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(1)(2)(3)(4)(5)(6)
InternationalOrthopaedics
SICOTaisbl201510.1007/s002640152712z
OriginalPaper
Areviewoffortyfiveopentibialfracturescoveredwithfreeflaps.Analysisofcomplications,microbiologyandprognosticfactorsUlrikKhlerOlesen 1,RasmusJuul 4,ChristianTorstenBonde 3,ClausMoser 2,MartinMcNally 6,LisaToftJensen 3,JensJrgenElberg 3andHenrikEckardt 5
DepartmentofOrthopaedicSurgery,Rigshospitalet,Blegdamsvej9,2100Copenhagen,DenmarkDepartmentofClinicalMicrobiology,Rigshospitalet,Copenhagen,DenmarkDepartmentofPlasticSurgery,BreastSurgeryandBurns,Rigshospitalet,Copenhagen,DenmarkDepartmentofOrthopaedicSurgery,SlagelseHospital,Slagelse,DenmarkDepartmentofTraumatology,UniversityHospitalBasel,Basel,SwitzerlandNuffieldOrthopaedicCentre,OxfordUniversityHospitals,Oxford,UK
UlrikKhlerOlesenEmail:[email protected]
Received:31December2014Accepted:12February2015Publishedonline:8March2015
Abstract
Purpose
Treatmentofopenfracturesiscomplexandcontroversial.Thepurposeofthepresentstudyistoaddevidencetothemanagementofopentibialfractures,wheretissuelossnecessitatescoverwithafreeflap.Weidentifiedfactorsthatincreasetheriskofcomplications.Wequestionedwhetherearlyflapcoverageimprovedtheclinicaloutcomeandwhetherwecouldimproveour
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antibiotictreatmentofopenfractures.
Methods
From2002to2013wetreated56patientswithanopentibialfracturecoveredwithafreeflap.Wereviewedpatientrecordsanddatabasesfortypeoftrauma,smoking,timetotissuecover,infection,amputations,flaplossandunionoffracture.Weidentifiedfactorsthatincreasetheriskofcomplications.Weanalysedtheorganismsculturedfromopenfracturestoproposetheoptimalantibioticprophylaxis.Followupwasaminimumofoneyear.Primaryoutcomewasinfection,bacterialsensitivitypattern,amputation,flapfailureandunionofthefracture.
Results
Whensofttissuecoverwasdelayedbeyondsevendays,infectionrateincreasedfrom27to60%(p
Conclusion
Flapcoverwithinoneweekisessentialtoavoidinfection.Highenergytraumaandsmokingareimportantpredictorsofcomplications.Wesuggestantibioticprophylaxiswithvancomycinandmeropenemuntilthewoundiscoveredinthesecomplexinjuries.
Keywords OpentibialfracturesAntibioticsInfectionMicrobiologyTimingFreeflapAmputationSmoking
Introduction
Openfractureshaveanincreasedriskofinfectionandnonunion.Thesecomplicationsmayresultinamputationandsepticshock.Themostseverecases,withsignificantsofttissueinjury,needbothosteosynthesisoftheboneandaplasticsurgicalprocedure,intheformofafreeflap,torestorethesofttissue.Furthermore,thefragilesofttissuemantleinthedistaltibiaandthelackofreliablelocalflapsinthisareaisachallengefororthopaedicandplasticsurgeons.Theultimategoalsofthetreatmentaretoavoidamputationandinfection,restoresofttissuecoverandachieveunionofthefracture(Figs.1,2and3).
http://staticcontent.springer.com.scihub.org/image/art%3A10.1007%2Fs002640152712z/MediaObjects/264_2015_2712_Fig1_HTML.gif
Fig.1
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Afreefibulagraftwithmuscleandskinfromtherightlegofthepatient,istransferredtotheleftside,wherethepatientsustainedanopendistaltibialfracture,withsubstantialboneloss
http://staticcontent.springer.com.scihub.org/image/art%3A10.1007%2Fs002640152712z/MediaObjects/264_2015_2712_Fig2_HTML.gif
Fig.2
Thefibulaisexposed
http://staticcontent.springer.com.scihub.org/image/art%3A10.1007%2Fs002640152712z/MediaObjects/264_2015_2712_Fig3_HTML.gif
Fig.3
6monthsafter.Donorandthegraftsite.Thepatientiswalkingunaided,withnopain
Theliteratureremainsinconclusiveonthetopicofantibiotictreatmentandtimingofsofttissuecover,probablyduetotherelativelysmallnumberofpatientsineachcentrewiththiscondition[15,79].Furthermore,hospitallogisticsmaydelaythemostoptimalcourse.Thedelayintimetoskincoverisprobablyrootedinalackofconsensusontiming,differentapproachestothetreatmentofseverelyinjuredpatientswithotherlifeorlimbthreateninginjuriesandlackofcapacity.Inourhospital,thedelayinflapcoveragewasrootedinacapacityproblemtypically,anelectivetumourpatientoperationmustbecancelledforthemicrosurgeryteamtooperateonanopenfracturepatient.
Thepurposeofourstudywastoinvestigatethedeterminingfactorsthatreducetheriskofamputation,infectionandnonunionandtoidentifyrelevantfirstlineantibiotics.Webelievethatourstudyisuniqueinitscombinationofdataonmicrobiologyandtimingofcoverofopenfractures.Theseaspectshavenotpreviouslybeendiscussedinthesamecontext,althoughtheyarecloselyassociated.
Methods
ThisstudywasconductedattheDepartmentofOrthopaedicSurgeryandTraumaandattheDepartmentofPlasticSurgery,CopenhagenUniversityHospital,Rigshospitalet,Denmark.Rigshospitaletisareferralcentreforfractureswithsofttissuelossandhasacatchment
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populationof1.7million.
Thestudyincludedallpatientswithopenfracturesofthetibia,coveredwithfreevascularizedflapsatourinstitutionfromJanuary2002toJune2013.Patientswithinitiallyclosedfracturesandpatientswithchronicosteomyelitiswereexcluded.ThepatientsincludedinthestudywereidentifiedfromourdatabaseofallmicrosurgicalproceduresconductedbytheDepartmentofPlasticSurgeryduringtheperiod.
Weretrospectivelycollecteddatafrompatientrecords(history,tobaccouse,fracturetype,fractureunion,timingofsurgicalprocedures,flapfailure,infection,amputation)andfromourlocalmicrobiologicaldatabase(samples,species,antibiotics,susceptibilitypatterns)andfromthemicrosurgicaldatabase(flaptypes,timing).
InjurytypewasrecordedaccordingtoMllerOTAfractureclassificationandtheGustiloAndersonsofttissuedamageclassification[1,12].InitialwoundtreatmentwasclassifiedasOpenwhennegativepressurewoundtherapy(NPWT),oranyothertypeofopendressingwasused.Closedwoundtreatmentdenotedcaseswhereprimarysuturingofthewoundproceededtowoundbreakdownandnecrosis.WedefinedinfectionwhenCRPand/orwhitecellcountwaselevatedincombinationwithpus,dischargeorwoundbreakdown,provideditwasrelatedtotheinitiallesion,includingtheflap.Superficialsignsofinfectionandexternalfixatorpintractinfectionswereexcluded.Positiveculturesorbloodtestswithoutclinicalsignsofinfectionwerenotincluded.
Unionofthefracturewasevaluatedradiographicallyandwedefinednonunionwhenlessthanthreeoutoffourcorticeshadbridgingcallusinanteroposteriorandlateralviews,oneyearorlater,afterinitialsurgery.Highenergytraumawasdefinedas:polytraumaingeneral,includingfallsfromaheightof2.5m,motorvehicleormotorcycleaccidents,bicycleaccidents,pedestriansbeinghitbyanyoftheaboveandcrushinginjuries.LowenergytraumawasdefinedasfallfromstandingheightoruptoThebacterialspeciesisolatedfromthewoundsandtheirsusceptibilitypatternsweredefinedwithrespecttotimefrominjury.Weincludedsampleculturesbetweenthesecondand30thdayafterinjury.Culturesfrominitialwoundrevisionswerenotincluded.Thisavoidedtheearlywoundcontaminationperiod(whichhaspreviouslybeenshowntohavepoorcorrelationwithlaterinfectionpathogens)[22,23].Thesamplesincludedwerebiopsiesharvestedfromdeeptissueduringsurgicalwoundrevisionsofpatientsthatwereclinicallyinfected.Blood,pinsiteandcathetercultureswerenotincluded.Identicalresultswerecountedonlyonce.Thesusceptibilityofidentifiedmicroorganismstorelevantantibioticswastestedbydiscdiffusion.Weincludedonlypositivesamplesthatwerefullysusceptibletotheantibiotictested.
WeusedFischersExacttestfordichotomousvariablesandsetthelevelofsignificanceatp=
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0.05.Wecalculatedtherelativeriskratioforeachoutcomemeasurerelatedtotheenergyofinitialtrauma.Clinicalfollowupwasaminimumofoneyearforallpatients.
Results
FromJanuary2002untilJune2013,56patientsreceivedafreevascularizedflaptocoveranopenfractureofthetibiaatourinstitution.Ofthese,11hadinsufficientorirretrievablepatientrecords,leaving45patientstobeincludedinthestudy.Thepatientswithirretrievablerecordswereallfromtheperiod(20022005),priortotheintroductionofelectronicpatientrecords.
Thestudygroupconsistedof13womenand32men.Theaverageagewas42years(range1671,SD18).GustiloAndersontypeIIIBfracturesaccountedfor26(57%)ofthelesions,andsix(13%)wereGustiloAndersonIIIC.Thirtyonepatients(67%)sustainedhighenergytrauma.Therewere15smokers(33%).Onepatienthadbilateralfractures.
Allpatientswereinitiallydebridedwithcopiouslavage.Theaveragetimetofirstdebridementwas6.8hours(rangeoneto26,SD6.2).Afterdebridement31patients(67%)with32fracturescontinuedwithopenwoundcare,typicallywithnegativepressurewoundtherapy(NPWT).Theremainder(15)hadclosedwoundtherapywithsteriledressingsandsuturingofthewound,thatlaterwentontowoundbreakdown.
Sixteenpatientswereprimarilystabilizedwithinternalfixation(plates,nailorscrews).Theremaining29patientsweretreatedwithtemporaryexternalfixation,whichwasconvertedtointernalfixationincombinationwiththefreeflap.
Theaveragetimetoflapcoverwas16days(rangetwoto54days,SD13,excludingoneoutlierat450days).Thefreeflapsconsistedof24latissimusdorsiflaps,13gracilisflaps,threevascularizedfreefibulas,fiveanterolateralthighflaps(ALT)andasingleradialforearmflap.Onepatienthadflapstobothtibias(patientno.7)(seeTable1).
Table1
Patientdemographics
Patient Age Year Smoker Fracture GAclassHighenergy
Woundtreatment
Flaptype
1 43 2005 Yes 44A GA3B Yes Open LD
2 39 2009 No 42A GA3B Yes Open ALT
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3 43 2013 Yes 41C3 GA3B Yes Open LD
4 25 2012 No 42C3 GA3C Yes Open LD
5 72 2011 No 42A GA3B Yes Open Grac
6 45 2002 Yes 42A3 GA3B Yes Closed LD
7 71 2011 No 42B1 GA3B Yes Open LD
7 71 2011 No 42A2 GA3B Yes Open LD
8 22 2008 Yes 42A3 GA3B Yes Open LD
9 44 2012 No 41C3 GA3B Yes Open LD
10 49 2011 No 42B2 GA3C Yes Open LD
11 52 2011 No 44B3 GA3B Yes Open ALT
12 16 2005 Yes 42A3 GA3B No Open LD
13 46 2012 Yes 44BC GA3B Yes Open LD
14 39 2009 Yes 43B2 GA3A No Open Grac
15 27 2011 No 41A1 GA3B No Open LD
16 61 2007 No 42C1 GA3B No Closed Grac
17 59 2007 Yes 43C3 GA3B Yes Closed LD
18 35 2010 No 42B2 GA3B No Open Grac
19 31 2005 No 43B2 GA3B Yes Closed Grac
20 17 2006 No 42C1 GA3B Yes Closed Grac
21 38 2011 No 42A1 GA3A No Open ALT
22 80 2011 No 44B2 GA3A No Open Radialis
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23 64 2010 No 43C3 GA3C Yes Open ALT
24 30 2009 Yes 43B2 GA3C Yes Open LD
25 29 2004 Yes 42A2 GA2 Yes Closed LD
26 34 2005 Yes 42B2 GA2 No Closed LD
27 77 2012 No 44B2 GA3B No Open LD
28 59 2012 No 41A3 GA3B Yes Closed LD
29 24 2003 Yes 44B1 GA3B Yes Open LD
30 56 2007 Yes 42C2 GA2 Yes Closed Grac
31 67 2011 No 44C1 GA2 No Open LD
32 21 2010 No 43A3 GA3C Yes Open Fib
33 42 2009 No 43B2 GA3B Yes Open LD
34 56 2013 No 41C1 GA3B Yes Open alt
35 41 2005 No 42C3 GA3B Yes Open Grac
36 35 2002 Yes 42B2 GA2 Yes Closed LD
37 67 2012 No 43B3 GA3B No Open Fib
38 15 2002 No 44B3 GA2 No Closed Grac
39 42 2005 No 42A2 GA3A Yes Closed LD
40 22 2013 No 43B2 GA2 No Open Grac
41 16 2002 No 42A2 GA3B Yes Closed Grac
42 19 2009 No 44C2 GA3A Yes Closed LD
43 29 2009 Yes 42C3 GA3C Yes Open Fib
44 28 2013 Yes 43C2 GA1 No Closed Grac
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44 28 2013 Yes 43C2 GA1 No Closed Grac
45 35 2012 No 42B3 GA2 No Open Grac
FracturetypeaccordingtoAOLDLatissimusdorsiALTanterolateralthighGracGracilisFibfasciomyocutaneousfibulaflapGAGustiloAndersonclassificationExfixexternalfixation
Infection
Twentytwofractures(48%)becameinfectedatanaverageof21daysfromtheinitialtrauma(rangefourto83days,SD21days,excludinganoutlierat360days).Inthegroupreceivingflapcoverbeforedayseven(earlycover),fiveoutof18becameinfected(27%),andinthegroupofpatientsreceivingtheflapafterdayseven(latecover),17outof28becameinfected(60%).Thedifferencebetweeninfectionratesinthetwogroupswasstatisticallysignificant(p
Nonunion
Nineteen(41%)fractureswerenotunitedoneyearafterosteosynthesis.Nonunionoccurredintenoutof16patientsinthesmokinggroup(63%),comparedtonineoutof30patients(30%)inthenonsmokinggroup.Thedifferencebetweennonunionratesinthesmokingandthenonsmokinggroupwasalmostsignificant(p
Limbsalvage
Infourpatients(9%),continuinginfectionrequiredtreatmentwithabelowthekneeamputation.Twoofthesehadaninfectednonunion.Meantimetoamputationwas17.2months(0.4,14,14and40months).Theassociationbetweenamputationandinfectionwasstatisticallysignificant(p
Flapfailure
Sevenpatients(19%)sustainedpartialorcompletelossofthefreeflap,resultinginasecondaryprocedure.Noneofthesepatientswereamputatedandallofthemunderwenteithersuccessfulrepairorreplacementoftheirflaps.Flapfailurewassignificantlyassociatedwithsmoking,withfiveoutofseven(71%)flapfailuresoccurringinthesmokinggroup(p
Injuryseverity
Allfourpatientswhowereamputatedwereinthehighenergytraumagroup.Seventeenof22infectedpatients(77%)wereinthehighenergygroup.Furthermore,sixoutofseven(86%)
SciHub
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flapfailuresand14of19(74%)nonunioncaseswereinthehighenergygroup.Whencomparinghighenergytraumawithlowenergytrauma,therelativeriskratiosforamputation,flapfailure,infectionandnonunionwere3.8,2.9,1.6and1.4,respectively.
Cultureresults
Weisolated43differentbacterialspeciesin22infectedpatientsfromdaytwoto30.Sixoftheinfectionsweremonomicrobial,ninehadtwodifferentbacteriaandtherestwerepolymicrobial.Sevenbacteriaaccountedfor75%oftheinfections,enterococcusspeciesandcoagulasenegativestaphylococcus(CoNs)beingthemostfrequent.ThepatternsofsensitivityareseeninTable2.
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Table2
Thenumberofculturesfrainfectedwoundsandtheirsensitivitypattern
Bacteria Number Vanco Mero Linez Genta Sulfa Amp Moxi
Enterococcusspecies 11 11 7 9
9 5
Coagulaseneg.staphylococci(CoNS)
9 9 9 5 3
Enterobacteriaceae 6 5 5 5 1
Miscellaneous 6 5 6 3 5 2 4
Otherpseudomonas 4
2 2 3 0
Anaerobicbacteria 2
2 1
Staphylococcusaureus 2 2
2 2
Haemolyticstreptococci 1 1 1
1 1
Corynebacteriumspecies 1 1 0 1
0 0 0
Pseudomonasaeruginosa 1
1 1
Total 43 29 24 24 15 14 13 13
Onlysampleswithfullsensitivitywereincluded.VancoVancomycinMeroMeropenemLinezLinezolidGentagentamycinSulfasulphonamideAmpAmpicillinMoximoxifloxacinEryErythromycinRifrifampicinCiprociprofloxacinCefurcefuroximAzitazitromycinMetrometronidazol
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Discussion
Theimportanceoftimingofcoverinopenfractureshasbeeninvestigatedbyanumberofauthors,mostnotablyGodina,whowasthefirsttoreporttheimportanceofearlyskincovertoreducetheriskofinfection[19].Later,anumberofotherobservershavecometosimilarconclusions,butmanyotheraspectsoftraumacaremayalsoplayaroleinpreventinginfectionandsecuringunionintheseinjuries.
Alleuyrandetal.foundthatpatientsreceivingflapcoverbeforedaysevenhadabetteroutcomeintermsofflapfailureandinfection,evenwhencontrollingforknownriskfactorssuchasseverityoftrauma[2].Choudyetal.alsofoundahighernonunionrateandinfectionrateinpatientswithflapcoverafterdayseven[20].
Gopaletal.andSinclairetal.reportedseriesofopentibialfractureswithveryearlyskincover(beforedaythree)anddefinitivestabilization9095%ofthesepatientshadsuccessfulflapcover,withnoinfection,unionofthefractureandexcellentoutcomewithoutpainorwalkingdisability[4,5].Suchresultsareexceptional.Inanotherseries,infectionrates,flapfailureratesandnonunionratesexceed3050%.Otherauthors,inlinewiththeguidelinesoftheBritishOrthopaedicAssociation,havereachedsimilarconclusions,albeitatvariousbreakpoints[25,711].
Ourstudysamplesizedidnotpermitamultivariateanalysisofallpossibleconfounders,butitconfirmedunequivocallythatpatientscoveredbeforedaysevenhadasignificantlylowerinfectionandnonunionrate,irrespectiveoftraumadegree.
Theseresultsshouldencouragesurgeonstostriveforanorthoplasticserviceenablingrapidfreeflapcoveranddefinitivestabilizationwithinoneweekaftertrauma.Weacceptthatnoneofthesestudiesarerandomizedtrialsofearlyandlatecover,whichisageneralweaknessoftheliterature.
Inourstudy,flapfailurewasnotapredictorofamputation.Thisisanimportantpoint,alsoobservedbyChoudryetal.,illustratingthataflaprevisionorasecondflapcanoftenallowlimbsalvage[20].Atourinstitution,localmuscleflapsarenotusedforimmediatesofttissuecoverafterlowerextremitytraumaduetohighcomplicationandrevisionrates[3,18,20].Choudryetal.alsofoundthatcoverlaterthanoneweekusingsoleuspedicledflapsforopentibiafracturesresultedinhighernonunionrates,higherflapfailureratesandmoreinfectionwhencomparedtofreemuscleflaps[20].Useoftobaccowasasignificantpredictorofflapfailure,awellknownprobleminplasticsurgery,alsodescribedbyChristyetal.,[17].Hence,smokerswithcomplexinjuriesshouldbecounseledonquittingsmoking.
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PatzakisandWilkins(in1989)wereamongthefirsttoobservethatimmediateantibioticprophylaxisinpatientswithopenfracturesisthesinglemostimportantfactorthatwillreducetheriskofinfections[6].Furthermore,gradeIIIopenfracturesinneedoftissuecoverposeaproblemfortheclinician.Thewoundmaybeopenforseveraldaysallowingcolonizationandadherenceofselectedbacteriathatareresistanttotheantibioticsgiven.Inlinewiththeseobservations,ithasbeenshownthatculturesobtainedatinitialdebridementscorrelatepoorlywithlaterinfections,whichiswhyweonlyincludedculturesfrompatientsthatwereclinicallyinfected,andnotculturesfromdayzerototwo[22,23].Thus,antibiotictreatmentshouldbebroad,targetbothGrampositiveandnegativeorganisms,andtheriskofgeneratingresistanceshouldbesmall[1316].Theriskcanbefurtherreducedbyusingantibioticsthatarerenallyexcretedwithminorimpactonthenormalflora,asproposedbySullivanetal.[21].Also,reducedselectionforresistantpathogenscanbeexpectedduetothereducedtimetosofttissuecoverage,andtheresultingdecreasedperiodwithneedforantibiotictreatment.
Gopaletal.,incommonwithPollacketal.,haveproposedtheuseofCefuroximeandmetronidazoleforopentibiafractures.Thiswasthecombinationofantibioticsusedatourinstitution,butinonly12of43(28%)caseswouldtheseantibioticshavebeeneffectiveagainstthebacteriaculturedfromourpatientsbeforeflapcover[3,4].
AsdepictedinTable3,vancomycin,whichisbacteriocidal,waseffectiveagainst29of43isolatedculturesandwasactiveagainstallGrampositivebacteriaidentifiedinthestudy.
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Table3
Outcomeofpatientdemographicsandcomplications
OutcomeLatecover(61%)
Earlycover
Highenergy(67%)
Lowenergy
Openwound(67%)
Closedwound
Proximalfracture(59%)
Amputation(9%) 1 3 4 0 3 1 2
Noamputation 27 15 27 15 28 14 25
pvalue 0.280 0.290 1.000 1.00
Infection(48%) 17 5 17 5 12 10 12
Noinfection 11 13 14 10 19 5 15
pvalue 0.038* 0.217 0.146 0.770
Flapfailure(15%) 6 1 6 1 4 3 3
Nofailure 22 17 25 14 27 12 24
pvalue 0.220 0.399 0.660 0.424
Nonunion(41%) 13 6 4 5 11 8 12
Union 15 12 17 10 20 7 15
pvalue 0.540 0.539 0.340 0.763
*Statisticallysignificantassociationsaremarkedwithanasterisk
Meropenemwaseffectiveagainst24of43organisms,withparticulareffectagainstthemiscellaneousgroup,enterobacteriacaeandotherGramnegativerods,enterococcusandanaerobes.Gentamicincovered15of43organisms,butnoneoftheimportantenterococcus
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species.
LinezolidalsocoveredtheGrampositiveorganismsinoursamples,andhasgoodpenetrationintotissues,butisonlylicensedforalimitedperiodoftimeandisverycostly.
Basedontheseresults,wesuggestacombinationofvancomycinandmeropenemasfirstlineantibioticprophylaxis.Incombination,theseantibioticsseldomleadtoresistance,aregenerallywelltolerated,andsupplementeachotherwell.Theyarebothmainlyrenallyexcreted.Inthisseries,vancomycinandmeropenemwouldhavecovered40of43(93%)organismscultured.Thishasalsobeendemonstratedinaseriesof166patientswithchronicosteomyelitisoccurringmainlyafterfracturewithinternalfixation,inwhichSheehyetal.recommendedvancomycinandmeropenemforempiricalinitialtreatmentoftheorganismsidentifiedatexcisionoftheboneinfection[13].
Thepatternsofresistancemaydiffergeographicallyandshouldalsobeconsideredinaregionalcontext.Weareawarethatprophylaxiswithbroadspectrumantibioticscouldresultinunwantedresistancepatterns,butthisproblemshouldbeseeninthelightofaverysmallnumberofpatientspresentingwithopenfractureswithcompromisedsofttissue.However,shortdurationtreatmentwitheffectiveantibioticregimesshouldalsominimizethedevelopmentofresistanceandpreventlaterinfectionthatwillinevitablyrequiremuchlongerantibiotictherapywithrisksforresistance.
Conclusion
Weconcludethatadelayinsofttissuecoverbeyonddaysevenfromtheinitialtraumaisassociatedwithanincreasedinfectionandnonunionrate.Smokingmarkedlyincreasestheriskofnonunionandflapfailure.Highenergytraumaincreasestherelativeriskofflapfailure,infection,nonunionandamputation.
Wealsoconcludethatcurrentlyproposedantibioticshavelimitedeffectonbacteriainfectinggrade3openfractures.
Wehavechangedthestandardantibioticprophylaxisatourinstitutiontovancomycinandmeropenem,thusimprovingtheexpectedcoverageoforganismsfrom28to93%.
Acknowledgments
TheauthorswishtothankMDMariaPetersenforvaluableacademicfeedbackandITconsultantChristian
E.Forrestalforassistancewithdatacollection,spreadssheetsandfigures.
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Conflictofinterest
Noconflictsofinterestdeclared.
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