Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections

130 Pages·2017·1.35 MB·English

CochraneDatabaseofSystematicReviews
Procalcitonin to initiate or discontinue antibiotics in acute
respiratory tract infections (Review)
SchuetzP,WirzY,SagerR,Christ-CrainM,StolzD,TammM,BouadmaL,LuytCE,WolffM,
ChastreJ,TubachF,KristoffersenKB,BurkhardtO,WelteT,SchroederS,NobreV,WeiL,Bucher
HC,BhatnagarN,AnnaneD,ReinhartK,BrancheA,DamasP,NijstenM,deLangeDW,Deliberato
RO,LimaSSS,Maravi
-Stojkovi
V,VerduriA,CaoB,ShehabiY,BeishuizenA,JensenJUS,CortiC,VanOersJA,FalseyAR,de
JongE,OliveiraCF,BegheB,BrielM,MuellerB
SchuetzP,WirzY,SagerR,Christ-CrainM,StolzD,TammM,BouadmaL,LuytCE,WolffM,ChastreJ,TubachF,KristoffersenKB,BurkhardtO,
WelteT,SchroederS,NobreV,WeiL,BucherHC,BhatnagarN,AnnaneD,ReinhartK,BrancheA,DamasP,NijstenM,deLangeDW,Deliberato
RO,LimaSSS,Maravi -Stojkovi V,VerduriA,CaoB,ShehabiY,BeishuizenA,JensenJUS,CortiC,VanOersJA,FalseyAR,deJongE,Oliveira
CF,BegheB,BrielM,MuellerB.
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections.
CochraneDatabaseofSystematicReviews2017,Issue10.Art.No.:CD007498.
DOI:10.1002/14651858.CD007498.pub3.
www.cochranelibrary.com
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review)
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 5
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Analysis1.1.Comparison 1Procalcitoninalgorithmversusnoprocalcitoninalgorithmstratifiedbyclinicalsetting,
Outcome1Mortalityat30days. . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Analysis1.2.Comparison 1Procalcitoninalgorithmversusnoprocalcitoninalgorithmstratifiedbyclinicalsetting,
Outcome2Treatmentfailureat30days. . . . . . . . . . . . . . . . . . . . . . . . . 91
Analysis2.1.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome1
Mortalityat30daysstratifiedbyadherence. . . . . . . . . . . . . . . . . . . . . . . . 93
Analysis2.2.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome2
Treatmentfailureat30daysstratifiedbyadherence. . . . . . . . . . . . . . . . . . . . . . 95
Analysis2.3.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome3
Mortalityat30daysstratifiedbyallocationconcealment. . . . . . . . . . . . . . . . . . . . 97
Analysis2.4.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome4
Treatmentfailureat30daysstratifiedbyallocationconcealment. . . . . . . . . . . . . . . . . 99
Analysis2.5.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome5
Mortalityat30daysstratifiedbyblindedoutcomeassessment. . . . . . . . . . . . . . . . . . 101
Analysis2.6.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome6
Treatmentfailureat30daysstratifiedbyblindedoutcomeassessment. . . . . . . . . . . . . . . 103
Analysis2.7.Comparison2Procalcitoninalgorithmversusnoprocalcitoninalgorithm,sensitivityanalyses,Outcome7
Mortalityat30daysstratifiedbyfollowup. . . . . . . . . . . . . . . . . . . . . . . . 105
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
FEEDBACK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
WHAT’SNEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 128
INDEXTERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) i
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Procalcitonin to initiate or discontinue antibiotics in acute
respiratory tract infections
PhilippSchuetz1,2,3,YannickWirz1,RamonSager1,MirjamChrist-Crain4,DaianaStolz5,MichaelTamm5,LilaBouadma6,Charles
ELuyt7,MichelWolff8,JeanChastre9,FlorenceTubach10,KristinaBKristoffersen11,OlafBurkhardt12,TobiasWelte12,13,Stefan
Schroeder14,VandackNobre15,LongWei16,HeinerCBucher17,18,NeeraBhatnagar19,DjillaliAnnane20,KonradReinhart21,Angela
Branche22,PierreDamas23,MaartenNijsten24,DylanWdeLange25,RodrigoODeliberato26,StellaSSLima27,VeraMaravi -Stojkovi
28,AlessiaVerduri29,BinCao30,YahyaShehabi31,32,AlbertusBeishuizen33,Jens-UlrikSJensen34,35,CasparCorti35,JosAVanOers
36,AnnRFalsey22,EveliendeJong37,CarolinaFOliveira38,BiancaBeghe39,MatthiasBriel3,18,BeatMueller1,2,3
1MedicalUniversityDepartment,KantonsspitalAarau,Aarau,Switzerland.2DepartmentofEndocrinology/Metabolism/ClinicalNu-
trition,DepartmentofInternalMedicine,KantonsspitalAarau,Aarau,Switzerland.3MedicalFaculty,UniversityofBasel,Basel,Switzer-
land.4ClinicforEndocrinology,DiabetesandMetabolism,DepartmentofClinicalResearch,UniversityHospitalBasel,Universityof
Basel,Basel,Switzerland.5ClinicofPneumologyandPulmonaryCellResearch,UniversityHospitalBasel,Basel,Switzerland.6Service
deRéanimationMédicale,HôpitalBichat-ClaudeBernard,UniversitéParis7-Denis-Diderot,Paris,France.7ServicedeRéanimation
Médicale,GroupeHospitalierPitié-Salpêtrière,AssistancePublique-HôpitauxdeParis,UniversitéParis6-Pierre-et-Marie-Curie,Paris,
France.8ServicedeRéanimationMédicale,UniversitéParis7-Denis-Diderot,Paris,France.9ServicedeRéanimationMédicale,Uni-
versitéParis6-Pierre-et-Marie-Curie,Paris,France.10DépartementBiostatistique, SantéPubliqueetInformationMédicale,AP-HP,
GroupeHospitalierPitié-SalpêtrièreCharles-Foix,INSERMCIC-P1421,SorbonneUniversités,UPMCUnivParis06,Paris,France.
11DepartmentofInfectiousDiseases,AarhusUniversityHospital,AarhusN,Denmark.12DepartmentofPulmonaryMedicine,Medi-
zinischeHochschuleHannover,Hannover,Germany.13GermanCenterforLungReearch(DZL),Gießen,Germany.14Departmentof
AnesthesiologyandIntensiveCareMedicine,KrankenhausDueren,Dueren,Germany.15DepartmentofInternalMedicine,Schoolof
Medicine,UniversidadeFederaldeMinasGerais,MinasGerais,Brazil.16DepartmentofInternalandGeriatricMedicine,ShanghaiJiao
TongUniversityAffiliatedSixthPeople’sHospital(Eastcampus),Shanghai,China.17MedicalFaculty,UniversityHospitalBasel,Basel,
Switzerland.18BaselInstituteforClinicalEpidemiologyandBiostatistics,DepartmentofClinicalResearch,UniversityHospitalBasel
andUniversityofBasel,Basel,Switzerland.19DepartmentofClinicalEpidemiologyandBiostatistics,McMasterUniversity,Hamilton,
Canada.20DepartmentofCriticalCare,HyperbaricMedicineandHomeRespiratoryUnit,CenterforNeuromuscularDiseases;Ray-
mondPoincaréHospital(AP-HP),Garches,France.21DepartmentofAnesthesiologyandIntensiveCareMedicine,JenaUniversity
Hospital,Jena,Germany.22DepartmentofMedicine,Division ofInfectiousDiseases, University ofRochesterSchoolofMedicine,
Rochester,NY,USA.23DepartmentofGeneralIntensiveCare,UniversityHospitalofLiege,DomaineuniversitairedeLiège,Liege,
Belgium.24UniversityMedicalCentre,UniversityofGroningen,Groningen,Netherlands.25DepartmentofIntensiveCare,University
MedicalCenterUtrecht,Utrecht,Netherlands.26CriticalCareUnit,HospitalIsraelitaAlbertEinstein,SãoPaulo,Brazil.27Graduate
PrograminInfectiousDiseasesandTropicalMedicine,DepartmentofInternalMedicine,SchoolofMedicine,UniversidadeFederalde
MinasGerais,BeloHorizonte,Brazil.28ImmunologyLaboratory,DedinjeCardiovascularInstitute,Belgrade,Serbia.29Departmentof
MedicalandSurgicalSciences,PoliclinicodiModena,UniversityofModenaandReggioEmilia,Modena,Italy.30CenterforRespiratory
Diseases,DepartmentofPulmonaryandCriticalCareMedicine,China-JapanFriendshipHospital,NationalClinicalResearchCenter
of Respiratory Diseases, Capital Medical University, Beijing, China. 31Critical Care and Peri-operative Medicine, Monash Health,
Melbourne,Australia.32SchoolofClinicalSciences,FacultyofMedicineNursingandHealthSciences,MonashUniversity,Melbourne,
Australia. 33Departmentof Intensive Care, Medisch SpectrumTwente, Enschede,Netherlands.34CHIP, Departmentof Infectious
DiseasesandRheumatology,Finsencentret,Rigshospitalet,UniversityofCopenhagen,Copenhagen,Denmark.35DepartmentofRes-
piratoryMedicine,CopenhagenUniversityHospital,BispebjergogFrederiksberg,CopenhagenNV,Denmark.36IntensiveCareUnit,
ElisabethTweestedenZiekenhuis,Tilburg,Netherlands.37DepartmentofIntensiveCare,VUUniversityMedicalCenter,Amsterdam,
Netherlands.38Departmentof Internal Medicine, School of Medcine, Federal University of Minas Gerais, BeloHorizonte, Brazil.
39DepartmentofMedicalandSurgicalSciences,AOUPoliclinicodiModena,Moderna,Italy
Contactaddress:PhilippSchuetz,MedicalUniversityDepartment,KantonsspitalAarau,Aarau,[email protected].
Editorialgroup:CochraneAcuteRespiratoryInfectionsGroup.
Publicationstatusanddate:Edited(nochangetoconclusions),commentaddedtoreview,publishedinIssue10,2017.
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 1
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Citation: SchuetzP,WirzY,Sager R,Christ-CrainM,StolzD,TammM, Bouadma L,LuytCE,WolffM,Chastre J,Tubach F,
KristoffersenKB,BurkhardtO,WelteT,SchroederS,NobreV,WeiL,BucherHC,BhatnagarN,AnnaneD,ReinhartK,BrancheA,
DamasP,NijstenM,deLangeDW,DeliberatoRO,LimaSSS,Maravi -Stojkovi V,VerduriA,CaoB,ShehabiY,BeishuizenA,Jensen
JUS,CortiC,VanOersJA,FalseyAR,deJongE,OliveiraCF,BegheB,BrielM,MuellerB.Procalcitonintoinitiateordiscontinue
antibioticsinacuterespiratorytractinfections.CochraneDatabaseofSystematicReviews2017,Issue10.Art.No.:CD007498. DOI:
10.1002/14651858.CD007498.pub3.
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Acute respiratory infections (ARIs) comprise of a large and heterogeneous group of infections including bacterial, viral, and other
aetiologies.Inrecentyears,procalcitonin(PCT),abloodmarkerforbacterialinfections,hasemergedasapromisingtooltoimprove
decisionsaboutantibiotictherapy(PCT-guidedantibiotictherapy).Severalrandomisedcontrolledtrials(RCTs)havedemonstratedthe
feasibilityofusingprocalcitoninforstartingandstoppingantibioticsindifferentpatientpopulationswithARIsanddifferentsettings
rangingfromprimarycaresettingstoemergencydepartments,hospitalwards,andintensivecareunits.However,theeffectofusing
procalcitoninonclinicaloutcomesisunclear.ThisisanupdateofaCochranereviewandindividualparticipantdatameta-analysisfirst
publishedin2012designedtolookatthesafetyofPCT-guidedantibioticstewardship.
Objectives
Theaimofthissystematicreviewbasedonindividualparticipantdatawastoassessthesafetyandefficacyofusingprocalcitoninfor
startingorstoppingantibioticsoveralargerangeofpatientswithvaryingseverityofARIsandfromdifferentclinicalsettings.
Searchmethods
WesearchedtheCochraneCentralRegisterofControlledTrials(CENTRAL),whichcontainstheCochraneAcuteRespiratoryInfections
Group’sSpecialisedRegister,MEDLINE,andEmbase,inFebruary2017,toidentifysuitabletrials.WealsosearchedClinicalTrials.gov
toidentifyongoingtrialsinApril2017.
Selectioncriteria
WeincludedRCTsofadultparticipantswithARIswhoreceivedanantibiotictreatmenteitherbasedonaprocalcitoninalgorithm(PCT-
guidedantibioticstewardshipalgorithm)orusualcare.Weexcludedtrialsiftheyfocusedexclusivelyonchildrenorusedprocalcitonin
forapurposeotherthantoguideinitiationanddurationofantibiotictreatment.
Datacollectionandanalysis
Twoteamsofreviewauthorsindependentlyevaluatedthemethodologyandextracteddatafromprimarystudies.Theprimaryendpoints
wereall-causemortalityandtreatmentfailureat30days,forwhichdefinitionswereharmonisedamongtrials.Secondaryendpoints
wereantibioticuse,antibiotic-relatedsideeffects,andlengthofhospitalstay.Wecalculatedoddsratios(ORs)and95%confidence
intervals(CIs)usingmultivariablehierarchicallogisticregressionadjustedforage,gender,andclinicaldiagnosis usingafixed-effect
model.Thedifferenttrialswereaddedasrandom-effectsintothemodel.Weconductedsensitivityanalysesstratifiedbyclinicalsetting
andtypeofARI.Wealsoperformedanaggregatedatameta-analysis.
Mainresults
From32eligibleRCTsincluding18newtrialsforthis2017update,weobtainedindividualparticipantdatafrom26trialsincluding
6708participants,whichweincludedinthemainindividualparticipantdatameta-analysis.Wedidnotobtainindividualparticipant
dataforfourtrials,andtwotrialsdidnotincludepeoplewithconfirmedARIs.AccordingtoGRADE,thequalityoftheevidencewas
highfortheoutcomesmortalityandantibioticexposure,andqualitywasmoderatefortheoutcomestreatmentfailureandantibiotic-
relatedsideeffects.
Primaryendpoints:therewere286deathsin3336procalcitonin-guidedparticipants(8.6%)comparedto336in3372controls(10.0%),
resultinginasignificantlylowermortalityassociatedwithprocalcitonin-guidedtherapy(adjustedOR0.83,95%CI0.70to0.99,P
=0.037).Wecouldnotestimatemortalityinprimarycaretrialsbecauseonlyonedeathwasreportedinacontrolgroupparticipant.
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 2
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Treatmentfailurewasnotsignificantlylowerinprocalcitonin-guidedparticipants(23.0%versus24.9%inthecontrolgroup,adjusted
OR0.90,95%CI0.80to1.01,P=0.068).Resultsweresimilaramongsubgroupsbyclinicalsettingandtypeofrespiratoryinfection,
withnoevidenceforeffectmodification(Pforinteraction>0.05).Secondaryendpoints:procalcitoninguidancewasassociatedwitha
2.4-dayreductioninantibioticexposure(5.7versus8.1days,95%CI-2.71to-2.15,P<0.001)andlowerriskofantibiotic-related
sideeffects(16.3%versus22.1%,adjustedOR0.68,95%CI0.57to0.82,P<0.001).Lengthofhospitalstayandintensivecareunit
stayweresimilarinbothgroups.Asensitivityaggregate-dataanalysisbasedonall32eligibletrialsshowedsimilarresults.
Authors’conclusions
Thisupdatedmeta-analysisofindividualparticipantdatafrom12countriesshowsthattheuseofprocalcitonintoguideinitiationand
durationofantibiotictreatmentresultsinlowerrisksofmortality,lowerantibioticconsumption,andlowerriskforantibiotic-related
sideeffects.ResultsweresimilarfordifferentclinicalsettingsandtypesofARIs,thussupportingtheuseofprocalcitonininthecontext
of antibiotic stewardship in people with ARIs. Future high-quality researchisneededto confirm theresults in immunosuppressed
patientsandpatientswithnon-respiratoryinfections.
PLAIN LANGUAGE SUMMARY
Testingbloodprocalcitoninlevelstodecidewhentostartandstopantibioticsinadultswithacuterespiratorytractinfections
Reviewquestion
Whataretheeffectsofusingprocalcitonintostartordiscontinueantibioticsinpeoplewithacuterespiratoryinfectionscomparedto
routinecareonmortalityandtreatmentfailure?
Background
Inpeoplewithacuterespiratoryinfections,unnecessaryantibioticusesignificantlycontributestoincreasingbacterialresistance,medical
costs,andtheriskofdrug-relatedadverseevents.Thebloodmarkerprocalcitoninincreasesinbacterialinfectionsanddecreaseswhen
patientsrecoverfromtheinfection.Procalcitonincanbemeasuredinthebloodofpatientsbydifferentcommerciallyavailableassays
with a turnaround time of around one totwo hoursand support clinical decision making about initiation and discontinuation of
antibiotictherapy.
Searchdate
Weconductedelectronicsearcheson10February2017.Weconductedsearchesforongoingtrialson12April2017.
Studycharacteristics
Allincludedtrialsrandomisedparticipantswithacuterespiratoryinfectionstoreceiveantibioticsbasedonprocalcitoninlevels(’procal-
citonin-guided’group)oracontrolgroup.Thetrialswereperformedinprimarycare,theemergencydepartmentandmedicalwards,
andtheintensivecareunit.Includedparticipantshadacuteupperorlowerrespiratoryinfections,includingpneumonia,bronchitis,
exacerbationofchronicobstructivepulmonarydisease,andothers.
Studyfundingsources
Allstudieswereinvestigator-initiatedtrials.Halfofthetrialswerefundedbynationalagenciesordidnotreportfunding,andhalfof
thetrialsreceivedfundingfromthebiomarkerindustry(e.g.ThermoFisherScientific).
Keyresults
We studied 6708 participants from 26 trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided
participantscomparedtocontrolparticipants(286deathsin3336procalcitonin-guidedparticipants(8.6%)versus336deathsin3372
controls (10.0%)). There was no significant difference with regard to treatment failures. Results were similar for different clinical
settings(primarycare,emergencydepartment,intensivecareunit)andtypesofrespiratoryinfection.Regardingantibioticexposure,
participantsintheprocalcitonin-guidedgrouphada2.4-dayreductioninantibioticexposureandareductioninantibiotic-relatedside
effects(16.3%versus22.1%).
Qualityoftheevidence
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 3
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Thequalityoftheevidencewashighformortalityandantibioticexposure.Mostofthetrialsdidnotuseblinding,howeverwedidnot
expectthatmortalitywouldbebiasedbythislimitation.Thequalityoftheevidencewasmoderatefortreatmentfailureandantibiotic-
relatedsideeffectsbecausethedefinitionsfortheseendpointsamongtrialswerenotidentical.
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 4
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CopyrightProcalcito SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
©2nin
01to Procalcitoninalgorithmcomparedtostandardcareforguidingantibiotictherapyinacuterespiratorytractinfections
7in
TheCitiate Patientorpopulation:peoplewithacuterespiratorytractinfections
ocor Settings:primarycare,emergencydepartment,intensivecareunit
hradis Intervention:PCT-guidedcare
neCocontin Comparison:standardcare
llaue
boration.Pubantibioticsin Outcomes IAllsussutmraetidverisckomparativerCisokrrse*s(p9o5n%diCnIg)risk R(9e5la%tiCveI)effect N(sotu.doifepsa)rticipants Q(GuRaAlitDyEo)ftheevidence Comments
lishedacute Standardcare PCTalgorithm
byre
Josp
hnira Mortality Studypopulation OR0.83 6708 ⊕⊕⊕⊕
Wtor Follow-up:30days (0.70to0.99) (26studies) High1
ileyytr 100per1000 86per1000
&Sact (76to95)
oin
ns,fec
Ltd.tions TCrlienaictmaleanstsfeasilsumreent3 Studypopulation O(0R.800.9to01.01) 6(27608studies) ⊕M⊕od⊕er(cid:13)ate23
(R
e Follow-up:30days 249per1000 230per1000
v
iew (216to245)
)
Antibiotic-related side Studypopulation 163per1000 OR0.68 3034 ⊕⊕⊕(cid:13)
effects 221per1000 (145to182) (0.57to0.82) (6studies) Moderate4
Follow-up:30days
Antibioticexposure Themeanantibioticex- Themeanantibioticex- - 6708 ⊕⊕⊕⊕
Total days of antibi- posure in the control posure in the interven- (26studies) High1
otic therapy in all ran- groupswas tiongroupswas
domisedparticipants 8.1days. 2.43dayslower
(2.15to2.71)
5
CP
opyright©201rocalcitoninto b*Tahseedboansitshefoarstshuemaesdsurimskedinrtihsekc(eo.mg.ptahreisomnegdrioanupcaonndtrothlegrroeulaptirvieskefafcercotsosfsthtuediinetse)rvisenptrioovnid(aenddinitsfo9o5t%noCteI)s.. The corresponding risk (and its 95%confidence interval) is
7in CI:confidenceinterval;OR:oddsratio:PCT:procalcitonin
TheCitiate
oo GRADEWorkingGroupgradesof evidence
cr
hradis Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateof effect.
neCocontin MLoowdeqruaatleitqyu:aFluitryth:eFrurrethseerarrcehseisarvcehryislilkikeelylytotohhaavveeaannimimppoortratannttimimppaaccttoonnoouurrccoonnfifdideenncceeininththeeeesstitmimaateteooffeefffefeccttaannddismlaikyeclyhtaongcehatnhgeeetshtiemeastteim. ate.
llaboration.Publishedueantibioticsinacute 12VNDeooeinrwmydtneholgorewgrwainendgqnteercuadryavdldoeiitnennygpet:iaoWflreontevmrgeaserlroenefurtoipvaore.nusrWdsyerieucnionoctuecnosnecnsresitinriavdnceisenoc.rnaausSbrniteosibltuslle,tienntttdhcthiyeeen:rdgeetsorsi.iutasTitmlcshsoeaoumrtmseeee.eisdacasdolsisnfeofcseessrorimnnmgeaendbtceooafuinsntcintueoinrotncnroaeonblefcovetuaratenllaeottdwfmoaareldntlhohtecefaraoetiuilnoutccnreeoiwmnanietsdheotsvfheodermeaPaleCtthTrra.iaarlelsgeoivnrietthnhmtes
byre werenotsystematicallyassessedamongtrials.
Josp 3Fortheprimarycaresetting,treatmentfailurewasdefinedasdeath,hospitalisation,acuterespiratoryinfection(ARI)-specific
hnWirato complications (e.g. empyema for lower ARI, meningitis for upper ARI), recurrent or worsening infection, and participants
iley&rytrac dreeppoarrttimngenatnsyesttyimngp,ttormeastmofenatnfaoinlugroeinwgarsedsepfirinaetodryasindfeeacttiho,nin(tee.ngs.ivfeevcear,recouungith(,ICdUys)pandomeias)saiotnf,orlelohwos-uppit.aFliosrattihoeneamfteerrginednecxy
Sotin hospital discharge,ARI-associated complications (e.g.empyemaoracuterespiratorydistress syndromeforlowerARI),and
ns,fec recurrentorworseninginfectionwithin30daysoffollow-up.FortheICUsetting,treatmentfailurewasdefinedasdeathwithin
Ltd.tions 30daysof follow-up.
(R 4Downgradedonelevelforincompletereporting:only6trialsreportedsideeffectsfrom antibiotics,andnoneof thesetrials
e
vie wereconductedintheICUsetting.
w
)
6
BACKGROUND non-specific inflammatory diseases (Muller 2000; Muller 2001;
Muller2010).Procalcitoninisreleasedinmultipletissuesinre-
Acuterespiratoryinfections(ARIs)accountforover10%ofglobal
sponsetobacterialinfectionsviaadirectstimulationofcytokines,
disease burden and are the most common reason for antibi-
otic therapy in primary care and hospital settings (Evans 2002; such as interleukin (IL)-1β, tumour necrosis factor (TNF)- ,
Gonzales1997;Zaas2014). andIL-6. Conversely,PCTproduction isblockedbyinterferon
gamma,acytokinereleasedinresponsetoviralinfections(Muller
2000).Hence,PCTmaybeusedtosupportclinicaldecisionmak-
Descriptionofthecondition ingfortheinitiationanddiscontinuationofantibiotictherapyin
differenttypesofinfectionsandindications(Sager2017;Schuetz
Acute respiratory infections comprise a heterogeneous group of
2016).Randomised controlledtrials(RCTs) havedemonstrated
infectionsincludingbacterial,viral,andotheraetiologies.Asmany
thefeasibilityofsuchastrategyindifferentARIpatientpopula-
as75%ofallantibioticdosesareprescribedforARIs,despitetheir
tions and differentsettings ranging fromprimary care to emer-
mainlyviralcause(Doan2014;Evans2002).Earlyinitiation of
gency departments and hospital wards to medical and surgical
adequate antibiotic therapy is the cornerstone in the treatment
ICUs (Bloos 2016; Branche 2015; Corti 2016; De Jong 2016;
of bacterial ARIs and is associated with improved clinical out-
Deliberato 2013; Layios 2012; Long 2014; Maravi -Stojkovi
comes(Hoare2006;Kumar2006;Kumar2009;Liberati2009b;
2011;Oliveira2013;Shehabi2014;Verduri2015;Wang2016).
Spurling2010).However,overuseofantibioticsbyoverprescrip-
tioninoutpatients withbronchitis (Arnold2005),forinstance,
andprolongeddurationofantibiotictherapyinpeoplewithbac-
Howtheinterventionmightwork
terialARIsinthehospitalandintensivecareunit(ICU)settings
isassociatedwithincreasedresistancetocommonbacteria,high Procalcitonin levels correlate with the risk of relevant bacterial
costs,andadversedrugreactions(Gonzales1997;Goossens2005; infectionsanddecreaseuponrecovery.Procalcitonintestingmay
Lawrence2009;Zaas2014). thereforehelpphysiciansdecideinwhichpatientsantibioticsare
neededand when itis safe to stop treatment(Kutz 2015). The
useofPCTinclinicalprotocolsmaythusdecreaseantibioticcon-
Descriptionoftheintervention sumptionintwoways:bypreventingunnecessaryantibioticpre-
scriptionsandbylimitingdurationsofantibiotictreatment(Sager
Thepresenceofadiagnostic’goldstandard’orreferencestandard
2017;Schuetz2011a).
representsthebestavailablemethodforestablishingthepresence
or absence of a disease. Optimally,a morphological verification
suchashistopathologyor,inthecaseofARIs,growthoftypical
Whyitisimportanttodothisreview
pathogensinbloodculturesorsputumculturescanbeobtainedto
establishthe’correct’diagnosis.Regrettably,theuseofbloodcul- WhileseveralRCTshaveevaluatedPCT-guidedantibiotictreat-
turesastheassumedgoldstandardinARIslackssensitivity,speci- ment,mostindividual trialsincludedparticipantswithdifferent
ficity,orboth,withonlyaround10%ofpeoplewithpneumonia typesofrespiratoryandnon-respiratoryinfectionsandlackedthe
having positive cultures and some of thembeing false positives statisticalpowertoassesstheriskformortalityandsevereinfec-
(Muller2010).Inthisdiagnosticuncertainty,surrogatebiomarker tiousdiseasecomplicationsassociatedwithPCT-guideddecision
toestimatethelikelihoodforthepresenceofabacterialinfection making. Previousmeta-analysesofRCTs investigating theeffect
andtogradediseaseseverityareofgreatinterest(Schuetz2015). ofPCTalgorithmsonantibioticusefocusedonthecriticalcare
Insuchacircumstance,twofundamentallydifferentconceptsare setting,peoplewithsuspicionofbacterialinfections,andpeople
employed.Oneconcepttendstoignorepotentialdilemmasinthe with sepsis and respiratory infections (Heyland 2011; Hoeboer
accuracyoftheallegedgoldstandardbutassumesawell-defined 2015;Tang2009;Wacker 2013).However,thesemeta-analyses
illness,whichisrepresentedbytheassumptiondrawnfollowinga usedaggregateddataandwerenotabletoinvestigatetheeffects
diagnostictestoraclinicaldiagnosis.Thesecondconceptdiscards ofPCTondifferentARIdiagnosesandonoutcomesotherthan
alleged gold standards and focuses on patient outcomes. In the mortality. A previous meta-analysis based on individual partici-
caseofARIs,theclinicalbenefitofadiagnosticbiomarker,such pantdatapublishedintheCochraneLibrarydidnotfindasig-
asprocalcitonin(PCT),canbemeasuredbyclinicaloutcomesof nificantdifferenceinclinicaloutcomes,butconfidenceintervals
randomisedinterventionstudies,assumingthatifthepersonre- remainedrelativelywide(Schuetz2012).SafetyofusingPCTfor
coveredwithout antibiotics thentherewas no relevantbacterial antibioticdecisionmakingremainedthusunproven.
illness.
Inrecentyears,PCThasemergedasapromisingmarkerforthedi-
agnosisofbacterialinfectionsbecausehigherlevelsarefoundinse-
verebacterialinfectionsbutremainfairlylowinviralinfectionsand OBJECTIVES
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 7
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Theaimofthissystematicreviewbasedonindividualparticipant Primaryoutcomes
datawastoassessthesafetyandefficacyofusingprocalcitoninfor 1. All-causemortalityfollowingrandomisationuptoafollow-
startingorstoppingantibioticsoveralargerangeofpatientswith uptimeof30days.
varyingseverityofARIsandfromdifferentclinicalsettings. 2. Setting-specifictreatmentfailurewithin30daysof
inclusion.
For the primary care setting, we defined treatment failure as
death,hospitalisation,ARI-specificcomplications(e.g.empyema
METHODS
forlowerARIs,meningitisforupperARIs),recurrentorworsening
infection,andstillhavingARI-associateddiscomfortat30days.
Fortheemergencydepartmentsetting,wedefinedtreatmentfail-
ureasdeath,ICUadmission,rehospitalisationafterindexhospital
Criteriaforconsideringstudiesforthisreview
discharge,ARI-associatedcomplications(e.g.empyemaoracute
respiratory distress syndrome for lower ARIs), and recurrent or
worseninginfectionwithin30daysoffollow-up.Forthemedical
Typesofstudies and surgical ICU setting, we defined treatment failure as death
within30daysoffollow-upandrecurrentorworseninginfection.
ProspectiveRCTscomparingastrategytoinitiateordiscontinue
antibiotictherapybasedonPCTlevelswithacontrolarmwith-
out PCT measurements were eligible for inclusion. Participants Secondaryoutcomes
wererandomisedtoreceiveantibioticseitherbasedonPCTlevels 1. Antibioticuse(initiationofantibiotics,durationof
(’PCT-guided’ group)oracontrolgroupwithoutknowledge of antibiotics,andtotalexposuretoantibiotics(totalamountof
PCTlevels,includingantibioticmanagementbasedonusualcare antibioticdaysdividedbytotalnumberofparticipants)).
orguidelines.Wedidnotincludenon-randomisedstudies. 2. Lengthofhospitalstayforhospitalisedparticipants.
3. LengthofICUstayforcriticallyillparticipants.
4. Numberofdayswithrestrictedactivitieswithin14days
Typesofparticipants afterrandomisationforprimarycareparticipants.
5. Antibiotic-relatedsideeffects.
We included adult participants with clinical diagnoses of ARIs:
either a lower ARI including community-acquired pneumo-
nia (CAP), hospital-acquired pneumonia (HAP), ventilator-as-
Searchmethodsforidentificationofstudies
sociated pneumonia (VAP), acute bronchitis, exacerbation of
asthma,orexacerbationofchronicobstructivepulmonarydisease WeupdatedthesearchstrategyforthisreviewinFebruary2017
(COPD);oranupperARIincludingcommoncold,rhino-sinusi- incollaborationwiththeCochraneAcuteRespiratoryInfections
tis,pharyngitis,tonsillitis,orotitismedia.Wealsoincludedpeople Group’s Information Specialist. We performed data collection
withsepsisandsuspectedARIsintheanalyses.Weexcludedtrials basedontheprotocolofapreviousmeta-analysisofindividualpar-
if they focused exclusively on children or used PCT to escalate ticipantdatapublishedintheCochraneLibrary(Schuetz2008).
antibiotictherapy.Wemadenoexclusionsbasedonlanguageof
reportsorclinicalsetting.Weincludedtrialsfromprimarycare,
Electronicsearches
emergencydepartments,andmedicalandsurgicalICUs.
WeupdatedthesearchesforthisreviewinFebruary2017,running
the search across all databases fromthe date of inception to 10
February2017. Wescreenedallnewreferencesidentifiedbythe
Typesofinterventions
search.Wesearchedthefollowingdatabasesforpublishedstudies:
Strategies to initiate or discontinue antibiotic therapy based on • TheCochraneCentralRegisterofControlledTrials
PCTlevelscomparedwithusualcarewereeligible. (CENTRAL;2017,Issue1),partoftheCochraneLibrary,
whichincludestheCochraneAcuteRespiratoryInfections
Group’sSpecialisedRegister,www.cochranelibrary.com/
Typesofoutcomemeasures (accessed10February2017)(Appendix1);
• MEDLINEOvid(1966to10February2017)(Appendix
Wedefinedprimaryandsecondaryoutcomestoafollow-uptime
2);
of30days.Fortrialswithshorterfollow-upperiods,weusedthe
• Embase.com(1980to10February2017)(Appendix3).
availableinformation(i.e.untilhospitaldischarge).Weexcluded
alltrialswithdifferentfollow-uptimesformortalityinasensitivity WeusedthesearchstrategyinAppendix4toconductsearchesfor
analysis. the2012versionofthisreview(Schuetz2012).
Procalcitonintoinitiateordiscontinueantibioticsinacuterespiratorytractinfections(Review) 8
Copyright©2017TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.