Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections

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Reference

Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections

BOUVET, Cindy, et al.

Abstract

Staphylococcus aureus is the most common cause of soft tissue infections. It is unknown, however, if a patient who has had such an infection is at greater risk for future soft tissue infections with S. aureus.

BOUVET, Cindy, et al . Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections. International Journal of Infectious Diseases , 2017, vol. 60, p. 44-48

DOI : 10.1016/j.ijid.2017.05.002 PMID : 28487239

Available at:

http://archive-ouverte.unige.ch/unige:95540

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Staphylococcus aureus soft tissue infection may increase the risk of subsequent staphylococcal soft tissue infections

Cindy Bouvet

, Shpresa Gjoni

, Besa Zenelaj

, Benjamin A. Lipsky

, Elif Hakko

, Ilker Uçkay

*

aOrthopaedicSurgeryService,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,Switzerland

bDivisionofGeneralMedicalRehabilitation,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,Switzerland

cServiceofInfectiousDiseases,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,Switzerland

dDivisionofMedicalSciences,GreenTempletonCollege,UniversityofOxford,Oxford,UnitedKingdom

eInfectionControlProgram,GenevaUniversityHospitalsandFacultyofMedicine,UniversityofGeneva,Switzerland

fAnadoluSaglıkHospital,Istanbul,Turkey

ARTICLE INFO

Articlehistory:

Received9January2017

Receivedinrevisedform3April2017 Accepted2May2017

CorrespondingEditor:EskildPetersen,Aar- hus,Denmark

Keywords:

Softtissueinfections epidemiology Staphylococcusaureus newepisodes

SUMMARY

Background:Staphylococcusaureusisthemostcommoncauseofsofttissueinfections.Itisunknown, however,ifapatientwhohashadsuchaninfectionisatgreaterriskforfuturesofttissueinfectionswith S.aureus.

Methods:Weconductedanepidemiologicalsurveyofadultpatientshospitalizedintheonlypublic hospitalinGenevafortreatment(usuallycombinedsurgicalandmedical)ofasofttissueinfectioncaused byS.aureus.Byreviewingnursingandmedicalrecordsfromtheemergencydepartmentandhospital wards, we assessed whetheror not they developed any othersoft tissue infections (excluding a recurrence)afterorbeforetheindexone.

Results:Among1023indexepisodesofsofttissueinfections,670(65%)werecausedbyS.aureus,ofwhich 47werecausedbymethicillin-resistantstrains(30healthcare-associatedand17community-acquired).

Thepatients’medianagewas51yearsand334(34%)wereimmune-compromised.Themediantimespan between the patient’s first and last consultation (forany reason)in our hospital was 21.4years (interquartilerange,10-30years).Inadditiontotheirindexinfection,124patients(12%)developedanew nosocomialorcommunity-acquiredsoft tissueinfection. AmongtheindexcaseswithanS.aureus infection,92(14%)hadanothersofttissueinfection,comparedto32(9%)whohadanon-staphylococcal indexinfection(Pearson-x^{2-test;p=0.03).Similarly,patientswithanindexS.aureusinfection,compared} tothosewithanon-S.aureusinfection,hadahigherrateofanothersofttissueinfectioncausedbyS.

aureus(x^2-test;p<0.01). Inmultivariateanalysis,anindexinfectionduetoS.aureusshowsahigh associationtofurtherS.aureussofttissueinfections(logisticregression;oddsratio2.5,95%confidence interval1.4-4.6).

Conclusion:Amongadultpatientshospitalisedforasofttissueinfection,thoseinfectedwithS.aureus (comparedwithotherpathogens)maybeathigherriskofasubsequentsofttissueinfection,particularly withS.aureus.

©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.

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

Introduction

Staphylococcusaureusisthemostcommoncauseofskinand softtissueinfections.CarriageofS.aureusintheanteriornaresor elsewhere,whichisfoundin20%to30%ofallhumans(Sollidetal., 2014; Brown et al., 2014), is an established risk factor for developingasurgicalsiteinfectionwiththisorganism(Bertrand etal.,2010;Uçkayetal.,2013;vanRijenetal.,2012).Thereareno publisheddata onwhetheror not long-termS. aureus carriage increasestheriskofsubsequentinfectionS.aureusotherthanin

$All authors declare no financial support, grants, financial interests or consultancythatcouldlead toconflictsofinterest. Theinformationhasbeen presentedinpartatthe6^thOxfordBoneandJointInfectionConference(OBIC), September 2016, Oxford,United Kingdom,and the SwissAnnual Meetingof InfectiousDiseases,September2016,Montreux,Switzerland.

*Correspondingauthorat:GenevaUniversityHospitalsandFacultyofMedicine 4,rueGabriellePerret-Gentil,1211Geneva14,Switzerland.Tel:+41223729828, Fax:+41223723987.

E-mailaddress:ilker.uckay@hcuge.ch(I.Uçkay).

http://dx.doi.org/10.1016/j.ijid.2017.05.002

1201-9712/©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International Journal of Infectious Diseases

j o u r n a lh o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / i j i d

theperioperativesettingorwiththeunusualentityofrecurrent furunculosis(Sollidetal.,2014;Tzermposetal.,2013).Specifically, itisunknownifapatientwhohasasofttissueinfectioncausedby S.aureus(asopposed toanotherpathogen) isatgreaterriskfor another soft tissue infection (caused by S. aureus or another pathogen) during hisor her lifetime. To address this issue,we conductedasingle-centercohortstudyofallpatientshopitalised for a soft tissue infection on our orthopaedic ward. Our main objectivewas to investigate how manydeveloped another soft tissue infection that requiresinpatient or outpatient treatment during their lifetime. In contrast, we did not investigate the outcome of these soft tissue infections, which we already published(Reberet al.,2012; Perez etal., 2010; Chargui etal., 2014;Mülleretal.,2015;Uçkayetal.,2015).

Methods

Geneva University Hospitals are the only public hospital in GenevaCantonandsomepartsofneighboringFrance.Thecovered area has an estimated population of 600,000 habitants. The prevalenceofcommunity-acquiredmethicillin-resistantS.aureus (MRSA)islowerthan1%inourregion(Longtinetal.,2009).

Datasampling

We performed a retrospective single-center, mixed cohort studyofadultpatientswithhealthcareandcommunity-acquired softtissueinfectionswhoweretreatedwithsurgeryaspartoftheir management. We noted the date, the microbiological results, patients’sexandage,andtheanatomiclocalisationofeachofthese infections.Additionalvariablesweretheoriginoftheseinfections, theantibiotic susceptibilitypatternof theS.aureusisolates,the professionofthepatients,andtheirimmunestatus.Thedatabase stems from the hospital’s clinical pathway for diabetic foot infections,theOrthopedicInfectious Diseasesconsultationsand differentOrthopaedicInfectionCohorts (Uçkay etal., 2009a)as wellasdatabases fromseveral ongoing studies (septicbursitis, three studies regarding diabetic footinfections) or past inves- tigations(softtissue abscesses,phlegmonasofthehand)(Reber etal.,2012;Perezetal.,2010;Charguietal.,2014;Mülleretal., 2015;Uçkay et al.,2015).For roughly40% of thesestudies,we consultedthehospital’scodingoffice,whileapproximately60%of case findings originated fromongoingstudies. Foreach patient withasofttissueinfection,werecordedwhentheywerefirstseen inourhospital(whichhasbeenelectronicallyrecordedsince1990) andtheirlastvisitasof29February2016.Thistimespanduring which thepatient wasfollowed up inourhospital servedas a surrogatefortheindividualobservationperiod.

Studydefinitionsandcriteria

Weonlyenrolledpatientsinthisstudywhohadasofttissue infection,whichwedefinedasthepresenceofintraoperativepus, togetherwithothersymptoms(newonsetoffeverorlocalpain, warmth,rednessordischarge).Inseekingevidenceofsubsequent softtissueinfectionsaftertheindexcase,weexcludedrecurrent infection episodes, recurrent furunculosis (Sollid et al., 2014;

Tzermpos et al., 2013), implant-related infections, and osteo- articular infections (Ferry et al., 2010; Post et al., 2014). A recurrencewasdefinedhastheclinicalre-apparitionofthesame infectionbythesamepathogenatthesameanatomicalplacedue tofailureofinitialtherapy.Subsequentsofttissueinfectionswere newinfections at any body site, any pathogen,at any time or reasonandnotduetofailureofinitialtherapy.Thereasonforthe exclusionofrecurrentepisodeswasavoiding“recurrencebiases”, becauseinourepidemiologicanalysis,microbiologicalrecurrences

duetothesamepathogensbelongedtothesameepisodethatwas nothealed,andwerenotconsideredasnewepisodes,whichisa differentsituation.

We defined a patientas beingchronically immune-compro- misediftheyhadany oneofthefollowingconditions:diabetes mellitus,solidorganorbonemarrowtransplants,untreatedHIV disease,chronic immune-suppressivemedication, activecancer, cirrhosisofCHILDclassC,renaldialysis,orsplenectomy.Transient immunesuppressionsuchaspolytrauma,sepsis,agranulocytosis without hematologic malignancy, limited steroid medication, cancerinremission,denutritionoradvancedagewerenotcounted aschronicimmunesuppression.Ahealthcare-associatedinfection wasdefinedasduetoaninvasivemedicalornursingprocedure within the last 30 days prior to the onset of infection. Auto- injections or traumatic wounds within the hospital were not regardedashealthcare-associated.

Microbiologicalanalyses

We processedallmicrobiologicspecimens accordingto CLSI (Clinical and LaboratoryStandard’s Institute) recommendations (PerformanceStandardsforAntimicrobialSusceptibilityTesting, 2007),beforeswitchingtoEUCASTcriteria(EuropeanCommittee on Antimicrobial Susceptibility Testing) in 2014 (European CommitteeonAntimicrobialSusceptibilityTesting,2014).Inour hospital, we keep only pathogens of bacteremia. Due to the retrospective and composite nature of our database, we lack typisationdatacomparingtheS.aureusbetweensubsequentand index episodes. As a surrogate we assessed differences in the antibioticsusceptibilitytestingofthedifferentS.aureusisolates.

Our laboratory routinelytested allclinicalS. aureusisolates for penicillin, flucloxacillin, cefuroxime, ciprofloxacin, clindamycin, erythromycin, fusidic acid, co-trimoxazole, tetracycline, and rifampicin.

Statisticalanalyses

ForgroupcomparisonsweusedthePearson

x

exacttestortheWilcoxonranksumtest.Anunmatchedlogistic regression analysiswiththeoutcome “subsequent S.aureus soft tissue infection” adjusted for the case-mix. We included 8 to 10 predictor variables per outcome event and checked key variablesforcollinearityandforinteraction(byMantel-Haenszel estimatesandinteractionterms).Weconsideredpvalues0.05as significant,andusedSTATA^TMsoftware(9.0;CollegeStation,Texas, USA).

Results

Wefoundatotalof1023indexepisodesofsofttissueinfection withoutvariationintherateofindexcasesoverthestudyperiod, or detected outbreak situations. The median age of enrolled patientswas51yearsand334(34%) werechronicallyimmune- compromised.Twenty-onepatientswereknownintravenousdrug abusersandnineindicatedtheirprofessionashealthcareworkers in closecontact of somaticpatients. Almostallinfections were associated to abscesses of various diameters (948/1023; 93%), including 401 septic bursitis cases. There were 27 necrotizing fasciitisand48solelyphlegmonousinfectionsrequiringsurgical intervention. Only a minority of episodes (48/1023; 5%) were clearlyhealthcare-associated.

Microbiology

Amongtheindexepisodesofsofttissueinfections,670(65%) werecaused byS.aureus,of which36 weredue tohealthcare-

associatedand18duetocommunity-acquiredMRSA.S.aureuswas thebiggestgroupofpathogens.Streptococcussp.wasthesecond groupintermsofnumbers(n=176,ofwhich59caseswerecaused byS.pyogenes),followedbygram-negativerods(n=175,ofwhich 64episodeswereduetonon-fermentingrods).Pseudomonassp.

accountedfor35cases.Lessfrequentisolatedorganismswereskin commensalssuchascoagulase-negativestaphylococciorcoryne- bacteria (n=89), enterococci (n=31), and obligate anaerobes (n=27). Overall, we witnessed 69 different microbiological findings. Table 1 comparesclinicalvariables in patientswith a softtissueinfectioncausedbyS.aureusversusotherorganisms.

Subsequentsofttissueinfections

The median time span between the patient’s first medical encounter(foranyreason)inourcenterandthelastwas21.4years (interquartilerange,10-30years).Withinthisobservationperiod, 124patients (12%)of those withan index soft tissue infection yielded another nosocomial or community-acquired soft-tissue infection. Among the index cases, those who had an infection caused by S. aureus, 92 (of 670, 14%) had another soft tissue infection, compared to 32 (of 353, 9%) who had a non- staphylococcal pathogen (Pearson-

x

patientswhoseindexinfectionwascausedbyS.aureus,compared toanon-S.aureuspathogen,hadahigherrateofothersofttissue infections due to S. aureus (70/86 vs. 16/86; Pearson-

x

p<0.01). Among all 70 episodes with subsequent S. aureus infections,37(37/70;53%)showednodifferenceintheantibiotic susceptibilitypatternsbetweentheepisodes.Incontrast,subse- quentisolatesswitchedbetweenMRSAandmethicillin-suscepti- bleS.aureus (MSSA)in9 cases.Amongsubsequentepisodesof MSSA,wewitnessedsusceptibilitydifferencesinthreeantibiotics (n=4),intwoantibiotics(n=11),andin1antibiotic(n=10).

Adjustingforcase-mix

Anunmatched logisticregressionanalysiswiththeoutcome parameter“subsequentS.aureussofttissueinfection”adjustedfor thecase-mix.Inthefinalmodel,anindexinfectionduetoS.aureus showedahighassociationtofurtherS.aureussofttissueinfections (oddsratio2.5,95%confidenceinterval1.4-4.6).S.aureuswasnot the only significant parameter. Many known clinical variables associatedwithinfectionsingeneral,suchasimmunesuppression, diabetesmellitus,septicbursitis,andespecially knownintrave- nousdrugabuse,wereprominentassociationswithsubsequent staphylococcalinfection(Table2).Ofnote,thegoodness-of-fitand theReceiver-OperatingCurve(ROC)valueswereinsignificantand

0.81,respectively;highlightingamorethanacceptableaccuracyof ourfinalmodel.

Discussion

In this retrospective, single-center mixed cohort study of 1023adultpatientswithsofttissueinfectionswithoutbone,joint orimplantinvolvement,anothersofttissueinfectionmoreoften occurredinthosewhohadhadasofttissueinfectioncausedbyS.

aureus compared to a non-staphylococcal infection. Prior or subsequentsoft tissueinfections werehighlylikely tobeagain causedbyS.aureus,whichwasequallyconfirmedinmultivariate analysisadjustingforthecase-mix.Eveniftherewerealsoother well-known associations for general infection such as diabetes mellitus (Uçkay et al., 2015) or intravenous drug abuse, our findingssuggestthatcarriageofS.aureusatanybodysitemaynot onlybeariskfactorforsurgicalsiteinfection(Uçkayetal.,2013), butmayalsobeanindependentriskfactorforfuturestaphylococ- calsofttissueinfections.

Previousstudiesofriskofinfectioninpatientswithstaphylo- coccalcolonizationhavemostlyfocusedonimmediatesurgicalsite infections, not long-termrisk. In one study, only a minorityof patients with prior culture-proven S. aureus skin infection remainedcolonizedwiththesame organismaftertreatmentin the convalescent phase, and onlya quarter of their household contactswerecolonizedwiththeindexinfectingstrain(Brown et al., 2014;Miller et al.,2012).Small studies of patientswith infections caused by methicillin-susceptible S. aureus, MRSA

Table1

ClinicalvariablesfoundinpatientswithsofttissueinfectioncausedbyStaphylococcusaureuscomparedtootherpathogens.

S.aureus p Otherpathogens

n=1023 n=670 value^* n=353

Femalesex 171(26%) n.s. 106(30%)

Medianage(95%confidenceintervals) 51years() n.s. 52years()

Septicbursitis 333(50%) 0.01 68(19%)

Healthcare-associatedinfection 34(5%) n.s. 18(6%)

Bacteremia 40(6%) n.s. 14(4%)

Intravenousdrugabuse 14(2%) n.s. 7(2%)

Professionalhealthcareworkers 7(1%) n.s. 2(1%)

Chronicimmunesuppression^a 227(39%) n.s. 117(33%)

–Diabetesmellitus 142(22%) n.s. 69(20%)

Anothersofttissueinfection^b 92(14%) 0.03 32(9%)

n.s.=notsignificant(p>0.05).

*Onlystatisticallysignificantpvalues,i.e.,0.05(two-tailed),aredisplayed.

aRenaldialysis,cirrhosisChildclassC,diabetesmellitus,activemalignancy,splenectomy.

b Afterandbeforetheindexcase,atanybodysite.

Table2

Univariateandmultivariatelogisticregressionanalysisassessingepidemiologic associationsofaninitialindexcaseofS.aureussofttissueinfectionwithsubsequent softtissueinfectionsduetoS.aureus.

n=1023 Univariateanalysis Multivariateanalysis

Femalesex 1.1,0.7-1.7 n.d.

Age(continuousvariable) 1.0,1.0-1.0 n.d

Septicbursitis 0.2,0.1-0.3 n.d.

Immunesuppression^a 5.2,3.4-7.2 n.d.

–diabetesmellitus 6.8,4.2-10.8 7.2,4.4-11.8 Polymicrobialinfection 1.6,1.1-2.5 1.2,0.7-2.2 PriorS.aureusinfection 1.6,1.1-2.4 2.5,1.4-4.6 –priorMRSAinfection 4.1,2.2-7.4 n.d.

–priorCA-MRSAinfection 1.5,0.4-5.1 1.3,0.3-6.5 Healthcare-associatedinfections 8.9,5.0-16.0 5.5,2.6-11.5 Knownintravenousdrugabuse 16.2,6.4-41.0 7.2,2.3-22.3 Resultsexpressedasoddsratioswith95%confidenceintervals.

Significantresultsaredisplayedinboldanditalic.n.d.=notdone.

MRSA=methicillin-resistantS.aureus;CA-MRSA=Community-acquiredMRSA.

a Renaldialysis,cirrhosisChildclassC,diabetesmellitus,activemalignancy, splenectomy.

(Zenelajetal.,2014)orstreptococci(Lebowitzetal.,2015)failedto showadifferenceinremissionincidencesonthelongterm.The durationofclinicalfollow-upinmostpublicationsregardingsoft tissueormusculoskeletalinfectionshasbeennomorethan2years, exceptinsomestudiesofarthroplastyinfections.Thus, ourtwo decadesoffollow-upprovideanunusualviewofthelong-term outcomeofsofttissueinfections.

S.aureusisthemostfrequentlyisolatedpathogeninskin,soft tissueandmusculoskeletalinfections.Skinandmucosalcarriageof S.aureus,whichisfoundin20-30%ofpeople(Sollidetal.,2014;

Brown et al., 2014), increases therisk of such infections. Skin carriagestillmaypersistin15%ofpatientsdespitetreatmentbased on sophisticated algorithms (Tzermpos et al., 2013) using decolonisationprotocols(Longtinetal.,2009).Interestingly,this S.aureuscarriageisnotnecessarilymonoclonal,asdifferentstrains cancoexist(Zürcher-Pfundetal.,2013;Betzetal.,2015;Landelle et al., 2014) and can also be found with coagulase-negative staphylococci.Wedonotyetknowhowtopredictwhichofthese colonizingorganismsmaycausefutureinfection.Forexample,in cases of trauma or surgery, evidence of healthcare-associated MRSAcarriagedoesnotpredictthelikelihoodornatureoffuture skin and soft tissue (Chargui et al., 2014) or implant-related infections(Uçkayetal.,2009b).Itisnoteworthythatinfectionsat varioussites,suchasarthroplasties,aremoredifficulttoeradicate whentheyarecausedbyS.aureuscomparedeventoothervirulent gram-positive pathogens, such as streptococci (Zürcher-Pfund etal.,2013;Betzetal.,2015).

Thereare severalpossible explanations for thetenacityofS.

aureusasa colonizer andpathogen, evenin absenceof foreign material(Brownetal.,2014;Ferryetal.,2010).Mechanismsthat helptheorganismevadethehost’sacquiredandinnatedefenses such as antimicrobial peptides (Sollid et al., 2014; Otto, 2010) certainlyplayarole.Microbiotaconsiderations(Brownetal.,2014), includinggeneproductsthatprotectagainstreactiveoxygenand desiccation(Sollidetal.,2014),areemergingasanother explanation for long-term carriage. S. aureus’ arsenal of defenses against eliminationincludesmodificationofclumpingfactors,cathelicidin, defensins,carbohydratemodifications,mannose-binding lectins, andotherproducts(Sollidetal.,2014).TransientorpersistentS.

aureus colonization induces specific host immune responses.

Humoralresponseshavebeenthemoststudied,andlittleisknown ofcellularresponses(Brownetal.,2014;Otto,2010).However,even if human antibody response to S. aureus bacteraemia differs betweenknownchroniccarriersandnon-carriers,theseantibodies donotappeartobeabletopreventfutureinfections(Kolataetal., 2011). Despite years of effort, an effective vaccine against staphylococcalinfectionsremainselusive(Brownetal.,2014).

Ourstudyhasseverallimitations,themostimportantofwhich arethatitisaretrospectivesingle-centerstudy,primarilytargeting patientshospitalisedforcombinedsurgicalandmedicaltherapyof a soft tissue infection,which limits the generalizabilityof our findings.Forexample,wemaynothavehadaccesstorecordsof patientsundergoingoutpatienttreatmentofasmallskinabscess by their general practitioner or those using private insurance.

Furthermore,in this studywe excluded implant-related, osteo- articular infections and recurrent infections, which may be associated with various concomitant soft tissue extension. We mayalsohavemissedpatientswhoweretreatedelsewhereduring theirlifetime, especially for those only staying a few years in Geneva.However,becauseourcenterhasbeenthelargestinthe areaandtheonlypublichospitalfordecades,wethinkthisislikely tobeonlyasmallbias.Wealsolackedinformationonthespecific typeofourpathogenicstrains,theirgenotypictypisationandcould notinvestigatespecificskindiseasesknowntobeassociatedwith staphylococcalinfections, e.g.,atopicdermatitis,psoriasis.Addi- tionally,wehavenodataonthedurationofindividualS.aureus

colonisationinthestudygroup.Ascreeningforthepresenceof methicillin-susceptible strains is usually performedonly in the context of a prospective scientific study(Landelle et al.,2014).

Finally,inourstudy,thecompositedatabasestemsfromdifferent pastandpresentretrospectiveand/orprospectivestudies(Reber etal.,2012;Perezetal.,2010;Charguietal.,2014;Mülleretal., 2015;Uçkayetal.,2015).Thesearchingstrategyforcaseswasthus differentamongtheindividualstudies.Ontheotherhand,wealso askedthehospital’scodingofficeand/orkeptprospectivecohorts for everyone of these studies.Moreover, ourstudyprincipally concerns operated casesthat are easy tobeidentifiedand our OrthopaedicServiceemploysInfectiousDiseasesphysicianswho noteeveryimportantconsultation.Therefore,wethinkthatour casefindingstrategywasadequate.

In conclusion, adult patients previously hospitalized and operated for a moderate to severesoft tissue infectioncaused byS.aureus,comparedtonon-staphylococcalinfections,maybeat higherriskofafuturesofttissueinfection,particularlyonewithS.

aureus. In centers or services where there is no program for screening and decolonisation of S. aureus body carriage before elective orthopaedic surgery (Uçkay et al., 2013), it may be appropriatefor patientswitha historyof aprevious softtissue infectiontoundergoscreeningforS.aureus,evenifa priora S.

aureusinfectionisnottheonlyvariableassociatedwiththeriskof subsequentinfections.

Ethicsstatement

Thisstudyisinlinewithseveralongoingstudiesapprovedby localethicsCommittee.

Conflictofinterest

Therewasnofundingforthepreparationofthismanuscript.

BALhasservedasaconsultanttoKCI/Acelity,Innocoll,Dipexium.

IU has received research funding from Innocoll. However, the contentofthispaperhasnorelationwiththeconsultancyofanyof theauthors.

Funding

Therewasnofundingforthisreview.

Acknowledgements

WethanktheteamsoftheLaboratoryofBacteriologyandthe OrthopaedicServicefortheirsupport.

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