Attualità in tema di polmoniti - SIMI – Società Italiana di … in... · ·...

Attualitàin tema di polmoniti

MarioVendittiDipartimentodiSanitàPubblica

eMalattieInfettive“Sapienza”UniversitàdiRoma

Confesso di aver ricevuto onorari per…

• Relatore a eventi ECM sponsorizzati: Astellas, Astra Zeneca, Angelini, Basilea, MSD, Pfizer, Gilead, Novartis.

• Partecipazione ad Advisory board: Angelini, MSD, Gilead, Nordic Pharma

T Phuong Quan et al. Thorax 2016 Feb 17

Diagnosis of CAP• Typical clinical features, chest x ray documented

pulmonary infiltrate +/- microbiology• Pretreatment blood samples for culture and an

expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized pts (Moderate recommendation; level I evidence.)

• Pretreatment Gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained (Moderate recommendation; level II evidence.)

• Pts with severe CAP, should at least have blood cultures, urinary antigen tests for L. pneumophila and S. pneumoniae performed, and sputum samples collected or culture. For intubated pts, an endotracheal aspirate sample should be obtained. (Moderate recommendation; level II evidence.)

IDSA/ATS guidelines Clinical Infectious Diseases 2007; 44:S27–72

•Ex fumatore•Ipertensione arteriosa•Pregresso IMA•Diabete mellito•BPCO, assumeva Ceftriaxone mensilmente a domicilio suconsiglio dello pneumologo curante•Encefalopatia multinfartuale con parkinsonismo, recentericovero•Portatore di mezzo di osteosintesi in sede calcaneale

Anamnesi patologica prossimaM 85 anniGiunge in reparto proveniente dal DEA per la

comparsa di dolore al bacino a seguito di caduta

a terra accidentale senza perdita di coscienza

Caso clinico

Ceftriaxone mensilmente a domicilio su consiglio dellopneumologo curante

caduta a terra accidentale senzaperdita di coscienza

Signsandsymptomsofpneumoniainfrailelderlypatients

Diagnosis of CAP• Typical clinical features, chest x ray documented

pulmonary infiltrate +/- microbiology• Pretreatment blood samples for culture and an

expectorated sputum sample for stain and culture (in patients with a productive cough) should be obtained from hospitalized pts (Moderate recommendation; level I evidence.)

• Pretreatment Gram stain and culture of expectorated sputum should be performed only if a good-quality specimen can be obtained (Moderate recommendation; level II evidence.)

• Pts with severe CAP, should at least have blood cultures, urinary antigen tests for L. pneumophila and S. pneumoniae performed, and sputum samples collected or culture. For intubated pts, an endotracheal aspirate sample should be obtained. (Moderate recommendation; level II evidence.)

IDSA/ATS guidelines Clinical Infectious Diseases 2007; 44:S27–72

caso clinico• Un uomo di 48 aa, non comorbidità,

giunge a PS per una sindrome di febbre elevata da 72 ore poi riconosciuta come CAP.

• CURB 65: 1. • Sfebbra in 48 ore con ceftriaxone iv

e viene dimesso con ceftriaxoneim,…..

• ....rientrerà dieci giorni dopo con una MOF, Antigenuria per Legionella positiva....guarirà dopo una lunga degenza in UTI......

Età, sesso, rischio

Rx, leucocitosi (L),

iposodiemia (IS)

Coinfezione Rx, esito

54, F, fumo Inf dx, L S. pneumoniae§

Amp/S+Ery, Ok

57, M, fumo Inf bil, IS S. pneumoniae§

Amp/S+Ery, Ok

68, F Inf sin, L, IS S. pneumoniae§

Amp/S, Recidiva

33, F, fumo Inf dx, L S. pneumoniae§

Meropenem, Ok…follow

up?73, M, fumo Inf bil, vers

pleur, LS. pyogenes Amp/S,

Recidiva74, M, cancro Inf bil, L E. cloacae§ Imip+tobra,

Recidiva

Polmonite da Legionella + Infezione concomitanteTan M.J. CID 35: 533, 2002

§ isolati dal sangue +/- espettorato

A clinical case from: Cunha CB Infect Control Hosp Epidemiol. 2016 Sep;37(9):1127-9

Epidemiology, Co-Infections, and Outcomes of ViralPneumonia in Adults. An Observational Cohort Study

Crotty et al. Medicine 94(50):e2332, 2015

835 pneumonias34% viral episodes!!!

Epidemiology, Co-Infections, and Outcomes of Viral Pneumonia in Adults. An Observational Cohort Study

Crotty et al. Medicine 94(50):e2332, 2015

Viruses Identified in Patients With Viral Pneumonia

Recommended empirical antibiotics for CAPIDSA/ATS guidelines Clinical Infectious Diseases 2007; 44:S27–72

1. punteggi di gravità.

2. Macrolide vs levofloxacina.

3. Terapia/profilassi per complicanze non infettive della

polmonite che insorge in comunità (CAP & HCAP)?

Expanded CURB-65: a new score system predicts severity of CAP with superior efficiency

Liu J , Xu F ,Zhou H , Wu X , Shi L , Lu R, Farcomeni A , Venditti M , Dong X, & Falcone M Sci Rep. 2016 Mar 18;6:22911.

• Derivation cohort:1640 pts (Zhejiang University); validation cohort: 1164 pts (Sapienza Univerity – Rome).

• Using age ≥ 65 years, LDH > 230 u/L, albumin < 3.5 g/dL, platelet count < 100 × 10(9)/L, confusion, urea > 7 mmol/L, respiratory rate ≥ 30/min, low blood pressure, we assembled a new severity score was assembled (expanded-CURB-65).

• The AUCs in the prediction of 30-day mortality in the 1640 chinese pts cohort were 0.826 (95% CI, 0.807-0.844), 0.801 (95% CI, 0.781-0.820), 0.756 (95% CI, 0.735-0.777), 0.793 (95% CI, 0.773-0.813) and 0.759 (95% CI, 0.737-0.779) for the expanded-CURB-65, PSI, CURB-65, SMART-COP and A-DROP, respectively.

• The performance of this bedside score was confirmed in CAP pts of the validation cohort although calibration was not successful in patients with HCAP.

1. punteggi di gravità.




Retrospective Analysis of Azithro vs FQs for Legionella Pneumonia Nagel JL et al P&T, 39: 203, 2014

Clinical outcomes

Nodifferences inpatients demographics, comorbidities, APACHE IIscore,direct admittance inICU,andcomplications

The Association of Antibiotic Treatment Regimen and Hospital Mortality in pts Hospitalized With Legionella PneumoniaGershengorn et al Clinical Infectious Diseases 2015;60(11):e66–79

Comparison of Outcomes of Azithro and Quinolone-Treated pts

Levo vs azithro for treating Legionellapneumonia: a propensity score analysis

Garcia Vidal C et al CMI 2017, in press

Neither univariate nor multivariate analysis showed a significantassociation of levofloxacin vs.

azithromycin on mortality [4(2.3%) vs. 9(5.1%) deaths; p=0.164].

The results did not change afterincorporation of the propensity score

into the models.

1. Punteggi di gravità




One-year outcomes of community-acquired and healthcare-associated pneumonia in the Veterans Affairs Healthcare System

Hsu JL InternJ Infect Dis 2011 on line early

CurvedisopravvivenzaKaplan–MeiersecondoHCAPstatusandcomorbidityscore;tutteledifferenzeHCAP–CAPrisultaronosignificative(p<0.05)

CDQ,Charlson–Deyo–Quancomorbidityindexscore

Cardiovascular Events and Short-Term Mortality Risk in CAP Violi F et al Clin Infect Dis 2017, early on line

Adjusted hazard ratios (HR), based on a Cox proportional hazards model, of intra-hospital CVE according to selected variables.

Cardiovascular Events and Short-Term Mortality Risk in CAP Violi F et al Clin Infect Dis 2017, early on line

Kaplan-Meier estimates of time to 30-days mortality in CAP ptswho experienced or not a CVE during the intra-hospital stay

Platelet Activation Is Associated With Myocardial Infarction in Patients With Pneumonia

Cangemi, R., et al., J Am Coll Cardiol. 2014; 64(18):1917–25.

Potential Mechanisms for Platelet Activation During Pneumonia

Estimated survival during hospitalization of the aspirin group, compared to the nonaspirin group,using Kaplan–Meier survival analysis.

Falcone et al J Am Heart Assoc. 2015 Jan 6;4(1):e001595

Non Aspirin group

Aspirin group

P= 0.001

aspirinplusmacrolides(A+M)improvessurvivalofptswithcommunity-onsetpneumoniapresentingwithsepticshock

FalconeM,etalIntensiveCareMedicine2016

aspirinplusmacrolides(A+M)improvessurvivalofptswithcommunity-onsetpneumoniapresentingwithsepticshock

FalconeM,RussoA,bertazzoniG,VioliF&VenditttiM,IntensivCareMedicine,2016

Cox regressionanalysis about effects of differentvariables onoverall survival during hospitalization

aspirinplusmacrolidesimprovessurvivalofpatientswithcommunity-onsetpneumoniapresentingwithsepticshock

FalconeM,RussoA,BertazzoniG,Violi F&VendittiMIntensveCareMedicine, 2016

Effect of Corticosteroids on Treatment Failure in pts With Severe CAP and High Inflammatory Response: A Randomized Clinical Trial

Torres et al JAMA, 2015

Clinical Outcomes Using Descriptive Statistics for Per-ProtocolPopulation

Secondary endpoint: no diffences (Los, time to stability…)

IDSAguidelines:maindifferencesbetween2017guidelinesandthe2005version

1. HAP denotes an episode of pneumonia not associated

with mechanical ventilation. Patients with HAP and VAP

belong to 2 distinct groups

2. Removal of the concept of HCAP…..

3. Recommendation for each hospital to generate

antibiograms to guide healthcare professionals with

respect to the optimal choice of antibiotics and to

decrease the unnecessary use of dual gram-negative and

empiricMRSA antibiotic treatment

WhataboutHCAP?”HCAPshouldnotbeincludedin

theHAP/VAPguidelines”!!!HCAP criteria

Thequestion…

…istheHCAPpredictiveofMDR

etiology?

Rischio di etiologie multiresitenti

CAP HCAP HAP/VAP

Rischio di morte

• Carratalà• Giannella

(Spain)

Shindo(Japan)

KollefMicek(USA)

Venditti(Italy)

Mortalità intra-ospedaliera

17.8%

p = 0.02p > 0.05

CAP HCAP HAP

18.4%6.7%

HCAPDoesNotAccuratelyIdentifyPotentiallyResistantPathogens:ASystematicReviewandMeta-Analysis

PrevalenceofMultidrug-ResistantPathogensinHCAPandCAPGroups

ChalmersJDetal.ClinInfectDis.2014;58:330-9.

IndividualizingRiskofMDRPathogensinCommunity-OnsetPneumonia

FalconeMetal.PLoSOne.2015;10:e0119528

Etiology of 300 isolations in the study population

DistributionofMDRpathogensinCAPandHCAPpopulations

FalconeMetal.PLoSOne.2015;10:e0119528

Multivariate analysis of factors associated with MDR isolation

Falcone M et al PLOS ONE | DOI:10.1371/journal.pone.0119528, 2015

Risk stratification of MDR isolation on the basis of ARUC score

DiagnosisofHAP/VAP

Versus

NEnglJMed2006;355:2619–30

A randomized trial of diagnostic techniquesfor ventilator-associated pneumonia

Thereisnoevidencethatinvasivemicrobiologicalsamplingwithquantitativeculturesimprovesclinicaloutcomescomparedwithnoninvasivesamplingwitheitherquantitativeorsemiquantitativecultures.

ATS2005versus IDSA2016Recommendeduseofnoninvasivesamplingwith

semiquantitativecultures

NoninvasivesamplingqMorerapid

qFewercomplications

qFewerresources

IDSAGuidelines,ClinInfectDis2016:63

Semiquantitative culturesqmorerapidly

qfewerlaboratoryresources

qlessexpertiseneeded

UsefulnessofprocalcitoninforthediagnosisofVAP

LuytCEetal.IntensiveCareMed.2008;34:1434-40

OnDay1nobestPCTcutoffvaluesforVAPdiagnosiscouldbeestablished.Usingathresholdof0.5ng/ml

yielded72%sensitivitybutonly24%specificity

UsefulnessofprocalcitoninforthediagnosisofVAP

LuytCEetal.IntensiveCareMed.2008;34:1434-40

PCTincreasebeforeDay1doesnotreachhighsensitivityandspecificity

PCT,CRP&CPISToDiagnoseVAPAndHAP

…useofclinicalcriteriaalone,ratherthanusingserumPCT+clinicalcriteria,todecidewhetherornot

toinitiateantibioticsstrongrecommendation,moderate-quality evidence

…useofclinicalcriteriaaloneratherthanusingCRP+clinicalcriteria,todecidewhetherornot

toinitiateantibioticsweakrecommendation, low-quality evidence

…useofclinicalcriteriaaloneratherthanusingCPIS+clinicalcriteria,todecidewhetherornot

toinitiateantibioticsweakrecommendation, low-quality evidence


Recommentation…

TreatmentofHAP/VAP

HAP-nonVAP VAP

2distinctgroups!!


vs

Empirictherapy

ATSversus

IDSAguidelines

EmpiricTherapyofHAP/VAP

Antibioticselectionforeachpatientbasedon:Timeofonset[late(≥5d)versusearlyonset(<5d)]

ATSGuidelinesAmJRespirCritCareMed,2005

TheriskfactorsforMDR

pathogens

EarlyonsetornoriskfactorsforMDR

ATSGuidelinesAmJRespirCritCareMed,2005EmpiricTherapyofHAP/VAP

LateonsetorriskfactorsforMDR

ATSGuidelinesAmJRespirCritCareMed,2005EmpiricTherapyofHAP/VAP

Newrecommendations

TimingconsideredonlyforVAP

EmpiricTherapyofHAP/VAP

EarlyandlateonsetHAP(ATS2005)

EmpiricTreatmentofHAP-nonVAP

riskofmortality!!


Itshouldbebasedon…

Needforventilatorysupportduetopneumonia

Septicshock

EmpiricTreatmentofHAP-nonVAPIDSAGuidelines,ClinInfectDis2016:63

riskfactorsforMDRItshouldbebasedon…


NoHighRiskofMortalityvnoneedforventilatorysupport

vnosepticshock

NoincreasedLikelihoodofMRSAvNoivantibiotictherapywithin90d

vunitwhereMRSArate<20%

AND

Oneofthefollowing:•Piperacillin-tazo4.5gIVq6h

•Cefepime2gIVq8h

•Levofloxacin750mgIVdaily

•Imipenem500mgIVq6h

•Meropenem1gIVq8h

IncludeCoverageforMSSAandP.aeruginosa


ONEAGENT!!


IncreasedLikelihoodofMRSAvIvantibiotictherapywithin90d

vunitwhereMRSArate>20%or

prevalencenotknown

AND

Oneofthefollowing:•Piperacillin-tazo4.5gIVq6h•Cefepime2gIVq8h•Levofloxacin750mgIVdaily•Ciprofloxacin400mgIVq8h•Imipenem500mgIVq6h•Meropenem1gIVq8h

IncludeCoverageforMRSAandP.aeruginosa


Vanco15mg/kgIVq8-12hwiththegoaltotarget15-20mg/mLtrough

level

Linezolid600mgIVq12h

OR

TWOAGENTS!!

NoHighRiskofMortalityvnoneedforventilatorysupport

vnosepticshock


HighRiskofMortalityvNeedforventilatorysupport

vSepticshock

FactorsincreasingthelikelihoodforP.

aeruginosa orotherGram-negativebacilliPriorantibioticusewithin90days

AND

Two ofthefollowing,avoiding2β-lactams•Piperacillin-tazo4.5gIVq6h•Cefepime2gIVq8h•Levofloxacin750mgIVdaily•Ciprofloxacin400mgIVq8h•Imipenem500mgIVq6h•Meropenem1gIVq8h•Amikacin15-20mg/kgIVdaily•Gentamicin5-7mg/kgIVdaily•Tobramycin5-7mg/kgIVdaily

IncludeCoverageforMRSAandP.aeruginosa

IDSAGuidelines,ClinInfectDis 2016:63

Vancomycin15mg/kgIVq8-12hwiththegoaltotarget15-20mg/mL

troughlevel

Linezolid600mgIVq12hOR

THREEAGENTS

EmpiricTherapyofVAP

EnsurecoverageforS.aureus,Pseudomonasaeruginosa,andothergram-negativebacilliinallempiricregimens

strongrecommendation, low-qualityevidence

Riskfactorforantimicrobialresistance•priorIVantibioticusewithin90d•septicshockattimeofVAP•ARDSprecedingVAP•5omoredaysofhospitalizationpriortotheoccurrenceofVAP•acuterenalreplacementtherapypriortoVAPonset

PatientsbeingtreatedinunitswhereMRSArate>10%–20%orinunitswheretheprevalenceofMRSAisnotknown

IncludeMRSAcoverage

IDSAGuidelines,ClinInfectDis 2016:63

EnsurecoverageforS.aureus,Pseudomonasaeruginosa,andothergram-negativebacilliinallempiricregimens

strongrecommendation, low-qualityevidence

Riskfactorforantimicrobialresistance•priorIVantibioticusewithin90d

•septicshockattimeofVAP•ARDSprecedingVAP

•5omoredaysofhospitalizationpriortotheoccurrenceofVAP•acuterenalreplacementtherapypriortoVAPonset

Patientsbeingtreatedinunitswhere>10%ofgram-negativeisolatesareresistant toanagentbeingconsideredformonotherapy

Use2antipseudomonal agents

IDSAGuidelines,ClinInfectDis 2016:63EmpiricTherapyofVAP

Avoidaminoglycosidesifalternativeagentswithadequategram-negative

activityareavailable(weakrecommendation,low-qualityevidence).

Avoidcolistinifalternativeagentswithadequategram-negative

activityareavailable(weakrecommendation,verylow-qualityevidence).

IDSAGuidelines,ClinInfectDis2016:63EmpiricTherapyofVAP

NewATS/IDSAguidelines:

Whataboutantibioticchoices?

Malattia da Aspergillus

• Sudbdola e indolente à capace di accellerare in una progressione fatale

• Necessità e possibilità di diagnosi precoce con surrogati marker?

• Nuove categorie a rischio• Prospettive terapeutiche….

Chest radiographs performed at day 1 (left) showing bilateral reticular-nodular infiltrates, and at day 10 (right) showing

extensive bilateral consolidations.

Fatal Invasive Pulmonary Aspergillosis Complicating Influenza A (H1N1)v Infection

Carfagna P, Brandimarte P, Caccese R, Campagna D, Brandimarte C, Venditti M.Mycoses on line early, 2011

Mycoses 2017

Diagnostic criteria for CPA according to ESMID/ERS/ECCM and IDSA guidelines

OtherrecommendationsPK/PDOPTIMIZATION

OFANTIBIOTICTHERAPY

ROLEOFINHALEDANTIBIOTIC

THERAPY

IDSAGuidelines,CID2016:63

MeropenemfortreatingKPC-producingKlebsiellapneumoniae bloodstreaminfections:Shouldwe

gettothePK/PDrootoftheparadox?DelBonoetal.Virulence 2017;8:66-73

Univariate logistic regression analysis of variables associated with clinical cure from KPC-producing Klebsiella

pneumoniae-related infections (n = 30 patients)Pea F et al IJAA, 2017

Variable OR (95% CI) P-value Age 1.032 (0.969–1.100) 0.322 Male sex 1.154 (0.218–6.097) 0.866 CCI ≥ 4 0.158 (0.025–0.999) 0.050 Length of therapy 1.091 (0.936–1.271) 0.264 Mero Css/MIC ³1 10.556 (1.612–69.122) 0.014 * Mero Css/MIC ³4 12.250 (1.268–118.361) 0.030 * Mero MIC 0.965 (0.930 – 1.003) 0.068 Site of infection .................No. of co-administered antimicrobials 1 active drug 3.267 (0.334–31.914) 0.309 2 active drugs 0.952 (0.179–5.081) 0.954 3 active drugs 2.059 (0.202–20.959) 0.542 ≥4 active drugs 0.167 (0.022–1.282) 0.085

BoissonMetalAntimicrobAgentsChemother2014;587331-7339

Comparison of Intrapulmonary and Systemic Pharmacokinetics of Colistin Methanesulfonate (CMS) and Colistin after Aerosol Delivery and

Intravenous Administration of CMS in Critically Ill Patients

Effect of Aerosolized Colistin as Adjunctive Treatment on the Outcomes of Microbiologically Documented VAP Caused by Colistin-Only

Susceptible Gram-Negative Bacteria Tumbarello M et al Chest 2015

Multivariate Analysis of Factors Associated With Clinical Cure in ptsWith VAP Caused by Colistin-Only Susceptible Gram-Negative Bacteria

P=0.001

caso• 63 anni, diabete tipo I e cirrosi CP:

B8àC• Profilassi con norfloxacina per

profilassi recidiva di peritonite primaria• Terapia con inibitori di pompa…• Piastrinopenia & IRCàIRA• Polmonite a insorgenza comunitaria

con criteri HCAP (frequenti ricoveri)• Terapia empirica?

Nuovi antibioticiAgente tipo di spettroCeftarolina ceftriaxone+MRSACeftibrolo cefepime+MRSA Ceftolozano/tazo pip/tazo + P aeruginosa MDRCeftazidime-avibactam ceftazidime+ KPC & ESBLTedizolid <tossico e >PK/PD di linezolidFosfomicina iv partner àMRSA,

ESBL, KPC & P aeruginosa MDR

LenghtoftherapyIDSAGuidelines,ClinInfectDis 2016:63

Discontinuationoftherapy

ProcalcitonintoGuideInitiationandDurationofAntibioticTreatmentinAcuteRespiratoryInfections:

AnIndividualPatientDataMeta-Analysis

SchuetzPetal.ClinInfectDis.2012;55:651-62

ProcalcitonintoGuideInitiationandDurationofAntibioticTreatmentinAcuteRespiratoryInfections:

AnIndividualPatientDataMeta-Analysis

Antibioticuseinallpatients

SchuetzPetal.ClinInfectDis.2012;55:651-62

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