

rugino

sa,S. a

ureu

s136

P. ae

rugin

osa,S. aureu

s137

Rabb

itearcham

ber2

1

Hum

anfibrob

lasts2

2

Corrosivetoskin,

depe

ndingon

concen

tration(H

PA)

1839

Iodine

Oxidatio

nofthiolgroup

s,am

inogrou

ps,bindingto

DNAand

red

uctio

noffatty

acidsinm

embranes

Re

naland

thyroid

dysfun

ction1

38

1887

Hydrogenpe

roxide

Form

sfre

eradicals,w

hich

oxidise

thiolsgrou

psin

proteinsand

causebreaksin

DNAstrands

S. ep

idermidis1

39

P. ae

rugino

sa, S. a

ureu

s136

P. ae

rugin

osa, S. au

reus

137

Hum

anfibrob

lasts2

2Cardiacarrestdu

eto

embo

lism

140

1933

Quaternaryam

mon

ium

compo

unds(cetrimide,

benzalkonium

chloride)

Disrup

tionofthe

bacteria

linne

rmem

brane

E. coli14

1

Serra

tias

marce

scen

s142

P. ae

rugino

sa14

3

E. coli, S

. aureu

s134

Murinefib

roblasts

144

Murinefib

roblasts

130

Possible

hype

rsen

titivity

145

Table3-2.Activebioburdencontrol:Propertiesofantisepticagentsusedinantimicrobialwounddressing


clinical

use

topical antimicrobial

agent

target site

/ mod

e of action

Resistant

bacteria first

isolated

Exam

ples of

antib

iofilm activity Ex

amples of

cytotoxicity

(in vitr

o tests)

Exam

ples of

system

ic tox

icity

and allergenicity

1954

Chlorhe

xidine

Disrup

tionofthe

bacteria

linne

rmem

braneand

coagulationofcytop

lasm

ic

compo

nents

Proteu

s mira

bilis

146

Pseu

domon

as

sp.14

7

S. au

reus

148,14

9

E. coli,S. au

reus

134

P. aerug

inos

a150

P. ae

rugino

sa, S. a

ureu

s137

Murinefib

roblasts

144

Murinefib

roblasts

130

Riskofanaph

ylactic

reactio

nto

chlorhexidineallergy1

51

1956

Povido

neio

dine

Oxidatio

nofthiolgroup

s,bind

ingtoD

NAand

redu

ctionoffattyacids

inm

embranes

P. ae

rugino

sa, S. a

ureu

s109

S. ep

idermidis1

39

Hum

anfibrob

lasts2

2

Murinefib

roblasts

130

Renaland

thyroid

dysfun

ction1

38

Allergicreactions

152

1981

Cadexom

erio

dine

Oxidatio

nofth

iolgroup

s,bind

ingtoD

NAand

redu

ctionoffattyacids

inm

embranes

S. au

reus

153

Hum

anfibrob

lasts1

54Re

naland

thyroid

dysfun

ction1

38

1984

Octen

idine

Disrup

tionofbacteria

lmem

branes

P. ae

rugino

sa, S. a

ureu

s155

Murinefib

roblasts

144

Murinefib

roblasts

130

Chron

icven

ous

legulcers

156

1994

Polyhe

xanide

(polyhexam

ethylene

biguanide[PHMB])

Disrup

tionofbacteria

lmem

branesbybind

ingto

phosph

olipids

E.

coli, S. au

reus

134

P. ae

rugin

osa1

50

Murinefib

roblasts

144

Murinefib

roblasts

130

Hypersensitivityrare,

butpo

ssible

157

2005

Slow

-releasehydrogen

peroxide

produ

cts(based

on

glucoseoxidaseand

lactop

erox

idase)

Form

sfre

eradicals,w

hich

oxidise

thiolsgrou

psin

proteinsand

causebreaksin

DNAstrands

P. ae

rugino

sa,M

RSA

158

Table3-2.Activebioburdencontrol:Propertiesofantisepticagentsusedinantimicrobialwounddressingcontinued


Antimicrobial agent organisms tested No. of passages

Chlorhexidine S. aureus159 100

Manuka(Leptospermum)honeyS. aureus, P. aeruginosa160

E. coli, P. aeruginosa, S. aureus,MRSA161Notstated28

OctenidineMRSA162

S. aureus159>13100

Polyhexanide(polyhexamethylenebiguanide[PHMB])

S. aureus159 100

PovidoneiodineE. coli, Klebsiella aerogenes, P. aeruginosa, Serratia marcescens163

S. aureus159

20

100

Silver S. aureus164 42

Table3-3.Activebioburdencontrol:Antimicrobialagentsdemonstratednottoselectforresistantmutants(listedalphabetically)


T hepurposeofthischapteristocoverthecontroversies,astheyareseenfromtheperspectiveofcareproviders:Recurrenceofinfection

QDowehaveclinicaldatathatprovethattheuseoftopicalantimicrobialtreatmentprevents/resolves

infectioninwoundsandnon-healingwounds,

and/ordecreases/increaseswoundhealingrate?

QDoestheuseoftopicalantimicrobialtreatmentinwoundsreducetherecurrenceofinfection?

Whattypeofevidenceshouldwebelookingfor?

Q Shouldwounddressingsandantimicrobialagentsbetestedonlyagainstplanktonicbacteria?

QWhatendpointsdoweneedtojustifytheuseoftopicalandlocalantimicrobialtreatmentsin

non-healingwounds?

Infectionasendpoint

QCaninfectionbeusedasanendpointinwoundhealingstudies?

Strengthsandlimitationsofthecurrentevidencebase

QWhatarethecontroversies?

Treatment

QWhatarewelookingforfromtheseproductsandareRCTsanadequatewaytoevaluate

them?

Where are we today?Decisionsrelatingtotheantimicrobialtreatment

ofwoundsareinfluencedbyclinicalevidence,

theavailabilityofappropriateantimicrobial

interventions,patientneedandpractitioner

expertise.Thechoicebetweensystemicorlocal

treatmentdependsontheperceptionofsignsand

symptomsofinfection,andpreviousmanagement

regimes.Incasesofspreadinginfection,systemic

antibioticsarenormallyselectedonanempirical

basis.Otherwise,localwoundcarestrategiesare

chosenand/orprophylacticmeasuresareinitiated.

Expertopinionandpersonalpreferencesarefactors

inselectingtreatments,butdecisionsareprimarily

informedbyavailableevidence.Thequantity

ofpublishedevidencerelatingtowoundcareis

substantialbutconflicting,andhigh-levelevidence

derivedfrommeta-analysesandRCTsislimited.A

recentanalysisof149Cochranesystematicreviews

assessedthestrengthoftheevidencepresentedin

44reviewsanddemonstratedthatfewinterventions

forlocalandsystematicwoundcaredemonstrated

strongconclusionsregardingeffectiveness.165

Active/passivecontrolStrategiestomanagethebioburdenofwoundscan

bedividedintoactiveandpassiveprocesses.Those


antimicrobialinterventionsthatinhibitthegrowth

anddivisionofmicrobialcellsassociatedwith

woundtissueexertactivecontrol,whereasthose

thatfacilitatetheremovalofmaterialfromwounds

withoutnecessarilyinhibitingthemicrobialflora

canberegardedaspassivecontrol.

Activecontrolofbioburdencanbeachieved

bytopicalantibioticsandantiseptics(Table3-1

andTable3-2).Manyareemployedinthe

decontaminationofwoundscolonisedby

antibiotic-resistantstrains.Antisepticsusedforskin

disinfectionorwoundcleansingareincludedin

Table3-2.Inhibitorsformulatedintoantimicrobial

agentsincludecadexomerandpovidoneiodine,

honey,hydrogenperoxide-generatingsystems,

hypochlorite,PHMB,octenidineandsilver.

Antimicrobialdressingsnormallyactasabarrier

eithertopreventmicrobesfromgainingaccessto

thewound,ortopreventthemfromescapingfrom

thewoundandcontributingtocross-infection.In

somedressings,theactiveantibacterialcomponent

migratesintothewoundbed,whereasinothersit

isconfinedtothedressing.Evidencethateffective

concentrationsoftheactivecomponentsare

achievedwithinthewoundislimited.

Passivecontrolofbioburdenoccurswhen

microbialcellsbindtodressingsandareremoved

fromthewoundenvironmentwhenthedressing

ischanged.Thiscanhappenwithdressingsthat

incorporateantimicrobialcomponents,aswellas

dressingswithoutactiveinhibitors.Inthelatter

case,adevicemayexploitthenetnegativecharge

associatedwiththesurfaceofthemicrobialcells

orhydrophobic/hydrophilicinteractionsto

establishirreversiblebindingbetweenthe

bioburdenandthedressing.Examplesof

thesebacteria-removingagentsarelimitedat

present.HydrationResponseTechnologyor

Dialkylcarbamoylchloride(DACC)hasbeenable

tobindandinhibitthegrowthofbacteriaand

resistancehasnotbeendescribed.166

FeaturesofdifferentcategoriesofantimicrobialagentsTheantimicrobialagentsusedinwoundcarecan

generallybedividedinantibiotics,antiseptics

anddisinfectants.Asdisinfectantsarenotusedon

livingtissue,andthereforenotappliedtohumans,

wewillonlydiscussantibioticsandantiseptics

below.Thedefinitionsofantibioticsandantiseptics

areprovidedinTable2-1.Whileantibioticsare

enterallyorparenterallyadministeredtopatients,

andcanbetransportedthroughthebloodor

lymphaticsystemtootherpartsofthebody,

antiseptics(andafewantibioticswhenapplied

locally)areconfinedtotopicaluselocally.Inthis

document,systemicapplicationofantibioticswill

notbecovered.

Ideally,antimicrobialpreparationsdestinedfor

woundcareshouldpossessabroadspectrumof

antimicrobialactivity,befastactingandstable,

withoutselectingforresistantstrains.Furthermore,

theseagentsshouldnotbecytotoxictohosttissue,

induceadverseeffects,possessmutagencity,be

carcinogenicorprolongwoundhealing,orbe

expensive.Mutagenicandcarcinogenicagentshave

noplaceinwoundcare,butbalancingantimicrobial

effectivenessagainstcytotoxicityisdifficult.

Antimicrobialefficacyisevaluatedin vitro.Although

standardisedteststodetermineminimuminhibitory

concentration(MIC)andminimumbactericidal

concentration(MBC)bysuspensiontestshavebeen

usedforantisepticsolutions,167andchallengetests

areavailableforointments,standardisedmethods

forevaluatingwounddressingsorbiofilmshavenot

yetbeenestablished.However,abiocompatibility

indexwasdevelopedtoevaluateantisepticefficacy

ofplanktonicantibacterialactivityinrelationto

cytotoxicity,whichdividestheconcentrationat

whicha50%solutionofmurinefibroblastsare

damagedbytheconcentrationrequiredtoachievea

3-logreductionoftestbacteriumwithin30minutes

at37C.Theidealtopicalantimicrobialagent


wouldbeonethatinhibitsawiderangeofpotential

pathogenswithoutexhibitingcytotoxicity.130

TopicalantibioticsGuidelinesforusingantibioticsboththerapeutically

andprophylacticallyhavebeendeveloped,168170

butitisapparentthatcompliancehasbeenless

thansatisfactory,171andthequalityoftheevidence

usedtoformulatetheseguidelinesmayappear

weak.172InaBritishhospital,avariedchoiceof

treatmentregimenswasselectedfortreatingwound

infections,173demonstratingthedifficultiesin

compliancewiththeguidelines.Furthermore,itis

thoughtthatmorethan50%ofallmedicinesare

inappropriatelyprescribed,dispensedorsold,and

thathalfofallpatientsfailtotakethemcorrectly.174

Resistancetoanantimicrobialagentmaybean

inherentfeatureofanorganism;otherwise,itcan

beacquiredbymutationorgeneacquisition.Since

antibiotic-producingorganismsarewidelydistributed

innature,itisnotsurprisingthatantibioticresistance

determinantshavebeenidentifiedinDNAextracted

from30000-year-oldsamplesofpermafrostrecovered

fromtheYukon(Canada).175Theuseofantimicrobial

agentsremovessensitivestrainsandallowsresistant

strainstoincreaseprevalence.Asuitableexample

ismupirocin.In100differentcountrieswhere

mupirocinwasavailable,mupirocin-resistant

strainsweredetectable;however,inNorway,where

mupirocinwasnotlicensed,mupirocin-resistant

S. aureushasnotbeendetected.176InBrazil,the

incidenceofmupirocin-resistantMRSAwasfoundto

increaseovera5-yearperiod,butwasreducedduring

thenext5yearswhentheuseofmupirocinwas

restricted.159,176,177

Geneticanalysisofantibioticresistancedeterminants

suggestswidelydifferingoriginsfordrug-resistant

organisms(MDROs),suchasMRSA,178andextended

spectrumbeta-lactamase-producingorganisms

(ESBLs).179Recently,antibiotic-resistantstrainswith

antiseptic-resistancehavealsobeenreported,180,181

andtheselectionofMDROsbybiocides,suchas

antiseptics,hasbeenrecognised.182,183

Thecontinuedemergenceofantibiotic-resistant

strainsandlimitedinvestmentbypharmaceutical

companiesinnewantibioticshascurtailedthe

clinicalefficacyofantibiotics.184,185Despiteincreasing

awarenessofantibioticresistance,ithasbeenshown

thatthepossibilityofcontributingtotheproblemof

antibioticresistancedoesnotinfluencephysicians

attitudeswithregardtoprescribingpatterns,186as

patientneedsareprioritisedoverbroaderpublic-

healthissues.Althoughthisstudyinvestigatedthe

treatmentofahypotheticalpatientwithcommunity-

acquiredpneumonia,suchaconflictwillexistin

treatingmanyotherinfections.

Theriskofdevelopingsideeffects,suchasallergy

andantibioticresistance,hasinsomecountries,

suchasDenmark,resultedinrecommendations

statingthatitiscontraindicatedtousetopical

antibioticsfortreatmentofnon-healingwounds.187

Itisthoughtthatmorethan50%ofallmedicinesareinappropriatelyprescribed,dispensedorsold,andthathalfofallpatientsfailtotake

themcorrectly


AntisepticsAntisepticsareusedextensivelyinhealthcareon

humantissue,whiledisinfectantsarerestricted

forthedecontaminationofenvironmental

surfacesandmedicalequipment.However,their

benefitshavenotbeenunchallenged.Concerns

abouttheireffectsonwoundtissuewereraisedin

1915,188andhavecontinueduntilpresent.Over

theyears,cytotoxicitytestshavereliedoneither

animalmodelsorthecultureofkeratinocytes,

fibroblasts,lymphocytes,andneutrophilsin vitro.

Twonotablepreclinicalstudiesdiscouragedtheuse

ofantisepticsinwoundcare.21,22Cytotoxicityhas

beenreportedforsomeoftheagentsusedtopically

inwounds(Table3-1andTable3-2).Another

limitationforsomeantisepticsandantibiotics

isthesensitisationofpatients(Table3-1and

Table3-2).Sensitisationorallergicreactionscould

befoundwitheveryingredientandcanleadto

anaphylacticreactionsinextremecases.189,190

Theemergenceofmicrobeswithreduced

susceptibilitytoantisepticswasfirstrecognisedin

the1950s,191andisacontinuingproblem.149,192,193

Whilethemicrobialadaptationsthatconfer

antibioticresistancearewellcharacterised,194they

arelesswellunderstoodforantisepticsandgenerally

dependoneitherrestrictingaccessofagentsinto

thecelloractivelypumpingthemout.193,195197The

prevalenceoforganismswithcross-resistanceto

antibioticsandantisepticsiscurrentlylow;however,

inordertominimisetheriskofprevalence,itis

importanttomonitortheuseofantisepticsinthe

health-careenvironment.193,198,199

IndicationsfortreatmentPreventInfectionGuidelinesondiabeticfootinfectionrececently

publishedbytheInternationalWorkingGroup

ontheDiabeticFoot(IWGDF)andtheInfectious

DiseasesSocietyofAmerica(IDSA)discusshow

andwhentotreatdiabeticfootinfections.200204

Thelimitedavailableevidencedoesnotsupport

useofsystemicantibioticsfortreatingclinically

uninfectedwoundsinthediabeticfoot,toeither

enhancehealingorpreventclinicalinfection.36,205

Currently,thereislittleevidencetosupportthe

beliefsofsomewoundspecialiststhatdiabeticfoot

woundsthatlackclinicalsignsofinfectionmaybe

subclinicallyinfected.Insuchsubclinicalinfections,

woundscontainahighbioburdenofbacteria

(usuallydefinedas105organismspergrammeof

tissue)thatwouldresultinnon-healingwounds34,35

(seeChapter3).Insomecases,whenitisdifficult

todecidewhetherachronicwoundisclinically

infected(suchasincaseofischaemia),itmaybe

appropriatetoseeksecondarysignsofinfection,

suchasabnormalcolouration,malodour,friable

granulationtissue,underminingofthewoundedges,

unexpectedwoundpainortenderness,orfailureto

showhealingprogressdespitepropertreatment.206In

theseunusualcases,abrief,culture-directedcourse

ofsystemicantibiotictherapymaybeappropriate.

However,inthestrictestsenseantibiotictreatment

ofsuchwoundsshouldbecalledtreatmentofacute

infection,notprophylactictreatmentorprevention

ofinfection.Additionally,inasystematicreview,

mostpatientswereonsystemicantibiotics.204

Inanothersystematicreviewofwound-care

managementindiabeticfootwoundhealing,the

useofaminoglycoside-loadedbeadsasatopical

antibioticonthewoundatthetimeofforefoot

amputationwasdescribed.205Inanon-randomised

cohortstudy,thetreatmentseemedtohaveaweak

butsignificanteffectontheneedforlatersurgical

revision.However,littlecanbedrawnfromthis

study,astheapparenteffectcouldhaveresulted

fromconfoundinginfluences.207

Todate,therehavebeenseveralstudiesof

antiseptics,dressingproductsandwoundcare

management.Theabove-mentionedsystematic

reviewontheuseoftheseproductsindiabeticfoot

ulcerswaspublishedinearly2012.208Init,alarge,


good-quality,observer-blindedRCTwasidentified,

whichreportednodifferencesbetweenthree

productswithorwithouttopicalantisepticeffects

intermsofhealingby24weeks,aswellasbetween

avarietyofsecondaryoutcomemeasures,including

theincidenceofsecondaryinfection.209Another

large,non-blindedRCTreportednodifferences

betweenanalginate-andasilver-impregnated

dressingintheincidenceandvelocityofhealing,

withnosignificantdifferencesinoccurrencesof

infectionbetweenthegroups.210Theresultsofthese

large,well-designedtrialscontradictedtheresultsof

asmall,earlierstudythatsuggestedsomebenefitof

thesilverdressing.InaCochranedatabasesystemic

reviewregardingtopicalsilverforpreventingwound

infection,itwasconcludedthatthereisinsufficient

evidencetoestablishwhethersilver-containing

dressingsortopicalagentspromotewoundhealing

orpreventwoundinfection.211

However,asmallstudyontheuseofoakbark

extractcomparedwithsilversulphadiazinefor

6weeksshowedasignificantbenefitintermsof

healingforoakbarkextract.Although,theeffecton

bacteriainthewoundandthequalityofthestudy

weredifficulttoassessduetomissingdetails.212

Onlyonecontrolledclinicalstudywasperformed

toassesstheeffectsofhoneyondiabeticfoot

ulcers.213Thisstudy,asmall,non-blindedstudy

ofpoordesign,reportednodifferencesinhealing

timebetweentheuseofhoneyandofpovidone

iodine;antimicrobialfeaturesofhoneywerenot

specificallyassessedinthisstudy.213

Insummary,thereislittleevidencetosupportthe

useofantibioticorantiseptictopicaltreatmentsto

preventwoundinfection,particularlyindiabetic

footulcers.Inaddition,therewaslittleevidenceto

supportthechoiceofanyonedressingorwound

applicationinpreferencetoanyotherinattempts

topromotehealingofchroniculcersofthefootin

diabeticpatientsinthissystematicreview.208

Anothersystematicreviewofwound-care

managementincludedantimicrobialagentsused

fornon-healingwounds.214Thirtystudieswere

evaluated,ofwhichnineconcernedtheuseof

systemicantibioticsand21topicalagents.No

evidencetosupportsystemicantibioticsinvenous

legulcers,mixedaetiologywounds,pressure

ulcers,pilonidalsinusesordiabeticfootulcers

wasfound.Conflictingevidenceforsilver-based

productsinvenouslegulcerswasreported,none

ofthetopicalagentsexaminedwereeffectivein

preventinginfectioninpressuresoresandthe

evidenceforothertopicalagentswasequivocal.

ThishasbeenconfirmedbyCochranedatabase

systemicreviews.211,215,216

InanRCTcomparingmanukahoneywith

hydrogel,manukahoneywasshowntoeradicate

MRSAfrom70%ofchronicvenouslegulcersat

4weekscomparedwith16%inthosetreatedwith

hydrogel.217Thepotentialtopreventinfectionwas

thoughttobeincreasedbyremovingMRSA.

Theclinicalevidencetosupporttheuseoftopical

antimicrobialinterventionstopreventinfection

inpressurelegulcersisalsosparse.Onesystematic

reviewconcerningtopicalsilver211identified

26RCTs(2066patients)inwhichsilver-containing

dressingsandtopicalagentscontainingsilver,

comparedwithnon-silver-containingcomparators,

wereevaluatedinuninfectedwounds.Theauthors

concludedthattherewasinsufficientevidenceto

demonstratethateithersilver-containingdressings

ortopicalagentspreventedwoundinfectionor

enhancedwoundhealing.Someweakevidence

suggestedsustainedsilver-releasingdressings

showedatendencytoreducetheriskofinfection

inchronicpressureulcerswasreported,butsample

sizesweretoosmallforeitherstatisticalanalysisor

formulatingconclusions.218

Theuse

antimicrobials and non-healing wounds

Documents

nonhealing woundsevidence

principal role

lecturerinwoundh peters