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Diabetic foot infections: what have we learned in the last 30 years?

UCKAY, Ilker, et al.

UCKAY, Ilker, et al . Diabetic foot infections: what have we learned in the last 30 years?

International Journal of Infectious Diseases , 2015, vol. 40, p. 81-91

DOI : 10.1016/j.ijid.2015.09.023 PMID : 26460089

Available at:

http://archive-ouverte.unige.ch/unige:90591

Disclaimer: layout of this document may differ from the published version.

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Review

Diabetic foot infections: what have we learned in the last 30 years?

Ilker Uc ¸kay

a,b,

*, Javier Arago´n-Sa´nchez

c

, Daniel Lew

a

, Benjamin A. Lipsky

a,d

aServiceofInfectiousDiseases,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,Geneva,Switzerland

bOrthopaedicSurgeryService,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,4,rueGabriellePerret-Gentil,1211Geneva14, Switzerland

cDiabeticFootUnit,ServiceofSurgery,LaPalomaHospital,LasPalmasdeGranCanaria,Spain

dDivisionofMedicalSciences,UniversityofOxford,Oxford,UK

1. Introduction

Theincidenceoffootinfectionsinpersonswithdiabetesranges fromalifetimeriskofupto25%inallpersonswiththediagnosis,to 4%yearlyinpatientstreatedinadiabeticfootcenter.1Diabeticfoot infections(DFIs)occasionallypresentascellulitisorpost-traumatic (including postsurgical) infections,2 but are most commonly a consequence of ulcerations secondary to progressive peripheral polyneuropathy.Thiscausesalossofprotectivesensation,aswellas footdeformities,gait disorders,anteriordisplacementofweight- bearingduringwalking,3andreducedmobility.Theseneurological problemsarecommonlyaccompaniedbyarterialinsufficiencyand immunological disturbances.Developing a DFI is now the most common diabetes-related reason for hospitalization and lower extremityamputation.4Thisreviewaimstoreviewthegrowthof

knowledgeoverthepast30yearsonthepathogens,5,6radiological diagnosis,7andmedical8,9,10andsurgicaltreatmentsofDFI.11

2. Managementofdiabeticfootinfections:1985and2015

Few of today’s clinicians appreciate how limited were the knowledgebaseandtherapeuticarsenalavailabletomanageDFI 30 years ago. Although the problem was common, there were remarkably few scientific papers publishedon DFIs.The major sourceofclinicalinformation wastextbooks,themostcompre- hensiveofwhichwasTheDiabeticFoot.Thechapteroninfectionin thefirstedition,publishedin1973,emphasizedtheimportanceof vascular insufficiency and gangrene, with little discussion of treatment,andnoneofthereferenceswerespecificallyonDFI.12 Thethirdedition(1983)wasthefirstwithaDFIreference,13andit wasnotuntilthefourthedition(1988)thattherewasadiscussion ofwoundculturetechniques.14Inthemid1980s,thegeneralbelief wasthat(1)themajorpathophysiologicalcauseofDFIswaslimb ARTICLE INFO

Articlehistory:

Received30July2015

Receivedinrevisedform29September2015 Accepted30September2015

CorrespondingEditor:EskildPetersen, Aarhus,Denmark

Keywords:

Diabeticfootinfection Pathogens

Antibiotic Surgery Treatment

SUMMARY

Background: Infectionisacommonepiphenomenonofadvanceddiabeticfootdiseaseandthemost commonreasonfordiabetes-relatedhospitalizationsandlowerextremityamputations.Majoradvances havebeenmadeinthepastthreedecadesinourunderstandingandmanagementofdiabeticfoot infections(DFIs).TheoptimaltreatmentofDFIsclearlyinvolvesmultidisciplinaryinput.

Methods:AcomprehensivesearchoftheliteratureonDFIsfromJanuary1960throughJune2015was performed,withanemphasisoninformationpublishedinthepast30years.

Results:Therehavebeenmanynewinsightsintothemicrobiology,diagnosis,andtreatmentofDFIs, althoughtheimplementationofthisknowledgeinclinicalpracticehasbeensuboptimal.Today,theuse ofevidence-basedguidelines,multidisciplinaryteams,andinstitution-specificclinicalpathwayshelps guideoptimalcareofthismultifacetedproblem.Patientsaremoreoftentreatedintheambulatory setting, withantibiotic regimens thatare more targeted,oral and shortercourse, and with more conservative(butearlier)surgicalinterventions.Newdiagnosticandtherapeuticmethodsarebeing developedatanacceleratingpace.

Conclusions: Theworldwideincreaseintheincidenceofdiabetesandlongerlifespanofdiabeticpatients willundoubtedlyincreasetheincidenceofDFIs.Clinicianscaringfordiabeticpatientsshouldhavean understandingofcurrentmethodsforpreventing,diagnosing,andtreatingDFIs.

ß2015TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by- nc-nd/4.0/).

* Correspondingauthor.Tel.:+41223723311;fax:+41223729802.

E-mailaddress:ilker.uckay@hcuge.ch(I.Uc¸kay).

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o urn a l hom e pa ge : ww w. e l s e v i e r. c om/ l o ca t e / i j i d

http://dx.doi.org/10.1016/j.ijid.2015.09.023

1201-9712/ß2015TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

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ischemia(especiallysmallvesseldisease),leadingtogangrene;(2) DFIswerealmostalwayspolymicrobial,withobligateanaerobes playingamajorrole;(3)nearlyallpatientswithaDFIshouldbe hospitalizedandtreatedwithbroad-spectrumparenteralantibi- otic therapy; and (4) severe or apparently non-responsive infections usually required a lower extremity amputation. We nowknowthatvirtuallyalloftheseconceptswerewrong.While theprevalence ofdiabeticfootdisease(especiallyasa causeof hospitalization)hasincreased,ulcersandinfection,notvascular disease,arenowthemajorunderlyingcause(Figures1and2).

Progress in the understanding of diabetic foot problems acceleratedwith the first(ofwhatarenowmany)diabetic foot meeting,heldinMalvern,UKin1986.In1987theAmericanDiabetes Association(ADA)startedaFootCouncil,whichheldasymposiumat theirannualmeetings.In1991theInternationalWorkingGroupon theDiabeticFoot(IWGDF)heldthefirstofitsquadrennialmeetings, andtheEuropeanAssociationfortheStudyofDiabetesfoundeda DiabeticFootStudyGroup(withanannualmeeting)in1998.

These scientific organizations and meetings helped trigger a dramaticincreaseinthenumberofpublications(andcitations)on DFIs(Figures3and4).Thegrowthofscientificevidenceallowed variousorganizationstoproduceguidelinesfordiabeticfootcare, beginningwiththoseoftheADAandIWGDFinthelate1990s.Oneof themajorachievementsinthelast30yearswastherecognitionof thevalueofamultidisciplinaryapproachtothiscomplexproblem,15 whichledtotheopeningofspecializeddiabeticfootcentresallover theworld.Unfortunately,theimplementationandtranslationofthis knowledgeintotherapeuticsuccesshasbeenmorelimited.While somecentreshaveimprovedvariousparametersofDFIcare,many, especiallyinresource-poorcountries,havenot.Table1summarizes theauthors’viewsonthemajorchangesinourunderstandingof,and approachto,DFIssince1985.

3. Internationalrecommendations,guidelines,and classifications

There hasbeen a proliferation of guidelines, checklists, and classificationschemesregardingDFIsinthelast30years.Thefirst

guidelines specifically devoted to DFI, both published in 2004, werethose commissionedby theInfectious DiseasesSociety of America(IDSA)andbytheIWGDF.Thesehavebeenupdated,16–18 and we refer readers interested in the literature regarding definitions, classifications, differential diagnoses of infection,19 andguidelinestootherliteraturetoourpriorpublications.8,20

4. Pathogens

Startinginthelate1970s,studiesdemonstratedthataerobic Gram-positive cocci (especially Staphylococcus aureus), often as monomicrobial infections, were the predominant pathogens in DFIs,withaerobicGram-negativerodsfoundmostlyinpatients

Figure1. Numberof hospitaldischarges,by year, for diabetes-relatedlower extremity conditions (in thousands), USA, 1988–2007 (http://www.cdc.gov/

diabetes/statistics,accessed30June2015).

Figure2.Majorcausesofhospitaldischarge,byyear,fordiabetes-relatedlower extremity conditions (in thousands), USA, 1988–2007 (http://www.cdc.gov/

diabetes/statistics,accessed30June2015).

Figure3.Publisheditemsperyearlocatedwiththesearchterm‘‘diabeticfoot infection’’inWebofScience.

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with chronic, previously treated wounds. In recent years DFIs caused by multidrug-resistant organisms, such as extended- spectrum beta-lactamase-producing Gram-negative rods21 or methicillin-resistant S. aureus (MRSA), have emerged as a substantialproblem.Infectionwithanantibiotic-resistantorgan- ismcertainlyrequirestheselectionofanagentactiveagainstthat isolate,butshouldnototherwisealtertherapeuticmanagement.22 StudiesofoutcomesofDFIscausedbymulti-resistantpathogens comparedwithotherorganismshaveproducedconflictingresults, withsomefindingnoworseoutcomes,23,24whileothershave.25In

a previous study, we found that among 48 papers published between 1999 and 2013, only five attempted a comparison of outcomesbetweenDFIscausedbyMRSAandthosecausedbyother pathogens.5Overall,therewerenocleardifferencesinoutcomes, but many trials failed to adjust for case-mix, or to seek a relationshipbetweenmicrobiologyandoutcomes.Notwithstand- ingthelimitationsoftheavailableliterature,wedonotbelieve thereisaneedforanyspecialtreatment(otherthanselectingan activeantibioticagent)forDFIscausedbyMRSA.5

Untilthemostrecent decade,themajorityof studiesonthe microbiologyofDFIwereconductedinNorthAmericaandEurope.

Inrecentyears,investigationsinwarmclimates(especiallyIndia, butalsotheMiddleEastandAfrica)havefoundthemostcommon isolates to be Gram-negative rods, particularly Pseudomonas aeruginosa.Wecanonlyspeculateonthereasonsforthisdisparity, buttheymayincludeahotclimatecausingfootsweating,theuse ofpoorfootwear,ahighincidenceofpatientself-treatmentwith antimicrobials, frequentfootwashing,and suboptimalperineal/

handhygiene.8Thus, cliniciansintheseregionsshouldconsider coveringEnterobacteriaceaeandPseudomonasspp,pendingculture andsensitivityresults.

WhentreatingDFIs,clinicianshavefrequentlyaddedantibiotic agents that are specifically directed against obligate anaerobic bacteria,especiallywhenthewoundisgangrenousorhasafetid odour. However, our recent literature review of DFI studies revealed that anaerobes were infrequent isolates, were not associatedwithanyspecificclinicalfindings,anddidnotclearly leadtomoreseveremanifestations.6BacteroidesandPeptostrepto- coccushavebeenthetwomainspeciesreported,butitisuncertain iftheyarepathogensorcolonizersassociatedwiththepresenceof agreaterdegreeoftissueischemiaornecrosis.Mostclinicaltrials of antimicrobial therapy for DFI have not employed adequate methods to cultureanaerobic organisms. One randomizedtrial Figure4.Numberofcitationsperyearforpublishedpaperslocatedwiththesearch

term‘‘diabeticfootinfection’’inWebofScience.

Table1

Keychangesintheknowledgeandmanagementofdiabeticfootinfectionsinthelast30years—summaryoftheauthors’views

Researchfield 1985 2015

Pathogens Methicillin-susceptibleStaphylococcusaureus, streptococci,Enterobacteriaceae

Moremultidrug-resistantorganisms(MRSA,ESBLs)

PredominanceofGram-negativepathogensin(sub)tropicalclimates Microbiologicaldiagnosis Standardcultures,usuallyofswabspecimens Aerobicandanaerobicculturesoftissuespecimens(softtissueandbone)

Molecularmicrobiology(e.g.,PCR) Metagenomics

Imaging PlainX-rays;scintigraphy(bone,leukocytescans) MRI;SPECT/CT;PET/CT Antibioticagents Penicillins;1stto3rdgenerationcephalosporins;

some2ndgenerationfluoroquinolones

4th/5thgenerationcephalosporins;carbapenems;3rd/4thgeneration fluoroquinolones;linezolid;daptomycin

Routeofadministration andsiteoftreatment

Initial(sometimesprolonged)intravenous administration,usuallyinhospital

Mostlyoral(sometimesafterabriefintravenouscourse),eveninthe presenceofvasculardiseaseorosteomyelitis;sometopical;outpatient exceptforsevereinfectionsorcomplextreatments

Spectrumofantibiotictherapy Relativelybroad(directedatGram-positiveand Gram-negativepathogens)

Verybroadempirictherapyforsevereinfections;moretargetedformild/

moderateinfectionsandfordefinitivetherapy Durationofantibiotictherapy Manyweeksforsofttissueinfections;6–12

weeksforbone

1–2weeksforsofttissueinfections;4–6weeksforosteomyelitis Surgicalapproach Aggressive(ablative)therapeuticsurgery;

inpatienttreatment

Moreconservative(tissuesparing)therapeutic(evenforosteomyelitis) andpreventivesurgery;correctivesurgery;

ofteninoutpatientfacilitiesandspecializeddiabeticfootcentres Revascularization Openvascularsurgery Morepercutaneousangioplastyanddistalbypasses,including

infragenicular Management

guidelines

Mostlyindividual,empiricalapproaches Individualrecommendationsandpracticesonthe hospitallevel

Clinicalguidelinesbasedonsystematicreviews;multidisciplinary teams,especiallyincludingpodiatry;clinicalpathways;some behaviouralsciences

nationalguidelines;validationofguidelines Adjunctivetreatments Stimulationwithgrowthfactors;platelet-rich

products;larvalbiotherapy(maggots)

Hyperbaricoxygentherapy;granulocyte-stimulatingfactors;researchin stemcellandbacteriophagetherapies;microbiomeconcepts Dressing Simpledressings,withseparateuseof

disinfectionagents

Morehydrofibreandsilver-containingdressings;studieswithtopical antibioticsembeddedindressings

Scientificpublications Mostlycaseseries Moreprospectiverandomizedtrials,multicenterstudies,andevidence- based(Cochrane)meta-analyses

ESBL,extended-spectrumbeta-lactamase;MRI,magneticresonanceimaging;MRSA,methicillin-resistantStaphylococcusaureus;PET/CT,positronemissiontomography/

computedtomography;SPECT/CT,singlephotonemissioncomputedtomography/computedtomography.

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optimizedfortheisolationofanaerobicpathogensreportedthat among six groups (i.e., Gram-positive anaerobic cocci, Peptos- treptococcus magnus, Peptostreptococcus asaccharolyticus, Gram- positive anaerobic bacilli, Gram-negative anaerobic bacilli, and Gram-negativeanaerobiccoccobacilli,includinghereBacteroides spp), none was associated with worse outcomes.26 Several randomizedtrials ofDFIs,includingsoft tissueorosteomyelitis cases,havereportedsimilarclinicalsuccessrateswhencomparing regimens with similar anaerobic spectra,27,28 and equivalent outcomes with drugs that have broad anaerobic coverage comparedtothosewithanarrowerspectrum.29–31Finally,local mycobacterialinfectionsortetanusarerarecausesofDFI.32 4.1. Microbiomeandmetagenomics

Standard culture methods, which have changed little in 150years,arelimitedbytakingseveraldaystocomplete,being falselynegativeinpatientsreceivingantibiotictherapy,andfailing toidentifymanyfastidiousbacteria.Newermoleculartechniques, suchas16SPCRandgenesequencing,typicallyidentifyagreater numberand varietyofbacteria, particularlyanaerobes.33Meta- genomicstudieshaverevealedinterplayamongbacterialcommu- nitiesinvariousenvironments,includingwounds, thatproduce specific clinical ‘syndromes’33–35 or phenotypic diseases. This recent and rapidly emerging research area may provide more insightsintothepotentialassociationoftheskin(andgastroin- testinal)microbiomewithDFI.33

5. Treatment 5.1. Podiatriccare

MostpatientswithaDFIrequiresomeformofpodiatriccare, along with medical, surgical, nursing, and physiotherapeutic interventions.20Theincreasingavailabilityofpodiatristsinmany countriesappearstohaveledtomajoradvancesindiabeticfoot care,althoughrobustevidenceforthisispending.36Podiatriccare isparticularlyaimedatpreventingfootcomplicationsandincludes debridementofcallus37andnecrotictissue,nail care(especially withonychomycosis),thetreatmentofblisters,prescribingproper footwear,andfittingorthoticdevices.Oncecomplicationsoccur, however,thegoalbecomesavoidingamputation.

5.2. Systemicantimicrobialtherapy

Systemic antibiotic therapy is always necessary for the treatmentofclinicallyinfectedwounds, butisofteninsufficient tocuremoderate tosevereDFIs.16 Thissystemic therapy must oftenbecombinedwithoneormoresurgicalprocedures,pressure off-loading,appropriatewoundcare,andinsomecases,arterial revascularization. With a few exceptions,38 almost all of the currentlyusedantimicrobial classes (ifnotthe currentgenera- tions) were available 30 years ago. What has changed is our awarenessof theneedtoreducethespectrum andduration of antibiotherapytotrytoslowthetideofantibioticresistance.While initial antibiotic therapy for most patients must be selected empirically, it should largely be based on the assessment of infection severity12 and knowledge of the local microbial epidemiology.Inmostregionsoftheworld,theantibioticregimen shouldalwayscoverS.aureus,butitmaybebroadenedtoinclude Gram-negativeisolatesinsevereinfectionsorifthepatienthas failedtorespondtopriornarrower-spectrumtherapy.Ofnote,DFIs can develop rapidly,39 making early follow-up after starting therapy imperative. Necrotizing soft tissue infections of the diabetic foot, including gas gangrene, are uncommon and are

usually caused by mixed aerobic (and sometimes anaerobic) bacteriaratherthanClostridiumspecies.40

Definitiveantibiotictherapy shouldbebased oncultureand sensitivityresults.Evenifculturesyieldmultipleorganisms,itmay besufficienttotreatonlythelikeliestpathogens,suchasS.aureus, streptococci, and Enterobacteriaceae. Skin commensals such as coagulase-negativestaphylococci,corynebacteria,orBacillusspp, andlow-virulenceorganismssuchasenterococci,canusuallybe ignoredunlessculturedfromdeep,asepticallycollectedtissueor infections involving osteosynthetic material or hardware. Like- wise, the merepresence of skin or mucosal colonization with healthcare-associated MRSA does not oblige the clinician to empirically cover this organism,40,41 even in the presence of underlyingosteosyntheticmaterial.42Quantitativecultures,which wereinvogueinthepast,arenowrarelydoneastheyaredifficult toperform,expensive,and donot addmuchtodecidingwhich woundsareinfectedorwhatorganismstotreat.35,43,44

BecausemostDFIsoccur inthesettingof peripheralarterial disease, some have raised concerns about how well various antibioticagentspenetratetheinfectedsite,especiallybone.This has led many clinicians to prescribe weeks of intravenous antibiotictherapy.Thecurrentavailabilityofhighlybioavailable oralantibiotics,aswellastheacquisitionoffurtherevidenceofthe efficacy of oral antibiotic regimens, has helped change this practice.When prescribed at standard doses, mostbeta-lactam antibioticsachieverelativelylow(albeittherapeutic)tissuelevels, asthesearetime-dependent(notconcentration-dependent)drugs.

Clindamycin,fluoroquinolones,linezolid,rifampicin,andtosome degree,tetracyclinesandco-trimoxazole,havegoodoralbioavail- ability and penetration in bone, synovia, biofilm, and necrotic tissue.8Fewdatasupporttheneedforparenteraltherapy,45and studies are currently underway to compare outcomes of oral versus intravenous therapy for complex musculoskeletal infec- tions,includingDFI.Likewise,inaretrospectiveanalysisofmore than 2000episodes of orthopaedicinfection,including DFI, we found no evidence of superiority of bactericidal agents over bacteriostatic agents.46 Similarly, published randomized con- trolledDFItrialshavefailedtoshowsuperiorityofanyparticular antibioticagent or routeof administration.8 Several systematic reviewsofantimicrobialtreatmentsforDFIhaveconcludedthat there is insufficient evidence to recommend any particular antimicrobialagentorrouteofadministration.47–49

5.3. Osteomyelitis:diagnosisandtherapy

DFIsgenerallybeginwhenabreakintheprotectiveskinbarrier allows pathogens to multiply in the soft tissues. Diabetic foot osteomyelitisusuallyoccursbythecontiguousspreadofinfection fromoverlyingsofttissue.Osteomyelitisisfoundinupto15%of patients witha clinicallyuninfected diabeticfootulcer;among those with a DFI, however, approximately 20% seen in the outpatient setting and two-thirds who are hospitalized have infected bone at presentation.8 Diagnosing osteomyelitisof the diabeticfootcanbedifficult,especiallyearlyinthecourse.Clinical findingssuggestinginfectionincludeadeepchroniculcerovera bonyprominence,‘sausagetoe’(red,warm,swollen)appearance, and an erythrocyte sedimentation rate >70mm/h. The only virtuallypathognomonicclinicalsignisthepresenceoffragments of bone discharging from a wound. The probe-to-bone test is helpfulindiagnosingdiabeticfootosteomyelitisifitiscorrectly performed (with a blunt metal probe) and interpreted (with considerationofthepre-testprobabilityofosteomyelitis).Based onseveralreports,thesensitivityrangesfromabout60%to87%, specificityfrom85%to91%,andpositivepredictivevaluefrom87%

to90%,butthenegativepredictivevalueisonly56–62%.50–52The criterionstandardfordiagnosingosteomyelitisremainsaculture

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of bone and, when possible, histopathological examination.53 Recentprospectivetrialshaveshownthatcultureresultsofsoft tissue or of needle puncture specimens of bone often fail to correlatewithtranscutaneousoroperativebonespecimens,54and non-invasive diagnostic approaches for the microbiological assessmentoftoeosteomyelitisshouldprobablybeabandoned.55

5.3.1. Radiologicalassessmentofosteomyelitis

Asinthepast,imagingtestsshouldgenerallybeginwithplain X-rays.Wenowknowthatinter-observerreproducibilityispoor, especiallyamonginexperiencedclinicians,56andearlyosteomye- litismaybemissedbecauseittakesseveralweeksforbonelesions to become radiologically detectable. When plain X-rays are inconclusive, or when more detail of bone or soft tissue abnormalitiesis required,magneticresonance imaging(MRI) is superiortothestandardradionuclidestudies(whichhavelower specificities).Meta-analyses of theperformance of three-phase bonescintigraphyfordetectingDFIusingonlyplanarimaging,or combined with single photon emission computed tomography (SPECT),reportsensitivityofapproximately90%,butspecificityof only approximately 50%.7 Newer hybrid imaging techniques (SPECT/CT, positron emission tomography (PET)/CT, and PET/

MRI)looktobeuseful,andimprovedradiopharmaceuticalsareon thehorizon.7

5.3.2. Treatmentofosteomyelitis

Thepastdecadehasprovidedmuchnewinformationonhowto treatdiabeticfootosteomyelitis. Onestudyof50 patients with chronictoeosteomyelitisreportedthatpatientswhounderwent widesurgicalresectionhadasignificantlylowerrelapseratethan thosewhounderwentlessaggressivesurgery.57Contrarytothe teachingof30yearsago,therearenowreportsofhundredsofcases of diabetic foot osteomyelitis treated without surgery, with remission rates of 60% to 70%;58,59 one recent randomized controlled trial showed similar cure rates for medical and for primarilysurgicaltherapy.60Thus,whenthepatientorthemedical team prefers to avoid surgery, a trial of exclusively antibiotic therapymaybereasonable.Regardingthedurationofantibiotic therapy,asystematicreviewofthetreatmentofosteomyelitisin patients with and without diabetes found that there was no evidence that antibiotic therapy for more than 4–6 weeks improvesoutcomescomparedwiththisduration.61Morerecently, asmallrandomizedcontrolledstudyfoundthat6weekscompared with12weeksofantibiotictreatmentofdiabeticfootosteomyeli- tisproducedsimilarresults.62

5.4. Topicalantibiotics,antisepticdisinfectants,andpeptides

Superficial, open wounds without extensive cellulitis can potentially be treated with topical antimicrobials.9 The few published studies of topical therapy for DFI have employed a variety of antibiotics (e.g., mupirocin, bacitracin, neomycin, chloramphenicol, polymyxin B, and gentamicin), as well as antiseptics.9,63 Wefoundno publicationreportingontheuseof topicalfusidicacidforDFI,anagentoftenmisusedinothertypesof superficialskininfectioninmanypartsoftheworld.9Studiesof topicaltherapycomparinganactiveagenttoaplacebo,toanother activeagent,orasadjunctstosystemicantibiotictherapy,have provided mixed results.64 In DFI, topical agents are typically applied in mildly infected (or, inappropriately, in uninfected) wounds, makingitdifficult todistinguishtheirclinical benefits from local wound care alone. Just eradicating or reducing microorganisms in the wound is not a sufficient endpoint for efficacy,65 any more than their presenceis sufficient to define clinicalinfection.Thereisno evidencethattopical(orsystemic) antimicrobialtherapyhastenshealing ofuninfected wounds,or

that itpreventsclinicallyapparent woundinfection.66,67Apilot randomized study of treatment in 56 DFI patients found that adding a topical gentamicin-collagen sponge as an adjunct to systemicantibiotictherapy(forupto28days),producedahigher infectioncureratecomparedtosystemicantibioticsalone(100%

vs. 70%, respectively)at2 weeks aftertheend of therapy.63In anotherrandomizedtrial,addingagentamicin-collagenspongeto systemic antibiotic therapy after a minor foot amputation in 50patientsresultedinasignificantlyshorter(byalmost2weeks) medianstumpwoundhealingtime.67Thelargeststudyoftopical antimicrobialtherapyinpatientswithaDFI(with835evaluable patients)foundthattreatmentwithaninvestigationalantimicro- bial peptide cream (pexiganan) produced rates ofclinical cure, pathogen eradication, and wound healing similar to those in patients treated withan oral fluoroquinolone antibiotic (oflox- acin).68 Further studies of this agent in treating mild DFI are currentlyunderway.

Manystudieshaveassessedtopicaldisinfectantsorantiseptics for the treatment of DFI, including compounds with silver,69 povidone orcadexomeriodine,orhypochlorite.Themajorityof these studies used ulcer healing, rather than resolution or preventionofinfection,as theprimaryoutcome.None ofthese agents has demonstrated superioroutcomescompared to non- antiseptic dressings.8 Likewise,recent systematic reviews have foundthatvariousotherdressings, suchas foam,70,71hydrocol- loid,72oralginate,73offernoadvantageoverotherdressingsfor ulcerhealingorresolutionofinfection.8Thus,aswastruethree decades ago, dressing changes with simple gauze and saline solutionaloneappearstobesufficientformostpatients.

5.5. Antibioticmisuse

Excessiveandinappropriateusesofantibioticshaveprofound negativeeffects,firstlyforthepatient,butalsoforthehealthcare system and society as a whole.9 Diabetic foot experts,74,75 including the authors of themost recent IDSA16 and IWGDF18 guidelinesonDFI,theEuropeanWoundManagementAssociation policy document,65 and the Scottish consensus statement,76 recommendnottreatingclinicallyuninfectedulcerswithantibi- otictherapy.Onedouble-blind,placebo-controlledtrialinwhich 39 patients with an ‘uncomplicated’ neuropathic diabetic foot ulcerweretreatedwitheitherantibiotictherapy(oralamoxicillin–

clavulanate)orplacebofoundnodifferenceinthewoundhealing rates.77Similarly,astudyofpatientswithneuropathic(presum- ablyuninfected)footulcersfoundnosignificantdifferenceinulcer healingfor25patientstreatedwithparenteralantibiotictherapy (ceftriaxone) compared to 25 controls not treated with anti- biotics.78AlargeregistrystudyinSwedenshowedthatproviding web-basedinformationonappropriateulcercarewasassociated with a highly significantreduction in antibiotic prescribing for thesewounds,from71%to29%.79Thisfindingnotonlysupports thepremisethatantibioticsarenotnecessaryinthemajorityof ulcers (presumably those that are uninfected) treated with appropriate woundcare,but alsothat itis possibletoimprove antibioticprescribingbyclinicians.

5.6. Surgery

Surgeryundoubtedlyplaysanimportantroleinthetreatment ofmanytypesofDFI(seeFigures5–7),80–82butuntilrecentlythere has been limited evidence regarding what constitutes optimal surgical treatment.83 The majoraims of surgery in DFIsare to evacuate pus,remove necrotic tissue, and minimizetherisk of furtherspread.80,84Badoutcomesareoftenrelatedtoadelayed diagnosis, leading toextensive destruction of thesoft tissue.85 Despite a strong emphasis in recent guidelines and consensus

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documentsontheimportanceofpromptsurgicalinterventionin many DFIs, it is frequently delayed, sometimes leading to amputation.86,87Moreconservativesurgeryforthetreatmentof DFIsisnowpossiblebecausewebetterunderstandthecompart- mental anatomy of the foot and the ways in which infection spreads.88,89Furthermore,itisclearthattherearemoretypesof footinfectionthanjust‘abscesses’and‘diabeticgangrene’.90We nowalsoappreciatethatcombiningneededablativefootsurgery with prompt revascularization can improve the rate of limb salvage.91And,finally,newwoundtherapieshaveimprovedthe postoperativecareforthesepatients.92

Anyfootcompartmentaffectedbyinfectionshouldbeopened quickly to reduce the compartmental pressure.93 Contrary to previouslyheldbeliefs,fascialplanesdonotconstrainthespreadof

infection.94Althoughunproven,MRImayplayaroleinplanning thesurgicalapproach.85,95Unfortunately,thereisnoclassification that defines either the point at which surgery is absolutely necessary,orwhenitislikelytoproduceabetteroutcomethan furthermedicaltherapy.96–98Itisnowclear,however,thatinmost cases‘conservative’surgery(i.e.,resectionofjusttheaffectedbone, withoutamputation)96,99–101orantibiotictherapyalonecantreat osteomyelitissuccessfully.

TheoptimaltimingofsurgeryforDFIisnotwelldefined,but promptsurgery,includingrevascularizationwhennecessary,may reducetheneedforabove-ankleamputations.102–104Therateof success,includingavoidinglowerextremityamputation,inDFIs, dependsontheapproachtakenbythetreatingsurgeon,105which oftenreflectshisorherexperienceandskills.Whenamputationis Figure5.Ulceroverthefirstmetatarsalhead:X-rayshowingcorticaldestructionofthefirstmetatarsalhead.

Figure6.Postoperativeview:X-rayshowingthebonethatwasremoved.

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performed, both the vertical level of the limb/foot and the horizontalanatomicalinvolvementhelpdeterminewoundheal- ing.Inarecentstudyofdiabeticfootosteomyelitiscasesthatwere treatedsurgically,thoseinvolvingthefirstmetatarsaljointwere lesslikelytohealthanthoseinotherlocations,suchasthelesser toes.106 For patients withwet gangrene or sepsis, a two-stage amputation (initial guillotine with later revision) may lead to better primary stump healing than a one-stage procedure.107 Contrarytopreviousbeliefs,softtissuecoveragebyskingraftingor flapsispossibleifneeded,eveninischemicareas.108

6. Negative-pressurewoundtherapy

We now have wound healing devices that were not even dreamed of 30 years ago. Negative-pressure wound therapy (NPWT),introducedabout20years ago,isnowwidelyusedfor accelerating woundhealing. There are,however,few published dataon theusefulnessofthis methodfortreatinginfected soft tissueorbone.109Asystematicreviewidentifiedfourrandomized trialsofNPWTfordiabeticfootwounds.110Whileall,includinga multicenter study that enrolled 342 patients,111 found that wounds treated with NPWT healed more rapidly than those receivingconventionaldressings,thequalityofeachofthestudies wasweakandtherewasheterogeneityintheoutcomesstudied andpatientsselected.112,113Amorerecentmeta-analysisoffour randomizedtrials in diabetic footulcers concludedthat NPWT resultsinmoreeffectiveandfasterwoundhealingandmayreduce potentialinfectivecomplications.113ACochranereviewidentified twolargetrialsthatreportedsuperiorulcerhealingresultswith NPWTcomparedtomoistdressingalone,butthreeothersmaller trialsdidnotconfirmthisfinding.Noneofthesetrialsdealtwith infection.114 NPWTcanbecombinedwithsimultaneouswound irrigationortheinstillationofantisepticsorantibioticstoreduce the‘woundbedbioburden,’buttheeffectivenessofthesemethods forcuringorpreventinginfectionisasyetunclear.115Onecase–

control study including 82 diabetic patients demonstrated a significantlyshorterlengthofhospitalstayandareducednumber ofsurgicalvisitsinpatientstreatedwithnegativepressuretherapy with antimicrobial installation compared to negative pressure therapywithoutinstallation.116Moretrialsareneededtobetter understand what role this instillation technique may have in treatingDFI.

7. Off-loading

Off-loadingpressurefromanulceriscriticaltogettingittoheal, includingthosethatareinfected.117Thiswas,is,andwillbethe

cornerstone of both treatment and secondary prevention. The criterionstandardmethodforoff-loading–thetotalcontactcast– leadstoulcerhealinginover90%ofcasesandhasbeenavailable for decades.117 What is new is recognizing that the key to its successisthatitisnon-removable,ensuringpatientadherence.118 Forpatients withlittleornofootdeformity,prefabricatedextra depthfootwearwithastiffrockerbottomwalkingsoleisusually sufficient.Caseswithamoderatedeformitymayrequirecustom- made shoes with custom-moulded, full-contact insoles. Off- loading can be partial and surgical, e.g., performing a flexor- tenotomyinapatientwithclawtoes.Anelectivesurgicalapproach may be right when conservative therapy has failed to prevent severe deformity or joint instability, or in the presence of ulceratinghammerandclawtoes.119

Cliniciansshouldgenerallyexplaintothepatientthebenefitof off-loading,butarecentCochraneanalysisofpatienteducationfor preventing diabetic foot ulcers found that it may positively influenceshort-termresults,butoverallthereisstillinsufficiently robust evidence that limited education alone is effective in achievingasignificantreductionintheincidenceoffootulceration andamputation.120,121

8. Adjunctivetreatments 8.1. Hyperbaricoxygentherapy

Thevalueofhyperbaricoxygentherapy(HBOT)forDFIcontinues tobehotlydebated.8A2012Cochranesystematicreviewconcluded thatHBOTsignificantlyincreasedulcerhealingintheshortterm,but notthelongterm;becauseoftheflawedtrials,however,theywere not confidentin the results.122Somestudies suggestthatHBOT facilitateswoundhealinganddecreasesratesoflowerextremity amputationindiabeticpatientswitha footulcer orpostsurgical amputationwound,123,124butmostexperienceisretrospectiveand non-comparative.125Thereare,however,nopublisheddatadirectly relatedtotheeffectofHBOToninfectiousaspects(eithersofttissue orbone)ofthediabeticfoot.126

8.2. Woundstimulatingfactors

Severalstudieshaveexaminedthevalueofgranulocyte-colony stimulatingfactorsfortreatingDFIorulcers.ACochranereview basedonfiverandomizedtrialsconcludedthatthesetreatments didnotincreaseinfectionremission,butmayreducetheneedfor surgicalinterventions,especiallyamputations,andthedurationof hospitalization.127 Well-designed studies of platelet-derived growth factors128,129and skinsubstitutes have not shown any specificbenefitregardingresolutionorpreventionofinfection.130 Likewise, a Cochrane review found no evidence of benefit for autologous platelet-rich plasma in the treatment of chronic wounds.131

8.3. Stemcelltherapy

Inrecentyearstherehasbeenlessresearchusinggrowthfactors ondiabeticfootwoundsandmoreemployingstemcells.132Mostof the initialstudies usedangiogenic growthfactorsalone,butthe limited efficacy prompted studies investigating the potential benefitsofcell-basedtherapy.133,134Studiesonthelocalinjection ofunselectedbonemarrow-derived(orperipheralblood-derived) mononuclearcellsinpatientswithsevereperipheralarterialdisease provided encouragingresults,but thetreatmentdidnotprovide completerevascularization,probablyduetothelimiteddeliveryof specific angiogenic cells in the mixed cell population.135 Later studiesfoundthatautologousbonemarrowcelltransplantationin ischemicdiabeticfootulcersincreasedlegperfusionandreduced Figure7.Totalhealingofthewound.

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theriskofamputations.136Studiesusingumbilicalcordstemcells have also reported encouraging results.136 One investigation of adipose tissue-derived stem cell implantation in patients with criticallimbischemia,someofwhomwerediabetic,demonstrated considerable angioneogenesis.137 Other investigators have also successfullyharvestedadiposetissuestemcellsfromtheabdominal subcutaneousfat.138Whilestemcelltherapyshowsencouraging resultsregarding angiogenesis,it currentlyhas noprovendirect effectoninfection.

9. Limbrevascularization

Peripheralarterialdiseaseispresentinabout50%ofpatients withaDFI,anditappearstobeanindependentriskfactorforlimb loss.139Revascularizationofthefootindiabeticpatientscannow beaccomplishedbyeitherarterialbypasssurgeryorendovascular interventions, with limited evidence to support selecting one techniqueovertheother.Availabledatasuggestthatpatientswith alife-expectancyofmorethan2yearsandextensivestenoseshave superioroutcomeswithopen surgery.140 However,using endo- vascularangioplasty canreach theinfragenicular region, which was not possible until the most recent decade.141 While revascularizationmaybecrucialforacriticallyischemiclimb,it probablyhasnodirectlybeneficialeffectoninfection,otherthanto provideadequateperfusiontoensurethedeliveryofsystemically administeredantibiotics.

10.Clinicalpathways,guidelines,andbundleinterventions

As noted above, there are now several evidence-based DFI guidelinesthathavebeenshowntoprovidevalidatedapproaches to optimize outcomes.20 All address the critical importance of multidisciplinaryteams,16whichhaverepeatedlybeenshownto helpavoid adverseoutcomesinbothinpatientsand outpatients withDFIs.142Thedeploymentofteamsis,however,hamperedby severallogisticalproblems:(1)itisoftendifficulttobringteam memberstogetheroutsideofafixedmeetingtime;(2)thenumber ofpatientsrequiringevaluationoftenrequiresmoretimethanis availableforfixedteammeetings;(3)membersoftheteamoften turnover; and (4) funding for team members’ time or for administrativesupportisoftenlacking.Anewconcepttoprovide theadvantagesofamultidisciplinaryteamwhileovercomingsome of the logistical problems is the use of a clinical pathway (preferably accompanied by electronic order-sets).143 Clinical pathways may uncover improper diagnostic or therapeutic approaches,orbottlenecksinprovidingoptimalcare.Order-sets provide a powerful tool to implement ‘bundles’ (multiple simultaneous interventions) and to encourage and facilitate optimal and evidence-based care.144 Although studies to date havebeenlimitedtobefore-and-afterdesigns,teamsandorder- setsmayhelp tooptimize(andminimize)theuseofantibiotic agents,reducecosts,andpreventunnecessaryamputations.142 11.Futureresearch

Increasingantibioticresistancehasstimulatedresearchaddres- singvarioustypesofnon-antibiotictreatmentforDFIs.Amongthese, photodynamic inactivation,145 bactericidal laser therapy,146 and bacteriophages147 appear to show promise. Using telemedicine diagnosticsupportinthehomeenvironmentmayalsoallowneeded footassessmentas well asexpert consultative advice. Recently, investigatorshavedevelopedaphotographicfootimagingdevicefor useinhomemonitoringfortheearlydiagnosisoffootulcersandpre- ulcerativelesionsindiabeticpatients.148Homemonitoringoffoot temperatures by infrared thermometry, with modification of activitywhenthetemperatureiselevated,hasbeenshowntobe

reducefootulcerationinpatientswithdiabetes.149Infraredthermal cameras maybeuseful todetect infectionsor topredict which patients are at risk of future foot complications,150 including infections.151Astudyof38patientswithadiabeticfootcomplica- tionfoundthatdiagnosisbasedonthecombinationofphotographic andtemperaturesensingdeviceswasbothsensitiveandspecific, withgoodintra-observeragreement.152Likewise,aquantumdot- basedfootmappingsystem(utilizingareddottoshowthepresence of bacteria and a green one to show areas of accumulating inflammation)mayhelptovisualizeinfectionanddifferentiateit fromsterileinflammation.153Finally,giventhehighrecurrencerates ofneuropathicfootulcers,helpingpatientstomodifytheirwalking pattern, perhaps with feedback-based approaches, may prove useful.154Employingotherformsofphysicaltherapyandrehabili- tationmayalsohelpimprovetheoutcomesofDFI.155

12. Conclusions

DFIs are a common, complex, and costly problem that will almostcertainlyincreaseinprevalenceinthenearfuture.Clinical researchoverthepastthreedecadeshasmarkedlyincreasedour understandingofthepathophysiology,diagnosis,andtreatmentof bothsofttissueandboneinfections.Thetasknowistoimplement availablevalidatedguidelines,toauditprocessesandoutcomes,to educateprovidersandpatients,andtofurtheradvanceresearch.

Acknowledgements

We are indebted to our colleagues in the services of Orthopaedic Surgery, Diabetology, and Microbiology of Geneva UniversityHospitals,Switzerland,UniversityofOxford,UK,andLa PalomaHospitalinLasPalmas,Spain.

Ethicsstatement:Notrequiredforthisreview.

Conflictofinterest:Therewasnofundingforthepreparationof this manuscript. BAL hasservedas a consultanttoKCI/Acelity, Innocoll,andDipexium.DLhasservedasaconsultanttoBasilea.IU hasreceivedresearchfundingfromInnocoll.JAShasnoconflictsof interest.However,thecontentofthispaperhasnorelationwith theconsultancyofanyoftheauthors.

Authorcontributions:Allauthorscontributedtothewritingand reviewingofthemanuscript.

Bulletpoints:

Our understanding of the pathophysiology, diagnosis, and treatmentofdiabeticfootinfectionshasimproveddramatically inthepast30years.

Thedevelopmentandvalidationofguidelinesondiabeticfoot infectionshave providedanevidence-basedapproachtotheir management.

Wenowbetterknowfactorsthataffectthecausativepathogens indiabeticfootinfections,allowingimprovedempiricantibiotic therapy.

Technologyhasimprovedourabilitytodiagnoseosteomyelitisof thediabeticfoot,andstudieshaveclarifiedtherolesofantibiotic andsurgicaltreatmentofthisinfection.

Manynewtechnologiesarenowunderevaluation,butthebasic principlesofproperlydiagnosinginfection,obtainingaspecimen for culture, selecting and refining antibiotic therapy, rapidly undertakingthesurgicalinterventionsrequired,ensuringade- quate arterial perfusion, and off-loading pressure remain the keystogoodoutcomes.

References

1.SinghN,ArmstrongDG,LipskyBA.Preventingfootulcersinpatientswith diabetes.JAMA2005;293:217–28.

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