(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:ulrik.kaehler@gmail.com

Received:31December2014Accepted:12February2015Publishedonline:8March2015

Abstract

Purpose

Treatmentofopenfracturesiscomplexandcontroversial.Thepurposeofthepresentstudyistoaddevidencetothemanagementofopentibialfractures,wheretissuelossnecessitatescoverwithafreeflap.Weidentifiedfactorsthatincreasetheriskofcomplications.Wequestionedwhetherearlyflapcoverageimprovedtheclinicaloutcomeandwhetherwecouldimproveour

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

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

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=

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

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

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

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

flapfailuresand14of19(74%)nonunioncaseswereinthehighenergygroup.Whencomparinghighenergytraumawithlowenergytrauma,therelativeriskratiosforamputation,flapfailure,infectionandnonunionwere3.8,2.9,1.6and1.4,respectively.

Cultureresults

Weisolated43differentbacterialspeciesin22infectedpatientsfromdaytwoto30.Sixoftheinfectionsweremonomicrobial,ninehadtwodifferentbacteriaandtherestwerepolymicrobial.Sevenbacteriaaccountedfor75%oftheinfections,enterococcusspeciesandcoagulasenegativestaphylococcus(CoNs)beingthemostfrequent.ThepatternsofsensitivityareseeninTable2.

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

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.

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.

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

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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