Hospital-acquired pneumonia in ICU

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Hospital-acquired pneumonia in ICU

Marc Leone, Lila Bouadma, Belaïd Bouhemad, Olivier Brissaud, Stephane

Dauger, Sébastien Gibot, Sami Hraiech, Boris Jung, Eric Kipnis, Yoann

Launey, et al.

To cite this version:

Marc Leone, Lila Bouadma, Belaïd Bouhemad, Olivier Brissaud, Stephane Dauger, et al..

Hospital-acquired pneumonia in ICU. Anaesthesia Critical Care & Pain Medicine, Elsevier Masson, 2018, 37

(1), pp.83-98. �10.1016/j.accpm.2017.11.006�. �hal-01788072�

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Guidelines

Hospital-acquired

pneumonia

in

ICU

§

Marc

Leone

a,

_*

_,

_Lila

_Bouadma

b

_,

_Be´laı¨d

_Bouhemad

c

_,

_Olivier

_Brissaud

d

_,

_Ste´phane

_Dauger

e

_,

Se´bastien

Gibot

f

,

Sami

Hraiech

g

,

Boris

Jung

h,i

,

Eric

Kipnis

j,k

,

Yoann

Launey

l

,

Charles-Edouard

Luyt

m

,

Dimitri

Margetis

n

,

Fabrice

Michel

o

,

Djamel

Mokart

p

,

Philippe

Montravers

q

,

Antoine

Monsel

r

,

Saad

Nseir

s

,

Je´roˆme

Pugin

t

,

Antoine

Roquilly

u

,

Lionel

Velly

v

,

Jean-Ralph

Zahar

w,x

,

Re´mi

Bruye`re

y

,

Ge´rald

Chanques

v,z,aa

a

Serviced’anesthe´siere´animation,hoˆpitalNord,Aix-Marseilleuniversite´,AP–HM,13015Marseille,France

b_Service_de_{re´animation}_me´dicale,_hoˆpital_{Bichat-Claude-Bernard,}_46,_rue_{Henri-Huchard,}₇₅₀₁₈_Paris,_France c_Service_{d’anesthe´sie}_{re´animation,}_CHU_de_Dijon,_BP_77908,₂₁₇₀₉_Dijon_cedex,_France

d

Unite´ dere´animationpe´diatrique,hoˆpitalPellegrin-Enfants,universite´ BordeauxII,CHUPellegrin,placeAme´lie-Raba-Le´on,33076Bordeaux,France

e

InsermU1141,PICU,Robert-Debre´ UniversityHospital,ParisDiderot-Paris7University,Assistancepublique–hoˆpitauxdeParis,48,boulevardSe´rurier, 75019Paris,France

f

Servicedere´animationme´dicale,hoˆpitalCentral,29,avenuedeLattre-de-Tassigny,54035Nancycedex,France

g

Servicedere´animationdesde´tressesrespiratoiresetdesinfectionsse´ve`res,hoˆpitalNord,Assistancepublique–hoˆpitauxdeMarseille,13015Marseille,France

h_Department_of_Anaesthesia_and_Intensive_Care,_Montpellier_University_Saint-Eloi_Hospital,₃₄₀₀₀_Montpellier,_France i_Inserm_U1046,_CNRS_UMR_9214,_PhyMedExp,_University_of_Montpellier,₃₄₀₀₀_Montpellier,_France

j

SurgicalCriticalCareUnit,DepartmentofAnesthesiologyandCriticalCare,CHUdeLille,59000Lille,France

k

EA7366,Host-pathogentranslationalresearch,universite´ deLille,59000Lille,France

l

DepartmentofAnesthesiaandCriticalCareMedicine,RennesUniversityHospital,35000Rennes,France

m

Institutdecardiologie,servicedere´animationme´dicale,groupehospitalierPitie´-Salpeˆtrie`re,universite´ Paris6-PierreetMarieCurie,Assistancepublique– hoˆpitauxdeParis,75000Paris,France

n_Service_de_{re´animation}_me´dicale,_hoˆpital_{Saint-Antoine,}_Assistance_{publique–hoˆpitaux}_de_Paris,_184,_rue_du_faubourg_{Saint-Antoine,}₇₅₀₁₂_Paris,_France o

AnesthesiaandIntensiveCareUnit,TimoneChildren’sHospital,Assistancepublique–hoˆpitauxdeMarseille,13005Marseille,France

p

IntensiveCareUnit,Paoli-CalmettesInstitute,232,boulevarddeSainte-Marguerite,13009Marseille,France

q

De´partementd’anesthe´sie-re´animation,universite´ ParisVIISorbonneCite´,CHUBichat-Claude-Bernard,AP–HP,46,rueHenri-Huchard,75018Paris,France

r

DepartmentofAnesthesiologyandCriticalCare,UniversityPierreandMarieCurie,75000Paris,France

s

DepartmentofIntensiveCareMedicine,CriticalCareCenter,CHUofLille,59000Lille,France

t_Hoˆpitaux_{universitaires}_de_Gene`ve,₂₇₂₃₀_Geneva,_GE,_Switzerland

u_Anaesthesia_Intensive_Care_Unit,_centre_hospitalier_{universitaire,}₄₄₀₀₀_Nantes,_France v

De´partementd’anesthe´siere´animation,hoˆpitaldelaTimone,13000Marseille,France

w

Unite´ decontroˆleetdepre´vention,durisqueinfectieux,de´partementdemicrobiologieclinique,groupehospitalierParisSeineSaint-Denis,CHUAvicenne, AP–HP,125,ruedeStalingrad,93000Bobigny,France

x

InfectionControlUnit,IAME,UMR1137,universite´ Paris13,SorbonneParisCite´,75000Paris,France

y

Servicedere´animation,centrehospitalierdeBourgenBresse,900,routedeParis,01000Bourg-en-Bresse,France

z_{De´partement}_{d’anesthe´sie}_{re´animation,}_hoˆpital_Saint-Eloi,_CHU_de_Montpellier,_80,_avenue_{Augustin-Fliche,}₃₄₂₉₅_Montpellier_cedex_5,_France aa

InsermU1046,CNRSUMR9214,PhyMedExp,universite´ deMontpellier,34295Montpelliercedex5,France

ARTICLE INFO Articlehistory:

Availableonline15November2017

ABSTRACT

TheFrenchSocietyofAnesthesiaandIntensiveCareMedicineandtheFrenchSocietyofIntensiveCare editedguidelinesfocusedonhospital-acquiredpneumonia(HAP)inintensivecareunit(ICU).Thegoalof 16French-speakingexpertswastoproduceaframeworkenablinganeasierdecision-makingprocessfor intensivists.Theguidelineswererelatedto3speciﬁcareasrelatedtoHAP(prevention,diagnosisand treatment)in4identiﬁedpatientpopulations(COPD,neutropenia,postoperativeandpediatric).The literatureanalysisandtheformulationoftheguidelineswereconductedaccordingtotheGradeof Recommendation Assessment, Development and Evaluation methodology. An extensive literature research overthe last 10 years was conducted based on publicationsindexed in PubMedTM _and

CochraneTM_databases._HAP_should_be_prevented_by_a_standardized_multimodal_approach_and_the_use_of

§

CommonguidelineSFAR–SRLFoftheFrenchSocietyofAnaesthesiaandIntensiveCareMedicine,FrenchIntensiveCareSociety,incollaborationwith:ADARPEFand GFRUP,AssociationofFrench-speakingAnaesthetistsandIntensivists,French-speakingGroupofIntensiveCareandPaediatricemergencies.

* Correspondingauthor.Serviced’anesthe´sieetdere´animation,hoˆpitalNord,chemindesBourrely,13015Marseille,France. E-mailaddress:marc.leone@ap-hm.fr(M.Leone).

https://doi.org/10.1016/j.accpm.2017.11.006

2352-5568/ C₂₀₁₇_The_Authors._Published_by_Elsevier_Masson_SAS_on_behalf_of_{Socie´te´ franc¸aise}_{d’anesthe´sie}_et_de_{re´animation}_(Sfar)._This_is_an_open_access_article_under_the

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Expertcoordinators

SFAR: Marc Leone, service d’anesthe´sie re´animation, hoˆpital Nord,Aix-Marseilleuniversite´,AP–HM,13015Marseille,France

SRLF:LilaBouadma,Servicedere´animationme´dicale,hoˆpital Bichat-ClaudeBernard,46,rueHenri-Huchard,75018Paris,France

Organisers

SFAR:Ge´raldChanques,de´partementd’anesthe´siere´animation, hoˆpitalSaint-Eloi,CHUdeMontpellier,80,avenueAugustin-Fliche, 34295 Montpellier cedex 5, France; InsermU1046, CNRS UMR 9214,PhyMedExp,universite´ deMontpellier,34295Montpellier cedex5,France

LionelVelly,de´partementd’anesthe´siere´animation,hoˆpitalde laTimone,13000Marseille,France

SRLF:Re´miBruye`re,servicedere´animation,centrehospitalier deBourg-en-Bresse,900,route deParis, 01000Bourg-en-Bresse, France

SFAR experts panel: Belaid Bouhemad, Eric Kipnis, Djamel Mokart,PhilippeMontravers,AntoineMonsel,AntoineRoquilly

Belaid Bouhemad:service d’anesthe´siere´animation, CHUde Dijon,Dijon,France,BP77908,21709Dijoncedex,France

EricKipnis:serviced’anesthe´siere´animation,CHUdeLille,Lille, France;RechercheTranslationnelleRelationsHoˆte-Pathoge`nes,EA 7366,universite´ deLille,Lille,France

DjamelMokart:Servicere´animation,InstitutPaoli-Calmettes, 232,boulevarddeSainte-Marguerite,13009,Marseille,France

Philippe Montravers:de´partement d’anesthe´sie-re´animation, CHUBichat-Claude-Bernard,AP–HP,universite´ ParisVIISorbonne Cite´,46,rueHenri-Huchard,75018Paris,France

Antoine Monsel:service d’anesthe´siere´animation,universite´ PierreandMarisCurie,Paris,France

Antoine Roquilly: service d’anesthe´sie re´animation, centre hospitalieruniversitaire,Nantes,France

SRLFexpertspanel:Se´bastienGibot,SamiHraiech,BorisJung, Charles-EdouardLuyt,SaadNseir,Je´roˆmePugin,Jean-RalphZahar Se´bastienGibot:servicedere´animationme´dicale,hoˆpitalCentral, 29,avenuedeLattre-de-Tassigny,54035Nancycedex,France

Sami Hraiech:hoˆpitalNord,re´animationdesde´tresses respi-ratoiresetdesinfectionsse´ve`res,Assistancepublique–hoˆpitauxde Marseille,13015,Marseille,France

BorisJung:serviced’anesthe´siere´animation,hoˆpital universi-taireSaint-Eloi Montpellier,Montpellier, France;Inserm U1046, CNRSUMR9214,PhyMedExp, universite´ deMontpellier, Mont-pellier,France

Charles-Edouard Luyt:service dere´animation me´dicale, ins-titutdecardiologie,universite´ Paris6-PierreetMarieCurie,groupe hospitalier Pitie´-Salpeˆtrie`re, Assistance publique–hoˆpitaux de Paris,Paris,France

Saad Nseir: service d’anesthe´sie re´animation, Critical Care Center,CHUofLille,Lille,France

Je´roˆme Pugin: hoˆpitaux universitaires de Gene`ve, 27230, Geneva,GE,Switzerland

Jean-RalphZahar:unite´ decontroˆleetdepre´ventiondurisque infectieux,de´partementdemicrobiologieclinique,groupe hospi-talierParisSeineSaint-Denis,CHUAvicenne,AP–HP,125,ruede

Stalingrad,9300,Bobigny;InfectionControlUnit,IAME,UMR1137, Universite´ Paris13,SorbonneParisCite´,Paris,France

Pediatricexpertspanel(ADARPEFandGFRUP):OlivierBrissaud, Ste´phaneDauger,FabriceMichel

Olivier Brissaud: unite´ de re´animation pe´diatrique, hoˆpital Pellegrin-Enfants, universite´ Bordeaux II, CHU Pellegrin, place Ame´lie-Raba-Le´on,33076Bordeaux,France

Ste´phaneDauger:InsermU1141,PICU,Robert-Debre´ Universi-tyHospital,ParisDiderot-Paris7University48,boulevardSe´rurier, Assistancepublique–hoˆpitauxdeParis,75019,France

FabriceMichel:serviced’anesthe´siere´animation,hoˆpitalpour enfants La Timone, Assistancepublique–hoˆpitaux de Marseille, Marseille,France

Bibliographicexperts:YoannLauney,DimitriMargetis Yoann Launey: service d’anesthe´sie re´animation, hoˆpital universitairedeRennes,Rennes,France

Dimitri Margetis: service de re´animation me´dicale, hoˆpital Saint-Antoine,Assistancepublique–hoˆpitauxdeParis,184,ruedu faubourgSaint-Antoine,75012,Paris,France

Reviewerpanels

SFARGuidelinescommittee: DominiqueFletcher (President), Lionel Velly (Secretary), Julien Amour, Sylvain Ausset, Ge´rald Chanques, Vincent Compere, Fabien Espitalier, Marc Garnier, EtienneGayat,PhilippeCuvillon,Jean-Marc.Malinovski,Bertrand Rozec

SRLF Guidelines and evaluation committee: Max Guillot (Secretary), Naı¨ke Bige´, Laetitia Bodet-Contentin, Re´mi Bruye`re, HenriFaure,ErwanL’Her,EricMariotte,VirginieMaxime,Chirine Mossadegh,VincentPeigne,FabiennePlouvier,ElieZogheib

Guidelinesreviewedand endorsedbytheSFAR(29/06/2017) andSRLFboards(08/06/2017).

1. Introduction

Hospital-acquired pneumonia (HAP) is the most common infectionintheintensivecareunit (ICU). Thisinfection encom-passestwodifferententities:pneumoniaassociatedwith mechan-ical ventilation (ventilator-associated pneumonia or VAP) and severe pneumonia developed during the hospital stay. The incidence of VAP ranges from 1.9 to 3.8 per 1000 days of mechanicalventilationintheUSandexceeds18per1000daysof mechanicalventilationinEurope[1].

NosocomialpneumoniaisthemostcommoninfectioninICU, whenconsideringthetimingoftheseinfections.Non-ventilator HAP occurs in patients admitted to the hospital for at least 48hoursandVAPisdeﬁnedasoccurringmorethan48hoursafter the initiationof mechanical ventilation. Accurate data on their epidemiologyarelimitedbythelackofstandardiseddiagnostic criteria.IntheUS,theincidenceofnon-ventilator-HAPwas1.6%, representingarateof3.63per1000patient-days[2],whilethe deﬁnitionofVAPisnotalteredbyconsideringtimeafteradmission tothehospitalandtheincidenceremainasmentionedabove[1]. IntheICU,HAP isassociatedwithanapproximatemortality rate of 20% [3]. However, the mortality attributable to HAP is

selectivedigestivedecontaminationinunitswheremultidrug-resistantbacteriaprevalencewasbelow 20%.Diagnosisreliesonclinicalassessmentandmicrobiologicalﬁndings.Monotherapy,intheabsence ofriskfactorsformultidrug-resistantbacteria,non-fermentingGramnegativebacilliand/orincreased mortality(septicshock,organfailure),isstronglyrecommended.Aftermicrobiologicaldocumentation, itisrecommendedtoreducethespectrumandtoprefermonotherapyfortheantibiotictherapyofHAP, includingfornon-fermentingGram-negativebacilli.

C ₂₀₁₇_The_Authors._Published_by_Elsevier_Masson_SAS_on_behalf_of_{Socie´te´ franc¸aise}_{d’anesthe´sie}_et_de

re´animation(Sfar).ThisisanopenaccessarticleundertheCCBYlicense(http://creativecommons.org/ licenses/by/4.0/).

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estimatedbetween 5and 13% [3].The attributablemortalityis probablyhigherinsomespeciﬁcpopulationssuchaspatientswith chronic obstructive pulmonary disease (COPD) [1]. In other populationssuchastraumapatients, HAPseemstohaveonlya minoreffectonmortality[1].Eventhoughthedirectimpactofthis infection on mortality remains debated, it is nonetheless associatedwithincreasedmorbiditythroughincreasedduration ofmechanicalventilation(ordecreaseinventilator-freedays)and increasedICUandhospitallength-of-stay[1].Asaresult,HAPis alsoresponsibleforanoveruseofhealthcareresources (ventila-tion,ICUandhospitalbedsandresources).Finally,itisassociated withincreasedcostsrelatedtohospitalstay[4].

Todate,theFrenchSocietyofAnaesthesiaandIntensiveCare Medicine(SFAR)andtheFrenchSocietyofIntensiveCare(SRLF) have not proposed guidelinesfocused on HAP. Sixteen French-speakingexpertswereselectedbyanorganisingcommittee,itself appointed by the guideline committees of each participating society, following approval by their respective boards. Two independentbibliographicexperts analysedtheliteratureofthe past10yearsintheﬁeldusingpre-deﬁnedkeywords.

RecentAmericanandEuropeanguidelineshavebeenpublished

(http://www.idsociety.org/Guidelines/Patient_Care/IDSA_Practice_

Guidelines/Infections_by_Organ_System/Lower/Upper_Respiratory/ Hospital-Acquired___Ventilator_-_Associated_Pneumonia_(HAP/

VAP)/).However,boththeSFARandSRLFwishedtosharetheirown

interpretationencompassingdatafromrecentlyavailable publica-tions. The boards of both societies designated an organising committee,whichappointed a panel ofsixteenFrench-speaking experts.Two members of the paneloversaw a literature search usingpre-deﬁnedkeywordslimitedtothepastdecade.

2. Guidelinesgoals

Thegoaloftheseexperts’guidelinesistogenerateaframework enablinganeasierdecision-making processforintensivists.The groupworkedtoproduceaminimalnumberofguidelinesinorder tohighlightthekeypointstofocusonineacharea.Whenindoubt, publisheddataprevailedoverexpertopinion.Thebasicrulesof universalmedical good practices— hygiene, antibiotictherapy, comprehensivecare—wereconsideredasknownand excluded fromthescopeoftheguidelines.

3. Deﬁnitions

ThecriteriatodiagnosepneumoniaareshowninTable1.In clinicalpractice,HAPissuspectedwhenapatientpresentswith fever,impairedoxygenationandsuppurativesecretions.

Non-ventilatorHAPoccursafter48hofhospitalstayandVAP occurs after 48h of mechanical ventilation [5]. By deﬁnition, neitherispresentnorincubatingathospitaladmissionnoratthe onsetofmechanicalventilation.TheonsetofeitherHAPorVAP relative to hospital admission discriminates early pneumonia

(<5 days) from late pneumonia (5 days). Microbiologically confirmedHAP wasdefined asthedefinitive identificationofa microorganism isolated from respiratory samples or in blood culturesinapatientwithsuspectedpulmonaryinfection. 4. Microbiologicalconfirmation

The pathogens usually responsiblefor HAP are Enterobacte-riaceae, Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter baumannii [1]. The infection is polymicrobial in 30%ofcases.Inearlypneumonia,themostfrequentlyidentiﬁed pathogens are methicillin susceptible S. aureus, Streptococcus pneumoniaandHaemophilusinﬂuenza[1].

Microbiologicalconﬁrmationisacrucialstepinthediagnosisof HAP. Routinely, it is based on the qualitative or quantitative culturesofrespiratorysamples.Apathogenisisolatedfromthese samplesandidentiﬁedinabout70%ofsuspectedcases[1].Other biologicaltestscanbecarriedouttosupportthemicrobiological diagnosis such as blood cultures and antigenuria. Molecular biologytechniquesappliedtoroutinemicrobiologyarestillbeing assessedandoutsideofthescopeoftheseguidelines.

5. Method

5.1. Generalorganisation

Theseguidelinesaretheresultoftheworkprovidedbyapanel ofexperts,broughttogetherbytheSFARandtheSRLF.Eachexpert was required to file a conflict-of-interest disclosure prior to participationinestablishingtheguidelines.Thestatedmissionwas to produce guidelines in three specific areas related to HAP: prevention, diagnosisand treatment as wellas thespecificities pertaining to different identified patient populations (COPD, neutropenia,postoperativeandpediatric).

Thescheduleofthegroupwasdefinedupstream(Table2).First, theorganisationcommitteeandtheguidelinecoordinatorsdefined thequestionstobeaddressedbythepanelists.Itthenappointed expertsinchargeofeachquestion.Thequestionswereformulated according to the Patients, Intervention Comparison Outcome (PICO) formatfollowinga firstmeetingoftheexpertpanel.The literatureanalysisandtheformulationoftheguidelineswerethen conducted according to the Grade of Recommendation Assess-ment, Development and Evaluation (GRADE) methodology. A level-of-evidencewasdefinedforeachreferencecitedaccordingto the type of study.This level-of-evidence couldbere-evaluated taking into account the methodological quality of the study. Overall ‘‘strong’’ level-of-evidence resulted in formulating a ‘‘strong’’ recommendation (‘‘we recommend...’’ or ‘‘we recom-mendnot...’’;GRADE1+or1 ).Overallmoderate,weakorvery weak level-of-evidence resulted in formulating an ‘‘optional’’ recommendation(‘‘wesuggest...’’,‘‘wesuggestnot...’’;GRADE2+ or2 ).Intheabsenceofsupportingliterature,aquestioncouldbe addressed by a recommendation under the form of an expert opinion(‘‘theexpertssuggestthat...’’).Recommendation propos-alswerepresentedtotheentirepanelanddiscussedone-by-one. Thegoalwasnottoobtainconsensusonalltheproposals,butto

Table2

Guidelinetimeline.

December5th2016 Start-upmeeting March6th2017 Vote:ﬁrstround

March13th2017 Post-votedeliberationmeeting April1st2017 Vote:secondround

April16th2017 Amendmentoftwoguidelines April28th2017 Voteofthetwoamendedguidelines May10th2017 Guidelineﬁnalisationmeeting Table1

Criteriafordeﬁningpneumonia. Radiologicalsigns

Twosuccessivechestradiographsshowingneworprogressivelunginﬁltrates Intheabsenceofmedicalhistoryofunderlyingheartorlungdisease,asingle chestradiographisenough

Andatleastoneofthefollowingsigns

Bodytemperature>38,3˚Cwithoutanyothercause Leukocytes<4000/mm3_or

12000/mm3

Andatleasttwoofthefollowingsigns Purulentsputum

Coughordyspnea

Decliningoxygenationorincreasedoxygen-requirementorneedfor respiratoryassistance

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identifypointsofagreementanddisagreementorindecision.Each recommendationwasthenevaluatedbyeachexpertratedusinga scalefrom1(completedisagreement)to9(completeagreement). Collective rating was established according to a GRADE grid methodology.Tovalidatearecommendationonacriterion,atleast 50%ofexpertshadtohaveconcordantopinions,whilelessthan 20%ofthemhadtohavediscordantopinion.Fora recommenda-tion to be strong, at least 70% of participants had to have concordant opinions. Without strong agreement, recommenda-tionswererephrasedandresubmittedtoreachaconsensus. 5.2. Areasofguidelines

Three areas related to HAP were: prevention, diagnosis and treatmentwith population-speciﬁcconsiderations. Fourrelevant speciﬁc populations were considered in the guidelines analyses (COPD, neutropenia, postoperative and pediatric). An extensive literatureresearchoverthelast10yearswasconductedbasedon publicationsindexedinPubMedTM_and_CochraneTM_databases._To beconsideredforanalysis,publicationshadtobewritteninEnglish orin French. Itwas decided ahead of the analysis to limit the numberofexpertopinionsandtonotproducerecommendations thatarenotsupportedbyliterature.Theanalysiswasfocusedon recentdata,accordingtodecreasinghierarchicalprioritisationof datafrommeta-analysesofrandomisedcontrolledtrials(RCTs)or individualRCTstoobservationalstudies.Studysamplesizeandthe relevanceoftheresearchwereconsideredatthelevelofeachstudy. 5.3. Synthesisofresults

TheexpertpanelanalysesandapplicationoftheGRADEmethod ledto15guidelines(andtwospeciﬁcguidelinesforthepediatric population) and four care protocols. Among the15 formalised guidelinesforadults,threehaveahighlevel-of-evidence(GRADE 1+/ ) and 11 a low level-of-evidence (GRADE 2+/ ). For one recommendation, the GRADE method could not be applied, resulting an expert opinion. Both paediatric guidelines had a weak level-of-evidence (GRADE 2). The four care protocols, providedonlyasanindication,arebasedonexpertopinionsbut weresubmittedtothesameratingandagreementprocessasthe guidelines. After two rounds of rating and one amendment, a strongagreementwasreachedforallguidelinesandprotocols.

Firstarea,PREVENTION:

WhichHAPpreventionapproachesdecreasemorbidityand mortalityinICUpatients?

R1.1 – We recommend using a standardised multimodal HAPpreventionapproach inorder todecrease ICUpatient morbidity.

GRADE1+,STRONGAGREEMENT

Evidencesummaryandrationalefortherecommendation: Theimplementationofstandardisedprotocolsisassociated withadecreaseinICUmorbidity[6–10].Inbefore/afterstudies, theimplementationofamultimodalpreventionstrategyand the adherence to a standardised multimodal approach are associatedwithadecreaseinHAP[11]andintheduration of mechanical ventilation, provided that an early weaning strategyispartoftheapproach[12].Expertssuggest increas-ing prevention measures, and applyingcostly measures to patients withahigh risk ofHAPand death, suchasCOPD patients[13]orimmunosuppressedpatients.

R1.1Paediatrics–Wesuggestusingastandardised multimod-alapproachaimingatpreventingHAPinorder todecrease pediatricICUpatientmorbidity.

Evidencesummaryandrationalefortherecommendation: Eight monocentric before/after or cohortstudiessuggest thatimplementingandapplyingstandardisedHAPprevention protocols in pediatric ICU patients are of interest in order to reduce the occurrenceof HAPand associated morbidity

[14–21].

R1.2–Inunitswheremultidrug-resistantbacteriaprevalence islow(<20%),wesuggestapplyingroutineselective diges-tivedecontaminationusingatopicalantisepticadministered enterallyandamaximal5-daycourseofsystemicprophylactic antibiotictodecreasemortality.

Evidencesummaryandrationalefortherecommendation: Meta-analyses ofRCTs comparing selectivedigestive de-contamination (SDD) to standard care show a significant decreaseinhospitalitymortality,lengthsofmechanical venti-lationandHAPincidenceinICUpatients[22].Inasub-group analysisfromamulticentretrial,theeffectofSDDonmortality decreasewassimilarinmedicalandsurgicalpatients[23].In thesub-groupanalysisofameta-analysisofRCTson pneu-moniapreventionstrategies,theeffectofSDDonthedecrease inmortalitywasonlyobservedforstrategiesincludingatopical antiseptic administered enterally and systemicprophylactic antibiotic use [24]. The effect of SDD on the decrease in mortalitywasgreaterinpatientswithhighoverallmortality, demonstratinggreaterefficiencyinthemorecriticallyill[24].In thesub-groupanalysisofalargemulticentertrial,SDDwas associated witha decrease in the acquisitionof multidrug resistantbacteria[25].NolinkbetweenSDDandthe develop-mentofbacterialresistanceinICUpatientswasshownina meta-analysisorinarandomised-controlledtrialcomparing SDD to standardcare [26]. It is probablybest to limit the durationof systemicantibiotictherapy inSDDprotocolsto amaximumof5days,becauseprolongedantibiotictherapy mayleadtotheemergenceofmultidrug-resistantbacteria[27]. Themajorstudiesthathavedemonstratedtheefficiencyof SDDwereconductedinenvironmentswheretheprevalenceof multiresistantbacteriawaslow[25].Itistherefore recommen-dedtofollowtheeffectsofthispreventionstrategyonthelocal bacterialecologyonaregularbasis.Consequently,wecannot recommendsuchastrategyinunitswheretheprevalenceof multiresistantbacteriaishigh.

R1.3 – Within a standardised multimodal HAP prevention approach, we suggest combining some of the following methodstodecreaseICUpatientmorbidity:

promotethe useofnon-invasive ventilationto avoid trachealintubation(mainlyinpost-operativedigestive surgerypatientsandinpatientswithCOPD);

favor orotracheal over nasotracheal intubation when required;

limit dose and duration of sedatives and analgesics (promotetheir use guidedbysedation/pain/agitation scales,and/ordailyinterruptions);

initiateearlyenteralfeeding(withintheﬁrst48hoursof ICUadmission);

regularlyverifyendotrachealtubecuffpressure; performsub-glotticsuction(every6to8hours)usingan

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Evidencesummaryandrationalefortherecommendation: Withinmultimodal HAPpreventionapproaches, methods with an effect on patient morbidity should be favored, in particularthosewithaneffectonlengthofmechanical venti-lation(ventilator-freedays),ICUandhospitallengths-of-stay anduseofantibiotics.

For each of the methods proposed above, a significant decreaseintheriskofHAPand/orinthelengthofmechanical ventilationand/orinICU/hospitallength-of-staywerereported in:

a meta-analysisofRCTs comparingnon-invasive and invasiveventilation [28], a RCT includingpatients in postoperativedigestivesurgerypatientsof[29]andtwo meta-analyses focused on weaning from mechanical ventilationinpatientswithCOPD[30,31];

two before/after studies on the implementation ofa sedationprotocoltitratedbynurses[32,33];

threemeta-analyses of RCTscomparing early enteral feeding(initiatedbefore48h)tolatefeeding[34–36]; RCTscomparingcontinuoustodiscontinuous

monitor-ingoftrachealintubationtubecuffpressures[37–39]; two meta-analyses comparing sub-glottic suction to standardcare [40,41].Trachealintubationtubeswith sub-glotticsuctionmayalsohaveapositivecost-beneﬁt ratio;

a randomised study comparing nasotracheal versus orotrachealintubation[42].

R1.4 – Within a standardised multimodal HAP prevention approach,we suggestnot using thefollowing methodsto decreaseICUpatientmorbidity:

systematic early (<day 7) tracheotomy (except for speciﬁcindications);

anti-ulcerprophylaxis(exceptforspeciﬁcindications); post-pyloricenteralfeeding(exceptforspeciﬁc

indica-tions);

administrationofprobioticsand/orsynbiotics; earlysystematicchangeofthehumidiﬁerﬁlter(except

forspeciﬁcmanufacturerrecommendations);

use of closed suctioning systems for endotracheal secretions;

useofantiseptic-coatedintubationtubesorwithtubes an‘‘optimised’’cuffshape;

selectiveoro-pharyngealdecontamination(SOD)with povidone-iodine;

useofprophylacticnebulisedantibiotics; dailyskindecontaminationusingantiseptics.

GRADE2 ,STRONGAGREEMENT

Evidencesummaryandrationalefortherecommendation: Althoughsomeoftheabovementionedstrategieshavebeen associatedwithsignificant decreasein the riskof HAP, no reductioninmorbidity(lengthofmechanicalventilationorICU/

hospitallength-of-stay)orinmortalitywasdemonstratedwith theuseofthesestrategiesindividually.However,itispossible thattheircombineduseinpreventionbundlesmayhavesome beneficialeffectonpatientmorbidity.However,thereislackof available data in the literature to support this hypothesis. Experts donot takeposition against these HAPprevention techniques,buttheirfirstlineuseisnotrecommended,either becauseofcostorpotentialadverseeffects.

Thus,nobeneficialimpactintermsofHAPwasfoundforthe following:

earlytracheotomy(beforeday-5followingICU admis-sion)comparedtolatetracheotomy(afterday-14)apart fromspeciﬁcindications[43,44];

the use of oro-pharyngeal decontamination using povidone-iodine(andpotentialtoxiceffects)[45]; anti-ulcerprophylaxisuse(apartfromspeciﬁc

indica-tion)comparedtonone[46];

post-pyloricenteralcomparedtogastricenteralfeeding

[47];

enteraladministrationofprobioticsorsynbiotics[48– 50];

enclosedtrachealsuctionsystemscomparedto conven-tionalopentrachealsuctioning[51];

endotrachealintubationtubeslined/coatedor incorpo-ratingsilverorantisepticscomparedtostandardtubes

[52] and conical-shaped cuffs compared to standard cuffs[53];

nebulised prophylactic antibiotics during invasive ventilation[24];

systematic change of heat and moisture exchangers

[54,55];

routineantisepticbathsforICUpatients[56,57].

R1.5 – In weaning of COPD patients from ventilation, we suggest using non-invasive ventilationto reduce lengthof invasivemechanicalventilation,incidenceofHAP,morbidity andmortality.

Evidencesummaryandrationalefortherecommendation: Invasivemechanicalventilationisthemostimportantrisk factorforVAP.Severalstudieshaveanalysedtheroleof non-invasiveventilation(NIV)withintheprocessofweaningfrom mechanicalventilation.Theirgoalswerethereductionofthe lengthofinvasivemechanicalventilationandinVAPincidence. Twometa-analyses[30,31]assessedtheimpactofNIV,asa meansofrapidweaningfrominvasivemechanicalventilation, ontheincidenceofVAP.

Inthefirstmeta-analysis(9studies,632patientswithCOPD), NIVreducestherisksofmortality(riskratio[RR]:0.36; confi-dence interval [CI] at 95% [0,24–0,56]; I2=0%), mechanical ventilation weaning failure (RR: 0.52; CI 95% [0.36–0.74]; I2₌_0%)_and_VAP_(RR:_0.22;_CI_95%_{[0.13–0.37];}_I2₌_3%)_[30]_.

Thesecondmeta-analysisincluded17studies(959patients withCOPD).Itfoundasignificantdecreaseinriskofmortality (RR:0.27;CI95%[0.17–0.42];I2=0%),mechanicalventilation weaningfailure(RR:0.25;CI95%[0.14–0.45];I2₌_0%)_and_VAP (RR:0.18;CI95%[0.12–0.27];I2₌_0%)_[31]_._However,_this meta-analysishadseveralissues:

severalstudiesincludedinthismeta-analysiswerenot randomised;

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numberofpatientsincludedinmostofthestudieswas under50;

deﬁnitionofVAPwasnotthesameineverystudy.

Secondarea,DIAGNOSIS:

WhatmethodstodiagnoseHAPshouldbeusedtodecrease ICUpatientmorbidityandmortality?

R2.1–Wesuggestnotusingtheclinicalscores(CPIS,modified CPIS)fordiagnosingHAP.

Evidencesummaryandrationalefortherecommendation: Theperformanceoftheclinicalpulmonaryinfectionscore (CPIS)inthediagnosisofpneumoniadependsonthe compar-ator.Itssensibilityandspecificityvaryfrom60to80% com-paredtomicrobiologicalsamplesobtainedbybronchoalveolar lavage[58–61].Thediagnosticperformancesarelowwhenthe comparator is based on histology and pathology of post-mortemlungbiopsiesinautopsyseries[62].Theperformance oftheCPISdependsonthepre-testprobabilityofpneumonia

[63].Nevertheless,CPISvariationovertimemaybeusefulin pneumonia resolution [64] and antibiotic de-escalation

[65,66].InitialCPISatHAPonsethaslittlevalueinpredicting

patientoutcomes,ascomparedtoseverityscores[67].

R2.2–Wesuggestcollectingmicrobiologicalairwaysamples, regardless of type, before initiation of or any change in antibiotictherapy.

Evidencesummaryandrationalefortherecommendation: Ameta-analysiscomparingdifferentairwaysamples (endo-tracheal aspirates, protected specimen brushand broncho-scopicorblindbronchoalveolarlavage)andmicrobiological culture methods (quantitative or not) found no significant effect onpatient outcomes(28-daymortality,ventilator-free days,orlength-of-stay)norantibiotictreatment[68].Therefore, bothsamplingandculturemethodsarelefttothediscretionof cliniciansaccordingtostrategicchoicesattheunit,department orinstitutionallevels.Therearelittledataspecifically address-ingtheeffectofsamplingandculturemethodsonantibiotic consumption or antibiotic-free days. One study found an approximateincreaseof2antibiotic-freedayswithinvasive comparedtonon-invasiveairwaysampling[69].Intheabsence ofanytruegoldstandard,usingpost-mortemhistologyand pathologyfindingsuponautopsyasgold-standardsurrogates suggestsaslightlygreaterdiagnosticperformanceof quanti-tativecultures,regardlessofairwaysampletype.Indeed,inthe variousautopsycaseseriessummarisedinthe2016IDSA/ATS guidelines [70] and in a dedicated meta-analysis [71]: (a) quantitativeculture,regardlessofairwaysampletypehada diagnosticodds-ratio(DOR)>1,i.e.couldestablisha diagno-sisinthepresenceofpneumonia,albeitwithahighvariationin DORrangingfromcloseto1tomuchhigher,whereas(b) semi-ornon-quantitativecultureshadalowDOR,sometimes<1,i.e. ahighprobabilityofestablishingadiagnosisintheabsenceof pneumonia,andc)allpositivelikelihoodratios(LR+)werelow, closeto0.5,i.e.eveninthecaseofhighprevalencetherewould be a low post-test probability (40–50%) of establishing a diagnosiscomparedto pre-testsuspecteddiagnosis regard-lessofculturemethodandthresholds.Therefore,theremaybe anadvantagetoquantitativeculturesinestablishingthe diag-nosisandtheremaybeanadvantagetoinvasivesamplingin increasing antibiotic-freedays.Whileobtainingairway sam-plesshouldnotdelayinitiationofantibiotictreatmentinsevere

casesand/oracuterespiratorydistresssyndrome(c.f.R3.1)and itremainsessentialtoguidingand/orde-escalatingantibiotic therapywhenmicrobiologicalidentificationis achieved(c.f. R3.6).

Inonco-hematologypatientsadmittedtotheICUfor respi-ratorydistress,lackofanestablisheddiagnosisissignificantly associatedwithincreased mortality[72]. However,inthese patientsthediagnosisismostoftenHAP,intwo-thirdsofthe cases[73].Inarandomisedtrial,119onco-hematologypatients admittedtotheICUforrespiratorydistress,amongwhich31% wereneutropenic,invasivelowerrespiratory tractsampling [BAL]comparedtonon-invasivesamplingwasnotassociated with increased risk of intubation nor increased mortality, neitherwasthereanydifferenceindiagnosticyieldbetween samplingmethods,around80%[74].

R2.2 Paediatrics – We suggest collecting microbiological airway samples, regardless of type, before initiation of or anychangeinantibiotictherapy.

Evidencesummaryandrationalefortherecommendation: Labenneetal.comparedprotecteddistalbrushandblind bronchoalveolarlavagesamplesforVAPdiagnosis[75].Ofthe 103patients,29werediagnosedwithVAP.Thecombinationof brushing with culture of the blind bronchoalveolar lavage sampleandabacteriologicalindex(BI)resultedinasensitivity (Se)of90%andaspecificity(Sp)of88%forVAPdiagnosis. Gauvinetal.comparedseveraltypesofmicrobiological sam-plesandqualitativeorquantitativeculturemethodsforVAP diagnosis,usingthe1988CDCVAPdiagnosiscriteria[76].The best performingmethod forthe diagnosis of VAP wasthe bacteriologicalindex,BI>5(Se78%,Sp86%,positive predic-tivevalue,PPVof70%,andnegativepredictivevalue,NPVof 90%)butthenumberofVAPwaslow.Sachdevetal. prospec-tively found in30 patients asuperiority of protecteddistal samplescomparedtoendotrachealaspiratestodiagnoseHAP

[77].Thesameauthorsconfirmedtheexcellentreproducibility ofprotecteddistalsamplesin34childrenwithVAP,bothforthe cellular analysis and bacteriological diagnosis [78]. From 335samples obtainedprospectively in 61children, Willson etal.reportedthelackofusefulnessoftrachealsamplesfor VAPdiagnosis,suggestingthatthedistinctionbetween colo-nizationandinfectionischallenging[79].

Tosummarise,sinceendotrachealtubeandupperairway colonisation occur rapidly following intubation, the use of protecteddistalsamplesmayprovidesuperiorspecificityto endotrachealaspirates.Intheabsence ofanydemonstrated impactonoutcomes,thechoiceofairwaysamplingandculture methodsdependsontheenvironment,institutionaland de-partmentalstrategicchoices,takingintoaccountthe appropri-ate threshold of the chosen method when paired with quantitativecultures.

R2.3–Wesuggestnotmeasuringplasmaoralveolarlevelsof procalcitoninorsolubleTREM-1todiagnoseHAP.

Evidencesummaryandrationalefortherecommendation: Eightstudieshaveassessedthecontributionofmeasuring procalcitonin(PCT)plasmaconcentrationstothediagnosisof HAP,ontheirownorincombinationwithclinicalcriteria[80– 87]. Atotalof 589patientswereincludedforapneumonia prevalence of 55% and the following test characteristics: Se=54% (48–59%), Sp=67% (51–73%), PPV=67% and NPV=54%.The positivelikelihoodratio(LR+)was1.65and negative likelihood ratio (LR ) 0.68. These performances are insufficient to contribute to the diagnosis decision process. Diagnostic test thresholds varied, ranging from 0.15to3.9ng/mL.

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Sevenstudiesassessedthecontributionofalveolar concen-trationsofthesolubleformoftheTriggeringReceptor Expres-sedonMyeloidcells-1(sTREM-1)tothediagnosisofHAP[87– 93].Atotalof317patientswereincludedforaprevalenceof 48%.ThesTREM-1testcharacteristicswere:Se=83%(76–89%) andtheSp=77%(69–83%),resultinginaPPVof77%andaNPV of83%n,aLR+of3.56andLR of0.22.Evenifthese perfor-mances seem interesting, mainly for the exclusion of the diagnosis,the diagnosticthresholdsvaried widely,ranging from5to900pg./Mr.Thiscouldbeexplainedbydifferentand non-standardiseddosagetechniques,excludingthepossibility ofusingthistestinclinicalpracticeatthemoment.

It is surprising to observe the low number of patients includedinthese biomarkerstudies(PCTorsTREM-1), con-tributingtotheirpoorrobustness.

Thirdarea,TREATMENT:

What therapeutic options for HAP should be used to decreaseICUpatientmorbidityandmortality?

R3.1–Wesuggestimmediatelycollectingsamplesand initi-atingantibiotictreatmenttakingintoconsiderationrisk fac-torsformultidrugresistantbacteriainpatientswithsuspected HAPandhaemodynamicorrespiratorycompromise(shockor acuterespiratorydistresssyndrome)orfrailtysuchas immu-nosuppression.

Evidencesummaryandrationalefortherecommendation: Theurgentneedforantibioticsinsepticshockdoesnotfall withinthescopeoftheseguidelines.Cliniciansshouldconsult currentguidelinesonthemanagementofsepticshock.The immunosuppressedpatientsreceivespecifictreatment.

InHAP, noRCT hascomparedastrategybasedonearly empiricalantibiotictherapytodefinitiveantibiotictherapyafter pathogenisolation,identificationandsusceptibilitytestingon patient outcomes, with stratification on pre-test diagnosis probabilityandclinicalseverity.However,several observation-alstudiesandameta-analysishaveshownthatinappropriate initialantibiotictherapy,i.e.ineffectiveaccordingto suscepti-bility testing of the causal pathogen, was associated with worse outcomes (length of mechanical ventilation, length-of-stayandmortality),suggestingthattheappropriate empiri-calantibiotictherapyisassociatedwithimprovedoutcomes

[94–99].

R3.2–WerecommendtreatingHAPinmechanically-ventilated immunocompetentpatientsempiricallybyamonotherapy,in theabsence ofriskfactorsformultidrug-resistantbacteria, non-fermentingGramnegativebacilliand/orincreased mor-tality(septicshock,organfailure).

Evidencesummaryandrationalefortherecommendation: WeidentifiedthreeRCTspublishedoverthelasttenyears

[100–102] and a meta-analysis [103] of these three studies

(includingapriorstudy[104])including1163patients.They compared monotherapy vs. combined therapy. All studies reported on theimpact of combined therapyon mortality. Onlytworeportedonclinicalcureandtheincidenceofadverse effects [100,104]. No difference between monotherapy and combinedtherapywasfoundintermsofmortality(oddsratio [OR]:0.97;IC95%[0.73–1.30]),clinicalcure(OR:0.88;IC95% [0.56–1.36]),ICUlength-on-stay(OR:0.65;IC95%[0.07–1.23]), oradverseeffects(OR:0.93;IC95%[0.68–1.26]).Themoderate methodologicalqualitymainlycomesfromtheinaccuracyof theresultsand/ortheheterogeneityofstudiesincludedinthe meta-analysis.Wedecidedtogradethisrecommendationas stronginspiteofamoderateoverallmethodologicalquality

becauseof:aconvergenceofpublishedstudiestowardsthe absenceofbenefitofcombinedtherapy,thehighrelevanceof theendpointsstudiedinthestudies,anddatademonstrating adverse effects of combinedtherapy interms of increased toxicity,emergenceofresistanceandcost[105,106].However, severalelementsissuesremain:

the methodological quality of analysed trials in the meta-analysis ranges from moderate (mortality, ICU length-of-stay, adverse effects) to very low (clinical cure);

thenumberandsizeofstudiesarelimited.Infact,ifthe mortalityanalysisisbasedonfourstudies(n=1163), the other judgment criteria are analysed using two studies(n=350forclinicalrecovery;n=921foradverse effects;n=813forICUlength-of-stay);

observationalstudiesandafewcontrolledstudieshave suggestedthat inthepresenceofmultidrug-resistant bacteria[102]ornon-fermentingGram-negativebacilli

[107–110], the risk of an inappropriate empirical

antibiotictherapyishigher,resultinginhigher mortali-ty,andICUorhospitallength-of-stay.

Empiricalcombinedtherapyincreasestherateof appropri-ateempiricalantibiotictherapyinVAPcausedby multidrug-resistant bacteria[102,109].It isthereforeimportantto sys-tematicallyscreenforriskfactorstodevelopaninfectiontoor the carrying of multidrug-resistant (MDR) bacteria or non-fermentingGram-negativebacilli,mainlyPseudomonas aeru-ginosa.

Theestablished riskfactorsforPseudomonas aeruginosa pneumoniaareCOPD,bronchiectasisandcysticfibrosis.The riskfactorsassociatedwithMDRbacteriaairwaycolonisation andHAPare[70]:

antibiotictherapyintheprevious90days;

ahospitalstayofmorethan5dayspriortosuspected HAP;

renalreplacementtherapyrequirementduringHAP; septicshock;

ARDS.

Inthepresenceofatleastoneoftheseriskfactors,combined empiricaltherapyisindicated.However,afterpathogen iden-tificationandsusceptibilitytesting,nostudyhasshownthat pursuingcombinedtherapyremainsbeneficialinVAs, includ-ingVAPduetoPseudomonasaeruginosa[70,103,111].

Finally,foragivenpatient,apredictablemortalityrate above25%probablyremainsanindicationforcombined empiricalantibiotictherapy.Inameta-analysis includ-ingobservationalandrandomisedstudies,abeneﬁtto combinedtherapyisfoundintermsofmortality(31%vs. 41%;hazardratio:0.71;IC95%[0.57–0.89])inpatients withsepsisduetolunginfection[112].Theseresults havetobetakencautiouslysincetheydependonthe spectrumoftheprimaryantibiotic;combination thera-pyyieldednoadvantage whentheprimaryantibiotic was itself a broad-spectrum antibiotic. This meta-analysisalsoshowedthatcombinedtherapyinpatients

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withlowexpectedmortalityrate(<10%)tendstohave deleterious consequences. The recommendation is thereforequitelimitedsinceitonlyappliesto immuno-competentpatients,withoutanyriskfactorfor multi-drug-resistantbacteria,andatlowriskofmortality.In the presence of one or several of such risk factors, empirical combined therapy is probably indicated beforepathogenidentiﬁcationandsusceptibilitytesting resultsareavailable.

R3.3–Theexpertssuggestnotsystematicallydirecting em-piricantibiotictherapyagainstmethicillin-resistant Staphylo-coccusaureusinthetreatmentofHAP.

EXPERTSOPINION,STRONGAGREEMENT

Evidencesummaryandrationalefortherecommendation: Astudy randomisingpatientstreatedempiricallywithan antibioticregimenincludingornotanantibioticactiveagainst methicillin-resistantStaphylococcus aureus (MRSA)did not showanydifferencebetweenthetwostrategiesintermsof length-of-stayandmortality[113].Anobservationaland pro-spectivestudyfoundadecreaseinmortalityinpatientswho hadreceivedanempiricalantibiotictherapyincluding vanco-mycin[114].TheprevalenceofMRSAVAP(15%)supportsthis result. The literature suggests that inappropriate empirical antibiotictherapyplaysamajorpartinthemortalityofpatients

withMRSAHAP[115].However,astudyfoundanincreasein

ICUlength-of-stayinpatientswithMRSAHAP,independently fromtheadequacyoftheempiricaltreatment[116].The ade-quacyoftheempiricalantibiotictherapyisacriticalfactorfor survivalandthelength-of-stay[113,117].Arandomized con-trolledstudyhighlightedanincreaseinMRSAemergencein patients treated empirically with vancomycin [113]. This encourageshighlyselectingpatientstobetreatedempirically withanantibioticdirectedagainstMRSA.

Inconclusion,onlyonestudyconductedinanenvironment in which the prevalence of MRSA was high (15% of VAP episodes)showedanassociationbetweentheempiricaluse of anantibioticagainst MRSAand animprovementinHAP outcomes.Thereisthereforenorationaleforthesystematic empiricaluse of anantibioticagainst MRSAin France,the prevalencebeinglowerthan3%[118].However,the consid-erationof thelocalecologyisimportant.Some riskfactors encourageincludinganantibioticactiveagainstMRSAinthe empiricalantibiotictherapyofHAP,withoutthepossibilityto establishanexhaustivelist(experts’opinion):

highlocalprevalenceofMRSA; recentcolonisationbyMRSA; chronicskinlesions;

chronicrenalreplacementtherapy.

R3.4 – We suggest reducing the spectrum and preferring monotherapyfortheantibiotictherapyofHAPafter microbi-ologicaldocumentation,includingfornon-fermenting Gram-negativebacilli.

Evidencesummaryandrationalefortherecommendation: Bothreducingthespectrumandpreferringamonotherapy for the antibiotic therapy of HAP after documentation are encompassed by theterm‘‘de-escalation’’.De-escalation is possibleassoonasthemicrobiologicalresultsareobtained. Nine studiesand ameta-analysis address thisquestion. A meta-analysisbySilvaetal.didnotdrawconclusions

regard-ingsafetyandefficacyofde-escalation[119].Tworandomized opencontrolledstudiescomparedmortalityina ‘‘de-escala-tion’’ comparedto a‘‘control’’ group [113,120]. Thesetwo studiesdidnotfindanysignificantdifferenceinoverall mor-talitybetweenthetwostrategies.

Kimetal.foundanincreaseinmortalityinthede-escalation groupforMRSAdocumentedVAP.Sevenobservational stud-ieshavealsocomparedthede-escalationtothemaintenance oftheinitialantibioticregimenintermsofmortality.Inthree prospectivestudies [114,121,122]and aretrospective study

[123],mortalitydecreasedinthede-escalationgroup.Finally,

threeretrospectivestudies[124–127]didnotfindanymortality differencebetweenthetwostrategies.TheICUlength-of-stay wasprolonged(non-inferioritynotobtained)inthe de-escala-tiongroupof arandomisedstudy [120]. Onthecontrary,a prospectiveobservationalstudyfoundanassociationbetween ashorterICUlength-of-stayandde-escalation[122].

Theriskofrelapseassociatedwithde-escalationremained unchanged in two observational studies [126,127] and in-creasedinonerandomised[120]andoneretrospectivestudy

[124]. Inarandomisedstudy,de-escalation wasassociated

withanincreaseinthedurationofantibiotictreatment,even thoughlessactiveantibioticsagainstPseudomonas aerugi-nosawereusedinthede-escalationgroup[120].However,itis importanttonotethatinthisstudy,VAPrepresented48%of includedpatients[120].Asub-groupanalysisonthe56VAPs didnotfinddifferencesintheseoutcomes.

Insummary,nodataallowstoconfirmthatade-escalation strategyisassociatedwithincreasedmortality.Itisimpossible toconclude concerningtheriskof increasedlength-of-stay, antibioticconsumptionandinfectiousrelapse.However,ina strategyofantibioticstewardship,preservationoflarge spec-trumantibiotics,andpreventingtheemergenceof multidrug-resistantbacteria, andintheabsence ofprovendeleterious effectsonsurvival,de-escalationstrategyseemsreasonable.

R3.5–Werecommendnotprolongingformorethan7daysthe antibiotic treatmentfor HAP, includingfor non-fermenting Gram-negativebacilli,apartfromspecificsituations (immu-nosuppression,empyema,necrotisingorabscessed pneumo-nia).

Evidencesummaryandrationalefortherecommendation: There are two meta-analyses comparing treatment dura-tionsof8daysorlessto9daysormore[128,129].Dataareonly availableintheareaofVAP.Thefirstofthesemeta-analyses reliesonsixRCTs,includingameetingsummary,whichwas not reported here [130–134]. This meta-analysis included 508patients.Mortality(28-day,ICUandhospital), length-of-stayandofmechanicalventilationdidnotchangeaccordingto treatmentduration.Patientsintheshort-coursegrouphada meanincreaseinantibiotic-freedaysatday28of4.02days;IC 95%=2.26to5.78days),andadecreaseinsecondary infec-tiousepisodesduetomultidrug-resistantbacteria.However, thismeta-analysishighlightedatrendtowardsanincreaseof thenumberofrelapsesandasignificantincreaseinthenumber of pneumonia relapses in patients with a non-fermenting Gram-negativebacillusinfection.Theweightofasingle mul-ticenterstudywasessentialtoexplainthisresult[130].The increaseinrelapseswasnotassociatedwithincreased mor-tality.Thesecondmeta-analysisfoundsimilarresultsbasedon

three randomised studies including 883 patients

[130,132,133]. However, the increased risk of relapses for

VAPlinkedtonon-fermentingGram-negativebacilliwasnot confirmed. Nomedico-economicstudy comparedthe costs andefficacyofshorterandlongerantibioticcourses.

Insummary,there is nobenefitto prolonged coursesof antibiotic therapy (longer than 7 days) for VAP. Ashorter course reduces the exposure to antibiotics and infectious relapsestomultidrug-resistantbacteria,albeitwithapotential riskofrelapseofVAPassociatedwithnon-fermenting

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Gram-negative bacilli. The studies excluded immunosuppressed patients(HumanImmunodeficiencyVirus,neutropenia, immu-nosuppressants,corticosteroids>0.5mg/kg/dformorethana month,cysticfibrosis)andsituationsknowntorequire pro-longedantibiotictherapy suchasempyema,necrotisingor abscessed pneumonia [131; 133, 135]. A shorter antibiotic coursehasyettobeevaluatedinthesespecificpatient popu-lationsorsituationsandthisrecommendationmaytherefore notbeappliedtothem.

R3.6–Wesuggestadministeringnebulisedcolimycin(sodium colistimethate)and/oraminoglycosidesindocumentedHAP due multidrug-resistant Gram-negative bacilli documented pneumoniaestablishedassensitivetocolimycinand/or ami-noglycoside,whennootherantibioticscanbeused(basedon theresultsofsusceptibilitytesting).

Evidencesummaryandrationalefortherecommendation: Amongthestudies publishedoverthelast10 years,four

RCTs[135–138](withalowtomoderatemethodological

quali-ty)outofseven[135–141]concludedtothefavorableimpactof nebulisedantibioticsintermsofclinical[135,138]and micro-biological[136–138]cureinVAP.Followingtheseresults,three meta-analyses [70,142,143] (with a very low to moderate methodologicalquality)concluded toabenefitofnebulised antibioticsforclinicalcure(RR:1.29CI95%[1.13–1.47])[70]; (RR:1.57;CI95%[1.14–2.15])(143);(RR:1.23;CI95%[1.05– 1.43])(144)).Onlyonemeta-analysisconcludedtothe superi-orityof nebulisedantibioticsinterms ofmicrobiological re-sponse[142]. Twopositivestudies(intermsof clinicaland microbiologicalcureforthefirst[138]andmicrobiologicalcure forthesecond[136])werenotincludedinthemeta-analyses. No meta-analysis has demonstrated a favorable effect of nebulised antibiotics onmortality.However,Valachis etal. foundabenefitonsepsis-inducedmortality(RR:0,58;CI95% [0,34–0,96];veryweakmethodologicalquality).

The benefits in terms of decrease in the emergence of multidrug-resistant bacteria were shown in five studies

[136–139,144],ofwhichfourwererandomisedandcontrolled

[136–139].Thedecreaseintheemergenceof

multidrug-resis-tantbacteriaduringtreatmentwassignificantinthreestudies

[136–138]. The effect on thedecrease in the emergenceof

multirdrug-resistantbacteriaistobetakenintoaccount accord-ingtotheepidemiologicalcontext.Inspiteoftheefavorable meta-analyses,itisimportanttonotethat:

theinvestigationareaislimitedtoVAPdueto Gram-negative bacilli, mainly Enterobacteriaceae or non-fermentingGram-negativebacilli,implyingatreatment withamikacinand/orcolimycintreatment.Infact,sixof thesevenrandomisedandcontrolledstudiestestedthe administration of nebulised aminoglycosides. The pathogensresponsibleforVAPweremainly[137,138]

orexclusively[135,136,139–141]Gram-negativebacilli. Three of these seven studies speciﬁcally tested the efﬁcacy of nebulised antibiotics in VAP caused by Pseudomonasspp.andAcinetobacterspp[135,139,141]; thereisaheterogeneityamongthecontrolledstudies included in the three meta-analyses concerning the modalities of nebulisation, dosing of nebulised anti-biotics, concomitant systemic antibiotics, and non-consensualcompositecriteriaforclinicaland/or micro-biologicalcure;

the meta-analysis of Valachis et al. included seven observationalstudies andone randomised controlled study, leading to an assessment of its level of

methodological quality, varying from weak to very weak,accordingtothestudiedjudgmentcriteria[142]; the literaturedoes not supportthe superiority of an empirical combined therapycontaining eitherof the twoantibioticsadministeredbynebulisation; deleteriouseffectsof nebulisedantibiotics havebeen

described,mainlyinthemosthypoxemicpatients[145].

Intermsofmicrobiologicaleradicationof multidrug-resis-tantGram-negativebacilli,nebulisedantibioticshaveproven superiorintwocontrolledstudies[137,138]andnon-inferiorin oneobservational[144]andonecontrolledstudy[141].Inthis context,ameta-analysisincludingsixrandomizedcontrolled studiesandfiveobservationalstudiesconcludedtoa thera-peuticbenefitofnebulisedcomparedtosystemicantibiotics onmortality(RR:0.64;CI95%[0.44–0.94]).Adecreaseintherisk ofnephrotoxicitywasalsoobservedusingnebulisation(RR: 0.33;CI95%[ 0.54, 0.12]).Consequently,despitetheweak methodologicalqualityofthismeta-analysis,dueto heteroge-neityandgiven:

studies assessing the eradication kinetics of bacteria causing VAPs [136–139,144] and PK/PD parameters

[136,140]haveshownrapidbactericidaleffect,through

thehighcolimycin and/oraminoglycoside concentra-tions obtained at the alveolar level, with nebulised antibiotics[146–148];

experimentaldatashowingthatpulmonarypenetration ofaminoglycosidesandcolimycinisnullorveryweak followingsystemicadministration[149–151],the ben-efit-risk balance of nebulised antibiotics is probably favorable for documented VAP due to multidrug-resistantGram-negativebacillithataresusceptibleto colimycinand/oraminoglycosides.Thespecificsofthe equipmentused(vibratingplateorultrasonic nebuliza-tionchambers,positionofthenebulisationchamberin theventilationcircuit,specificformulationsofnebulised antibiotics) andthe specificmodalitiesofmechanical ventilationduringnebulisationrequirepriortrainingof teams,inordertoreproducetheconditionsdescribedin thepositivestudies.

R3.7–Werecommendnotadministeringstatinsasadjuvant treatmentforHAP.

Evidencesummaryandrationalefortherecommendation: Fiverandomisedcontrolledstudies[152–156]includedina meta-analysis (n=867) [157]) and one observational study

(n=349) [158] were analysed. Among these studies, three

controlledstudiesincludedpatientswithHAPoutsideofthe

ICU [153,154,156], two controlled studies[152,155] and an

observationalstudy [158]included patients admittedto the ICU and requiring mechanical ventilation [155,158] or not

[152].Papazianetal.[155]andBruye`reetal.[158]included

patients with sepsis from all causes, inwhom pneumonia represented approximately 50% of patients. Nobenefits in termsofmortality,ICUorhospitallength-of-stay,andinlength of mechanical ventilation were demonstrated with statins. Given the overall high methodological quality(high in the controlledstudies[152–156]andinthemeta-analysis[157]), the importance ofthe tested judgmentcriteria, therelative diversityofpopulation(outsideICU,ICU,

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mechanically-venti-latedornot)andthevariedtherapeuticregimens(atorvastatin orsimvastatin,loworhighdose),weobtainastrong recom-mendationcoveringalargeapplicationrange.Thesub-group of27observationalstudiesofthemeta-analysisistheonlyone tosuggestabeneficialeffectofstatinsonmortality[157].High heterogeneity,publicationbiasandthelimitstotheformatsof observationalstudiespublishedoverseveraldecadeslimitthe relevanceofthisresult.Thiseffectwasthereforenotretained asopentointerpretationbytheexperts.Finally,itisimportant tonotethehightoleranceofthetreatmentbystatins, regard-lessofmoleculeordose,withoutanyincreaseintheriskof rhabdomyolysisorhepaticcytolysis.

Wedidnotidentifyanystudiespublishedontheeventual roleofcorticosteroidsadministeredforHAPinICUpatients. Theonlystudypublishedthathastested anti-lipopolysaccha-ride monoclonal antibodies as an adjuvant treatment is a posteriorianalysis[159]ofapreviousstudyofthePhaseIIA

[160]comparing17patientsintreatmentand17patientsusing

placebos.Thepost-hoccharacteristic,thesmallstudysample size,addedtotheheterogeneousdemographiccharacteristics betweengroups,andthenon-crucialjudgmentcriteria(clinical resolutionofpneumonia),donotallowconcludingtoaneffect ofthistypeoftreatment.Norecommendationwasformulated ontheadjuvantadministrationoftheseadjuvanttreatments forHAPinadultICUpatients.

Disclosureofinterest

Se´bastienGibot:InotremS.A;EricKipnis:Astellas;LFB;Pfizer; MarcLeone:MSD;Basilea;Charles-EdouardLuyt:BayerHealthcare; ThermoFisherBRAHMS;MSD;Biomerieux;DjamelMokart:Gilead; Basilea;MSD;PhilippeMontravers:Pfizer;MSD;Basilea; AstraZe-neca;Bayer;Menari;Parexel;CubistSaadNseir:Medtronic; Cielme-dical;Bayer;Je´roˆmePugin:Bayer;partofthescientificcommitteefor theAmikacinInhalestudy;Jean-RalphZahar:MSD;Bard.

The remainingauthorsdeclarethattheyhaveno competing interest.

AppendixA

Protocol 1 suggested by experts: Multimodal healthcare associatedpneumoniapreventionprotocol(EXPERTS’OPINION) Multimodalhealthcare associatedpneumoniasprevention protocol

1–Favournon-invasiveventilation(NIV)(mainlyfollowing digestivesurgeryandforCOPDpatients)

Wheninvasiveventilationisrequired:

2 – Apply*aselectivedigestivedecontaminationprotocol withprophylacticsystemicantibiotictreatment<5days

*Iftheprevalenceofmultiresistantbacteriaislow(<20%). 3–Associatesomeofthefollowingmethods(1stline): favourtheuseofNIVtopreventintubation;

limitdoseanddurationofsedativesandanalgesicsassociated withmechanicalventilation;

initiateearlyenteralfeeding;

regularlyverifyendotrachealtubecuffpressures;

performsub-glotticsuction(/6-8hours)usinganappropriate endotrachealtube;

favourtheorotrachealrouteforintubation.

NB: The association of head of bed elevation <30˚ and/or oropharyngeal decontamination with 0.12 or 0.2% chlorhexidine

could be proposed in association to these measures, despite low efﬁciency,becausetheydonotcostmuchandarewell-tolerated.

4–Avoidusingthefollowingmethods:

systematicearlytracheotomy(apartfromspecificindications); anti-ulcerprophylaxis(apartfromspecificindications); post-pyloricenteralfeeding(apartfromspecificindications); probiotics;

systematic earlychanging of humidiﬁer ﬁlters (apart froma recommendationfromthemanufacturer);

closedendotrachealsuctionsystems;

theuseofintubationtubeslined/coatedorincorporatingsilver orantiseptics,orwithan‘‘optimised’’cuffshape;

oropharyngealdecontaminationusingpovidone-iodine; prophylacticnebulizedantibiotics;

dailyskindecontaminationusingantiseptics.

Protocol2suggestedbyexperts:Selectivedigestive decon-tamination(EXPERTS’OPINION)

Oro-pharyngealapplication(4/day,untiltracheal extuba-tion)ofapasteorgelcontaining

polymyxinE(2%); tobramycin(2%); amphotericinB(2%).

+

Administration(4/day,untiltrachealextubation)through anasogastrictubeof10mlofasuspensioncontaining 100mgpolymyxinE;

80mgtobramycin; 500mgamphotericinB.

+

Intravenous administration of a prophylactic antibiotic treatment during 48 to 72 hours for patients who do not requirecurativeantibiotictherapy

cefazolin1g3/d*;

Incaseofallergytocephalosporins: oﬂoxacin200mg2/d*;

ciproﬂoxacin400mg2/d*.

(*dosagesintheabsenceofrenalfailure,providedforinformation purposesonly)

Preparation for selective digestivedecontamination (pro-videdforinformationpurposesonly)

Oralgel (jar125mL) Suspension (bottles15mL) PolymyxinE Gentamicin AmphotericinB Sterilewater Methylcarboxycellulose Methylparahydroxybenzoate Propyleneglycol Mentholalcohol 4g 4g 4g 134mL 6g 0.3g 50mL 6mL 1g 0.8g 5g 100mL

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Protocol

3:

suggested

diagnostic

procedure

(EXPERT’S

OPINION)

*_N.B.:_In_case_of_radiographic_doubt,_it_is_possible_to_search_for_inﬁltrates_using_non-contrast_thoracic_computed_tomography_or_{consolidation} usingultrasound.

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References

[1]KoulentiD,TsigouE,RelloJ.Nosocomialpneumoniain27ICUsinEurope: perspectivesfromtheEU-VAP/CAPstudy.EurJClinMicrobiolInfectDis2016.

[2]GiulianoKK,BakerD,QuinnB.Theepidemiologyofnon-ventilator hospital-acquiredpneumoniaintheUnitedStates.AmJInfectControl2017[pii: S0196-6553(17)31056-8].

[3]MelsenWG,RoversMM,GroenwoldRH,BergmansDC,CamusC,BauerTT, etal.Attributablemortalityofventilator-associatedpneumonia:a meta-analysisofindividual patientdatafromrandomised prevention studies. LancetInfectDis2013;13(8):665–71.

[4]Branch-EllimanW,WrightSB,HowellMD.Determiningtheidealstrategyfor ventilator-associated pneumonia prevention. Cost-beneﬁtanalysis. Am J RespirCritCareMed2015;192(1):57–63.

Protocol4suggestedbyexperts:treatmentoptions(EXPERTS’OPINIONS)

Nosologicalframework Therapeuticclass Antimicrobials Dosingregimena

Earlypneumonia<5days

b

-lactam,inactiveagainst P.aeruginosa

Amoxicillin/clavulanicacid 3to6g/d

Absenceofsepticshock 3rdgen.cephalosporin,

cefotaxime

3to6g/d AbsenceofMDRbacteriarisk

factors

Incaseofallergyto

b

-lactam: levoﬂoxacin

500mg2/d Earlypneumonia<5days

b

-lactam,inactiveagainst

P.aeruginosa

Amoxicillin/clavulanicacid 3to6g/d

Presenceofsepticshock 3rdgen.cephalosporin,

cefotaxime

3to6g/day AbsenceofMDRbacteriarisk

factors

+Aminoglycosideb_or₊

Fluoroquinolone

Example:gentamicinor Example:oﬂoxacin

Incaseofallergyto

b

-lactam: Levoﬂoxacin+ Gentamicin 8mg/kg/d 200mg2/d 500mg2/d 8mg/kg/d Latepneumonia5days

or

presenceofotherriskfactorsfor nonfermentingGram-negative bacillie

b

-lactam,ACTIVEagainst P.aeruginosa Ceftazidime or 3to6g/d Cefepime or 4to6g/d Piperacillin-tazobactam orincaseofESBLc 16g/d Imipenem-cilastatine or 3g/d + Meropenem + 3to6g/d Aminoglycosideb or Amikacind or 30mg/kg/d Fluoroquinolone Ciproﬂoxacin 400mg3/d

Incaseofallergyto

b

-lactam Aztreonam

+

3to6g/d

Clindamycin 600mg3to4/d

Anypresentation,presenceof MRSAriskfactorsf

Addagentactiveagainst MRSA Vancomycin or 15mg/kgloadingfollowed by30to40mg/kg/dcontinuous Linezolid 600mg2/d

a_Doses_are_given_for_information_purposes_only_in_patients_with_normal_renal_function_and_standard_weight. b _Favour_the_use_of_{aminoglycosides}_over_{ﬂuoroquinolones}_to_limit_emergence_of_MDR_bacteria.

c _According_to_the_{guidelines’}_criteria_‘‘Reduce_de_use_of_antibiotics_in_intensive_care_unit’’.

d _Favour_the_use_of_amikacin_over_gentamicin_due_to_enhanced_efﬁcacy_against_{non-fermenting}_{Gram-negative}_bacilli.

e_Risk_factors_for_{non-fermenting}_{Gram-negative}_bacilli:_antibiotic_therapy_in_the_previous₉₀_days,_prior_hospital_stay_of_more_than₅_days, renalreplacementtherapyrequirementduringpneumonia,septicshock,acuterespiratorydistresssyndrome.

f_{Methicillin-resistant}_{Staphylococcus}_aureus_(MRSA)_risk_factors:_high_local_prevalence_of_MRSA,_recent_colonisation_by_MRSA,_chronic_skin lesions,chronicrenalreplacementtherapy.