Antimicrobials and Non-healing Wounds
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Transcript of Antimicrobials and Non-healing Wounds
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EWMA Document:Antimicrobials and Non-healing WoundsEvidence,controversiesandsuggestions
A EWMA Document
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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.
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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
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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
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JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S5
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
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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
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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.
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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.
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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
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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
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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
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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
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S22 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3
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.
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JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S23
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
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S24 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3
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
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JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S25
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
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S26 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3
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)
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JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S27
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
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S28 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3
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
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JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3 S29
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
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S30 JOURNAL OF WOUNDCARE Vol 2 2 . No 5 . EWMA DocuMENt 2 0 1 3
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,
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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