Article
Reference
Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term
remission for 6 weeks as compared to 12 weeks
CHAUSSADE, Hélène, et al .
Abstract
The required duration of antibiotic treatment for prosthetic joint infections (PJI) with debridement and retention of the implant (DAIR procedure) is unknown.
CHAUSSADE, Hélène, et al . Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term remission for 6 weeks as
compared to 12 weeks. International Journal of Infectious Diseases , 2017, vol. 63, p. 37-42
DOI : 10.1016/j.ijid.2017.08.002 PMID : 28804007
Available at:
http://archive-ouverte.unige.ch/unige:99055
Disclaimer: layout of this document may differ from the published version.
1 / 1
Antibiotic therapy duration for prosthetic joint infections treated by Debridement and Implant Retention (DAIR): Similar long-term
remission for 6 weeks as compared to 12 weeks
Hélène Chaussade
a, Ilker Uçkay
b,*, Albert Vuagnat
c, Jérôme Druon
a, Guillaume Gras
a, Philippe Rosset
a, Benjamin A. Lipsky
b,d, Louis Bernard
a,baToursUniversityHospital,France
bGenevaUniversityHospitals,Switzerland
cStatisticalDepartment,Paris,France
dUniversityofOxford,UnitedKingdom
ARTICLE INFO Articlehistory:
Received6June2017
Receivedinrevisedform31July2017 Accepted3August2017
CorrespondingEditor:EskildPetersen,Aar- hus,Denmark
Keywords:
Prostheticjointinfections Debridementandretention Antibioticduration Rifampin
ABSTRACT
Background: Therequiredduration ofantibiotic treatmentforprosthetic jointinfections(PJI) with debridementandretentionoftheimplant(DAIRprocedure)isunknown.
Methods:Multicenterretrospectivestudyemphasizingtheduration ofantibiotictherapyinpatients treatedwithbyDAIR.
Results:Weincluded87hiporkneePJIepisodesin87patientsfromthreeuniversityhospitalsinFrance andSwitzerland.Alldebridementswereperformedwithin3weeksofsymptomonset.Afteramean follow-upof52.1months,60patientswithPJI(69%)remainedinremission,withnosignificantdifference betweenhipand kneecases (73.3%vs.59.3%,95%confidenceinterval(CI), 0.20–1.38),orbetween patientsreceiving6comparedwith12weeksofantibiotictreatment(70.5%vs.67.4%,95%CI0.27–2.10, p=0.60).Methicillin-resistantStaphylococcusaureuswasisolatedfrom13.8%ofinfectionsandthiswas theonlyvariableassociatedwithapooreroutcome(remissionin41.7%vs.73.3%forthosewithother pathogens,95%CI0.05–0.77,p=0.02).
Conclusions:InpatientsundergoingDAIRforhiporkneePJI,thelikelihoodoflong-termremissionwas not significantlydifferentforthose receiving6 versus 12 weeksof antibiotictherapy. Prospective randomizedtrialsarerequiredtoconfirmthisobservation.
©2017TheAuthor(s).PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.
ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by- nc-nd/4.0/).
Introduction
PJIs areassociated with considerablemorbidity.Their treat- ment is challenging and costly (Zimmerli et al., 2004). PJI management requires both surgery and antimicrobial therapy.
Thesurgicaloptionsclassicallyincludeone-ortwo-stageimplant exchange,resectionarthroplasty(withorwithoutarthrodesis)or DAIR.IDSAguidelinesrecommendedDAIRonlyforPJIwithawell- fixedprosthesis;absenceofasinustract;occurringwithin30days
of implantation or less than three weeks of symptoms; or for elderly patients for whom alternative surgical strategies are unacceptable or very risky (Osmon et al., 2013). Patients undergoing DAIR witness long periods of antibiotictreatment, e.g.threetosixmonthsforstaphylococcalinfections(Osmonetal., 2013;Zimmerlietal.,1998).
However, personal experience in several French tertiary hospitalsandGenevasuggeststhatshortercoursesofantibiotic therapymaybeappropriateformostPJIorosteomyelitis(Bernard etal.,2010,2015;Farhadetal.,2010)andassociatedwithareduced incidence of adverse events and emergence of microbiological resistance(Bernardetal.,2015;Meropoletal.,2008).Wetherefore undertookathree-center,bi-nationalstudyevaluatingifashorter durationofantibiotictreatmentinDAIR(6weeks)isaseffectiveas alongercourse(3months).
Abbreviations:PJI,prostheticjointinfection;DAIR,debridementandimplant retention; MRSA, methicillin-resistant Staphylococcus aureus; IDSA, Infectious DiseasesSocietyofAmerica;95%CI,95%confidenceinterval.
* Correspondingauthorat:GenevaUniversityHospitals,4,RueGabriellePerret- Gentil.1211Geneva14,Switzerland.Tel.:+41223723723311;fax.:+41223729803.
E-mailaddress:[email protected](I.Uçkay).
http://dx.doi.org/10.1016/j.ijid.2017.08.002
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 l h o m ep a g e : w w w . e l s e v i e r . c o m / l o c a te / i j i d
Methods
Weperformedaretrospective,multicenterstudyofPJIpatients hospitalizedinFranceorSwitzerland(involvingtheorthopaedic unitsofToursandGenevaandtheinfectiousdiseasesdivisionof Garches University Hospital) between 1989 and 2011. Geneva keeps an ongoing prospective cohort of total hip and knee arthroplasties since 1996 (one Number of Ethical Commission 05-041 (NAC 05-017)). Regarding the aforementioned French centers,wereviewedallPJIcodes.Allinvestigationsinvolvedour ownpatientsandwerepartofanongoingqualityassessment.
Settinganddefinitions
WedefinedPJI asthepresenceofintraarticularpus together withatleastonepositivemicrobiologicalcultureofintraoperative tissue sampling. For the main analysis, we included only PJIs treatedbyDAIR(whichincludestheremovalofany hematoma, fibrousmembrane,sinustract,inlayanddevitalizedboneandsoft tissue)occurringwithin3weeksafterthefirstclinicalsymptoms, andonlyifthepatientcompletedsystemicpostsurgicalantibiotic treatmentofeither exactly 6or exactly12 weeks. In a second analysiswewereinterestedifthedurationofantibioticprescrip- tionwasspecifictotheDAIRprocedure,i.e.iftheremissionrates were different with and without DAIR. For all analyses, we excludedfungal and mycobacterial infections and casestreated withotherdurations ofantibiotic therapy. PJI was classifiedas early (infection within three months of arthroplasty), delayed
(3–12monthsafterarthroplasty)orlate (morethan 12months afterarthroplasty)(Osmonetal.,2013).Remissionwasdefinedas:
1)theabsenceofclinical,imagingandbiological(i.e.,inflamma- torymarkers)signsofinfectionafteraminimumfollow-upperiod of 12 months after surgery; and, 2) no need for continuing antibiotictherapy,e.g.forsuppressivetreatment.Thedurationof antibiotictherapywasatthediscretionofthetreatingsurgeonor physician.However,thechoiceoftheantibioticagents mustbe appropriateaccordingtonationwideSwissorFrenchrecommen- dations.
Statisticalanalyses
GroupcomparisonswereperformedwiththePearson-
x
2-test.Auni-andmultivariatelogisticregressionanalysisinvestigatedthe association of various variables with the outcome parameter
“remissionat1yearafterDAIR”.Survivalcurveswerecomputed withthe logrank-test and plotted asKaplan-Meier curves. In a secondstep,weperformedanexploratoryanalysisbyincludingall caseswhichwereexcludedbecause‘surgicaltreatmentwasnota DAIR’and‘DAIRmorethan3weeksaftersymptoms’.Weusedthe SAS9.2statisticalprogramandconsideredpvalues0.05(two- tailed)assignificant.
Results
Weidentified384PJIepisodes.Amongthem,88wereineligible forthefollowingreasons:28werelosttofollow-up;23didnot
Figure1.Flowchartdisplayingtheinclusionandexclusioncriteriaofourstudy.
38 H.Chaussadeetal./InternationalJournalofInfectiousDiseases63(2017)37–42
finishtheantibioticcourse;9diedduringtreatment(sixrelatedto thePJI);and28weretreatedwithantibioticsforfewerthan6or greaterthan12weeksforvariousreasons.Forthemainanalysis, weexcludedafurther178PJIcasesbecausethesurgicalprotocol wasnotconsistentwithaDAIRprocedureand31patientsbecause surgery was performed more than 3 weeks after the onset of symptoms (Figure 1). For the explanatory analysis of all PJI (independently of DAIR and the delay of symptoms), we incorporatedthemintothefinalmodelsumming296PJI.
Table1 shows characteristicsof the87 PJIsin 87 individual patientsin theDAIR analysis. Their median agewas 71 years;
42episodes(48.3%)occurredinwomen.Therewere60totalhip arthroplasties (16 cemented) and 27 total knee arthroplasties (8 cemented). On admission, 44 PJI patients(50.6%) had fever 38C,and51(58.6%)witnessedpainintheaffectedjoint.Median serumC-reactiveproteinconcentrationonadmissionwas120mg/l (range,8–569mg/l)andthemedianserumleukocyte countwas 7715/mm3(range,1240–65300/mm3).Weclassified60(69.0%)PJI as early, 7 (8.1%) as delayed and 20 (23.0%) as late PJI. Most infectionsweremonomicrobial(n=72,82.8%).Thepredominant pathogens were methicillin- susceptible Staphylococcus aureus (n=34, 39.1%), coagulase-negative staphylococci (25, 28.7%), Streptococcussp.(12,13.8%),andMRSA(12,13.8%).
Treatment
DAIR was performed at a median of 6days after the first symptoms.After surgicaldebridement and exchange of mobile parts of the prosthesis, the targeted systemic antibiotic was administeredforexactly6weeksin44episodes(50.6%)andfor exactly12weeksin43episodes(49.4%).Overall,durationsdidnot significantlydifferamongthethreecenters.Rifampinwasthemost frequently prescribed agent (69% and always in combination therapy),followed bya fluoroquinolone (62.1%), a glycopeptide
(21.8%), amoxicillin (11.6%) and trimethoprim-sulfamethoxazole (5.8%). Combination treatments were administered in 78.2% of cases.Forinfectionscausedbystaphylococci,rifampincombina- tiontherapywasprescribedin80%ofcases,and wascombined withafluoroquinolonein75%ofcases.AntibiotictherapyforPJI was administered intravenously in 31 cases (35.6%) and by a combinationofinitialintravenousfollowedbyoraltherapyin55 (63.2%)cases.Inonecase,oraltreatmentwasprescribedfromthe start. In patients receiving therapy by both routes, the mean durationofinitialparenteraltherapywas10daysforthe6-week group (range,2–45 d)and 13days for the12-weekgroup. The mediannumberofsurgicaldebridementswas1inbothgroups.
Outcome
Overall,60PJI(69%)remainedinfinalremissionafterminimal andmedianfollow-upsof14and52months:70.5%inthe6week treatmentgroup,and67.4%inthe12weektreatmentgroup.The Kaplan–Meier curves (time-to-treatment-failure) paralleled re- garding remissionwhen plotted against theantibiotic duration (Figure2).Similarly,wefoundnodifferencesbetweenthe6-and the 12-week groups when performing uni- and multivariate analyses(adjustedoddsratio(OR)0.76,95%CI0.27–2.10)(Table2).
Incontrast,PJIduetoMRSA,ascomparedtootherpathogens, was the only variable significantly associated with reduced remission (adjusted OR 0.20,95% CI 0.05-0.77), while age, sex, the duration of sepsis, the duration of intravenous antibiotic treatment,antibioticmonotherapy,ordelaybetweenarthroplasty implantation and infection didnotinfluence outcome. Ofnote, rifampin, or its combination with a fluoroquinolone, was not associatedwithremission(OR0.91,95%CI0.34–2.44forrifampin withanyotherantibiotic;andOR2.22;95%CI0.87–5.65forthe rifampin/fluoroquinolonecombination).
AdditionalexploratoryanalysiswithallPJIcases
WerealizedanexploratoryanalysisofallPJIcasestreatedfor 6or12weeks,independentlyofthesurgicalapproach,DAIRorthe delaybetweensymptomsandfirstsurgery.Atotalof296PJIwere included.Afterameanposttreatmentfollow-upof 59months, 226PJI (76.4%)wereinremission. Surgicaltreatmentsincluded debridementandretention(DAIR)oftheprosthesis(39.9%),one- (6.7%) or two-stage (32.1%) exchange or resection arthroplasty (21.3%).RemissiondidnotdifferregardinghiporkneePJI(79%vs.
72%, p=0.24), proportion of patients with more than two co- morbidities(77%vs.77%,p=0.95)ortotalantibioticduration.The same remission rate was obtained with 6 weeks of antibiotic treatmentaswith12weeks(78%vs.74%,P=0.76).Remissionrates stratified upon thesurgicaltreatment were85.3% in two-stage exchange, 84.1% inresectionarthroplasty,70%inone-stage and 66.1%inDAIR.
Discussion
Weconsideredeligible87DAIRproceduresforhiporkneePJI and included them in the analyses. Minimum follow up was 14 months. The primary outcome measure was remission of infection (without suppressive antimicrobial therapy) for 12 months following surgery. Overall, remission rate was 69%
andtherewasnosignificantdifferencebetween6and12weeksof antimicrobialtherapy,independentlyofrifampincombinationfor staphylococcalPJI,ordurationoftheinitialparenteralantibiotic administration,theDAIRprocedureorthedelayofsymptomsprior to first surgery for infection. The overall DAIR successin both durationgroupswas roughly70%,a percentagewhichislargely reproducedintheDAIRliterature,whichindicatessuccessrates Table1
Demographicandclinicalcomparisonsoflong-termremissionratesof87patients withaprosthesisjointinfectiontreatedbydebridementandimplantretention (DAIR),stratifieduponthedurationofantibiotictreatment.
Variables Sixweeks
n=44(%)
Twelveweeks n=43(%)
Comparison P-value
Femalesex 20(45.45) 22(51.16) .59
Medianage(years) 71 71 .96
Joints
Hiparthroplasty 31(70.45) 29(67.44) .76 Kneearthroplasty 23(29.55) 14(32.56) .76 Center
Garches 2(4.55) 4(9.30) .67
Geneva 10(22.73) 10(23.26) .67
Tours 32(72.73) 29(67.44) .67
Indicationforarthroplasty
Arthritisorfracture 34(82.93) 38(92.68) .18 Infectiononset
Early(<3months 26(59.09) 34(79.07) .045 Delayed(3–12months) 3(6.82) 4(9.30) .045 Late(>12months) 15(34.09) 5(11.63) .045 Causativepathogens
MRSA 5(11.36) 7(16.28) .51
CoNS 13(29.55) 12(27.91) .87
Antibiotictreatment
Combinationtreatment 32(72.73) 36(83.72) .21 Rifampin+other 30(68.18) 30(69.77) .87 Fluoroquinolones+other 26(59.09) 28(65.12) .56 Flurooquinolone+Rifampin 22(50.00) 22(51.16) .91 Exclusivelyintravenoustherapy 17(38.64) 14(32.56) .55
Death 11(25.00) 13(30.23) .59
CoNS:coagulase-negativestaphylococci;MRSA:methicillin-resistantStaphylococ- cusaureus.
around70%(Byrenetal.,2009;Martínez-Pastoretal.,2009;Kuiper etal.,2013),albeitwithmuchlongerantibiotictherapies.
DAIR is different from what is often called “suppressive therapy,” i.e., the planned life-long treatment for very elderly andbedriddenpatients.RemissionwithDAIRiscommon,despite thefactthatthejointimplantisleftinplace.WithDAIR,afterthe initialsurgicaldebridement(s)andexchangeofallmobileparts, the therapeutic activity relies on the antibiotic treatment (Zimmerlietal.,2004;Osmonetal.,2013).However,theoptimal durationofthistreatmentremainsunclear.Recommendationsare only based on expert opinion, which usually suggests that staphylococcalinfections shouldbetreatedforthree monthsin casesofhipPJIandsixmonthsincasesofkneePJI,whereasnon- staphylococcalinfectionsshouldbetreatedforatleastsixweeks (Zimmerli et al., 2004; Osmon et al., 2013). For non-implant- related orthopaedic infections, six weeks seems to be largely sufficient. We have previously demonstrated that 6 weeks of antibiotictreatmentisnotinferiorto12weeksforpatientswith vertebral osteomyelitis and spodylodiscitis, including S. aureus (Bernardetal.,2015).Similarly,anotherstudyrevealedthatthere wasnosignificantdifferenceinremissionratesfornon-amputated diabeticfootosteomyelitistreatedfor6weeksversus12weeks (Tone et al., 2015). Moreover, non-randomized studies of PJI patients failed to reveal differences in treatment outcomes betweenthose receiving antibiotics for six weeks compared to longerperiods(Bernardetal.,2010;Farhadetal.,2010)orbetween episodestreated for three months compared to longerperiods (Puhtoetal.,2012;Vilchezetal.,2011).Likewise,a prospective observationalnon-randomizedstudyon144PJIcasesbyBernard etal.foundsimilarremissionrates(80%)for6and12weeksof therapy,regardlessofthetypeofsurgicaltreatment(Bernardetal., 2010).Inthepresentstudy,weconfirmtheseassociations.
Frenchrecommendationssuggestthatthedurationofantibiotic therapyforPJIcouldbereducedtosixweeks(Recommendations forClinical Practice, 2009; Aboltinsetal., 2014).Certain highly bioavailableoral antibiotics,suchasfluoroquinolones,rifampin, linezolid,andco-trimoxazole,reachlevelsinbonethatexceedthe minimal inhibitory concentrations (MICs) for most organisms (SpellbergandLipsky,2012).Thereareseveral linesofevidence suggestingthatanearlyswitchtooralantibioticsisaseffectiveas
prolongedparenteralregimensforpatientswithPJI(Sorianoetal., 2006;Berdalet al., 2005), S.aureus osteomyelitis (Daver et al., 2007), and vertebralosteomyelitis (Bernardet al.,2015).In our study,theuseof intravenousantibioticsdidnotachievehigher remissionthanoralmedicationorearlyswitchtooralmedication.
As oral therapy is less complicated and less expensive than intravenous,makinganearlyswitchisbeneficialtobothpatients andthehealthcaresystem.
Manyretrospectivestudiessuggestthatrifampincombinations mayincreaseremissionratesforstaphylococcalPJI(Aboltinsetal., 2014;Berdaletal.,2005;Drancourtetal.,1993;Sennevilleetal., 2011;Lora-Tamayoetal.,2013;Wielandetal.,2012;SanJuanetal., 2010), but its benefit in the DAIR procedure has not yet been formallyelucidated.Inourpatients,theinclusionofrifampininthe antibiotic regimen for the subset of patients with S. aureus infectionappearedtoconfernostatisticallysignificantadvantage althoughthenumbersanalysedweresmall.Asrifampinmayhave adverseeffectsandisknowntointeractwithmanyotherdrugs,it is important to determine whether or not it has a role in combination therapy for pure staphylococcal PJIs treated with DAIR.Forexample,inanotherpreviouslypublishedexperienceat the Geneva site, 393 patients with osteoarticular infections receivedantibiotictreatmentforamedianof8weeks,including 2weeksintravenously.Amongthem,115(29%)reportedvarious adverseevents(e.g.,diarrhea,nausea,cholestasis,gastricdistress, rash, and mycosis), of which most were due to rifampin. By multivariate Cox regression analysis, the total duration of antibiotic therapy and duration of intravenous administration were significantly associated with adverse events (all p<0.01) (Schindler et al., 2013). Finally, poorer outcomes have been reportedforPJIscausedbyMRSAthanwithotherpathogens(Peel etal.,2013;Salgadoetal.,2007).Wealsoconfirmthisassociation which is widely believed in the literature, although a large retrospectivestudyof345casesofPJIduetoMRSA(n=81)orMSSA (n=264)treatedbyDAIRreportedsimilartreatmentfailurerates forthesetwopathogens(Lora-Tamayoetal.,2013).
In conclusion, withrising concerns about adverse effects of prolonged treatmentintheelderlypopulation(Schindleret al., 2013),itisimportanttodefinetheoptimaldurationofantibiotic treatmentfor PJIsthataretreatedwithDAIR.Weconcludethat Figure2. KaplanMeierremissioncurveforpatientstreatedfor6or12weekswithantibiotics(withtreatmentfailuresasevents).Line:6weeks.Dottedline:12weeks.
40 H.Chaussadeetal./InternationalJournalofInfectiousDiseases63(2017)37–42
extendingthetreatmentdurationfollowingDAIRforhiporknee PJImayoffernoclinicaladvantagebutislikelytobeassociated withan increasedrisk of adverse events. Prospective trialsare welcome to confirm these findings, to determine the optimal durationofantibiotictherapyandtodefinetheplaceofrifampinin theDAIRprocedure.
Conflictofinterest
Therewasnofundingforthepreparationofthismanuscript.
BALhasservedasaconsultanttoKCI/Acelity,Innocoll,Dipexium.
IU has received research funding from Innocoll. However, the contentofthispaperhasnorelationwithanyconsultancy.
Ethicsstatement
NumberoflocalEthicalCommissionforarthroplastycohort05- 041.
Authorcontribution
All authorscontributed tothewriting and reviewing of the manuscript.
Acknowledgements
WeareindebtedtoAliceRivièreforherinvaluablehelpfordata collection.Wethank theteamsof theorthopaedicservicesand microbiologylaboratories.
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Table2
Oddsratios(OR)and95%confidenceintervals(CI)ofprostheticjointinfectionstreatedwithdebridementandimplantretention(DAIR).
Remission (%)
UnadjustedOR(95%CI) P-value AdjustedOR
(95%CI)
P-value Sex
Female 28(66.67) 1
Male 32(71.11) 1.23(.50–3.06) .65
Age(years)
<64 17(77.27) 1
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>78 14(66.67) .59(.15–2.27) .44
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Obesity
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Yes 15(75.00) 1.47(.47–4.55) .51
Immune-suppression
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Joint
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Microbiology:CoNSa
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