AdjunctiveTreatmentofCommunity-AcquiredPneumonia:
ANewRoleofCorticosteroids?
SarahKlembith,Pharm.D.
PGY1PharmacyResident
CentralTexasVeteransHealthCareSystem
TheUniversityofTexasatAustinCollegeofPharmacy
January15,2016
LearningObjectives:
1. Understandtheepidemiology,pathophysiology,diagnosis,andseverityofpneumonia
2. Reviewcurrentguidelinesforthetreatmentofcommunity-acquiredpneumonia
3. Reviewcorticosteroidsandtheirroleininflammation
4. Analyzeliteratureregardingthebenefitofcorticosteroidsinthetreatmentofcommunity-acquiredpneumonia
5. Formulaterecommendationsregardingtheuseofcorticosteroidsincommunity-acquiredpneumonia
I.
BACKGROUND:PNEUMONIA
Epidemiology
A. Overfivemillionadultsareaffectedbycommunity-acquiredpneumonia(CAP)eachyearintheUnitedStates(U.S.)1
B. Highmorbidityandmortality
1. Pneumoniaandinfluenzacombined2
a. EighthleadingcauseofdeathintheU.S.
b. Mostcommoncauseofinfection-relatedmortality
2. Despiteadvancesinantimicrobialtherapy,ratesofmortalityduetopneumoniahavenotdecreasedsignificantly2
a. Hospitalinpatientdeaths:3.4%
b. MortalityrateforCAPpatientsadmittedtointensivecareunit(ICU)rangesfrom21-58%1
C. Pneumoniaoccursatallages3
1. Morecommoninelderly
D. EstimatedannualeconomicburdenofCAPintheU.S.exceeds10billiondollars4
II. Pneumoniaclassification3
A. Community-acquired:nocontacttoamedicalfacility
B. Hospital-acquired:developing>48hoursafterhospitaladmission
C. Healthcare-associated:non-hospitalizedpatientsatriskofmulti-drugresistant(MDR)pathogens
1. TwoormoreriskfactorsforMDRpathogen
a. Recenthospitalization≥2dayswithinpast90days
b. Nursinghomeorlong-termcarefacilityresident
c. Recentantibioticuse(past30days),chemotherapy,woundcare,orinfusiontherapy
d. Hemodialysis
e. ContactwithfamilymemberwithinfectioncausedbyMDRpathogen
D. Ventilator-associated:developing>48hoursafterintubationandmechanicalventilation
III. Pathophysiology3
A. Pathogenenterslowerrespiratorytractbythreeroutes
1. Inhaled
2. Hematogenous
3. Aspiration(oropharyngealcontents)
B. Componentsofinnateimmunesystemfailtoclearpathogen
1. Normallyexpelledbymucociliaryclearance,cough,antimicrobialpeptides,andlocalinnateimmunedefenses5
C. Systemicinflammationfollows6-8
1. Increasedpro-inflammatorycytokines
2. Highlevelsofinflammationareassociatedwithhigherratesoftreatmentfailure
3. PatientswithsevereCAParefoundtohaverelativeadrenalinsufficiency
D. Canprogresstoacuterespiratoryfailure,septicshock,multi-organfailure,anddeathifleftuntreated
E. MostcommonpathogensinCAP3,9
1. Streptococcuspneumoniae-mostcommon
2. Atypicalorganisms:Mycoplasmapneumoniae,Legionellaspecies,Chlamydophilapneumoniae
3. Haemophilusinfluenzae
4. Varietyofviruses
F. Riskfactors3
1. Chronicobstructivepulmonarydisease(COPD)
2. Humanimmunodeficiencyvirus(HIV)infection
3. Diabetesmellitus
4. Age>65years
5. Depressedmucociliarytransport
a. Ethanolandnarcoticuse
b. Bronchusobstruction
6. Alteredsensoriumandneuromusculardisease–mayresultinincreasedinoculumsize
IV. Clinicalpresentation
A. Signsandsymptoms3,5,10
1. Beginsasmildupper-airwayirritation
2. Fever,chills,malaise,cough,dyspnea,pleuriticchestpain
3. Rust-coloredsputumorhemoptysis
Klembith|2
B.
C.
Physicalexam3
1. Tachypneaandtachycardia
2. Dullnesstopercussion
3. Diminishedbreathsoundsoveraffectedarea
4. Inspiratorycrackles
5. Increasedtactilefremitus,whisperedpectoriloquy,andegophony
6. Chestwallretractions
Oftenmoresubtleinolderpatients10
1. Oftenpresentswithweaknessanddeclineinfunctionalormentalstatus
Diagnosis9,10
A. Lungimagingshowinginfiltraterequiredfordiagnosis
1. Chestradiographmostcommon
a. Denselobarorsegmentalinfiltrate
b. Patchyconsolidationoccasionally
c. Lobarconsolidation,cavitation,andpleuraleffusionssuggestabacterialetiology
B. Clinicalfeatures
1. Cough
2. Fever
3. Pleuriticchestpain
C. Laboratorytesting9
1. Investigatedforspecificpathogensthatwouldsignificantlyalterstandardempiricalmanagement
a. Overalllowyieldandinfrequentpositiveimpactonclinicalcare
i. Againstroutineuseofcommontests(bloodandsputumcultures)
b. Specificclinicalindicationsformoreextensivediagnostictesting(AppendixA)
i. Resultwilllikelychangeindividualantibioticmanagement
2. Sputumandbloodculturesrecommendedforinpatientswithsevereillness10
VI. Severityandsite-of-caredecision9
A. Hospitalizationrecommended
1. CURB-65score≥2(moderaterecommendation)
a. Confusion
b. Bloodureanitrogen(BUN)≥20mg/dL
c. Respiratoryrate≥30breaths/min
d. Systolicbloodpressure<90mmHgordiastolicbloodpressure≤60mmHg
e. Age≥65years
2. PneumoniaSeverityIndex(PSI)riskclassIVandV
a. Assessespatientdemographics,comorbidities,physicalexaminationfindings,laboratoryandradiographic
findings11(AppendixB)
b. Riskstratificationintofiveseverityclasses
3. Objectivecriteriaofscoresshouldalwaysbesupplementedwithclinicaljudgement
B. DirectadmissiontoICU
1. Onemajorcriteriaforseverepneumonia(strongrecommendation)
a. Septicshockrequiringvasopressors
b. Acuterespiratoryfailurerequiringintubationandmechanicalventilation
2. Threeormoreminorcriteriaforseverepneumonia(moderaterecommendation)
a. Respiratoryrate≥30breaths/minute
b. Arterialoxygenpressure/fractionofinspiredoxygen(PaO2/FiO2)ratio≤250
c. Multilobarinfiltrates
d. Confusion/disorientation
e. BUNlevel≥20mg/dL
f. Leukopeniaresultingfrominfection(whitebloodcell[WBC]count<4000cells/mm3)
g. Thrombocytopenia(plateletcount<100,000cells/mm3)
h. Hypothermia(coretemperature<36°C)
i. Hypotensionrequiringaggressivefluidresuscitation
V.
Klembith|3
TREATMENTGUIDELINES:COMMUNITY-ACQUIREDPNEUMONIA
I. InfectiousDiseasesSocietyofAmerica/AmericanThoracicSociety(IDSA/ATS)CAPGuidelines9
A. Empiricalantimicrobialtherapydependingonsite-of-caredecision,riskfactorsfordrug-resistantpathogens,and
comorbidities(AppendixC)
1. Firstdoseofantibioticshouldbegivenwhilestillintheemergencydepartment(ED)ifadmittedthroughtheED
B. Durationofantibiotics(moderaterecommendation)
1. Treatedforaminimumof5days
2. Afebrilefor48-72hours
3. NomorethanoneCAP-associatedsignofclinicalinstabilitybeforediscontinuationoftherapy
C. Criteriaforclinicalstability
1. Temperature≤37.8°C
2. Heartrate≤100beats/min
3. Respiratoryrate≤24breaths/min
4. Systolicbloodpressure≥90mmHg
5. Arterialoxygensaturation≥90%orpartialpressureofoxygen(pO2)≥60mmHgonroomair
6. Abilitytomaintainoralintake
7. Normalmentalstatus
II. Adjunctivecorticosteroidrecommendations
Table1.Corticosteroidrecommendationsaccordingtovariouspneumoniaguidelines
Guideline
Recommendation
BTS,2015
• SteroidsarenotrecommendedintheroutinetreatmentofhighseverityCAP
annotated12
NICE,201413
• DonotroutinelyofferglucocorticosteroidsinCAPunlesspatienthasotherconditionsfor
whichtreatmentisindicated
• BenefitofglucocorticosteroidtreatmentseeninICUsetting;however,cannotmakespecific
positiverecommendationinthissetting
Dutch,201114
• Corticosteroidsarenotrecommendedasadjunctivetherapy
IDSA/ATS,20079
• ScreenpatientswithsevereCAPforcorticosteroidinsufficiencyandreplacementis
appropriateifinadequatecortisollevelsaredocumented
• Criteriaforsteroidreplacementremainscontroversial
• Recommendtightglucosecontrolifcorticosteroidsadministered
BTS–BritishThoracicSociety;NICE–NationalInstituteforHealthandCareExcellence
GLUCOCORTICOIDSANDINFLAMMATION
I. Inflammation15,16,17
A. Reflexiveresponsetodetectionofmicrobialinfection
B. Complementandtoll-likereceptorsactivated
C. Synthesisandreleaseofinflammatorymediators
D. Effectsonthevasculature
1. Localizedvasodilation
2. Increasedvascularpermeability
3. Extravasationofplasmaproteins
4. Migrationofleukocytes
E. Beneficialroleininhibitionandeliminationofprimaryinfection
F. Excessiveorpersistentinflammationleadstotissuedestructionanddisease
1. Down-regulationofinflammatoryresponsemayimproveclinicalcourseofCAP18
a. Glucocorticoidsareoneofthemostprescribedclassesofanti-inflammatorymedicationsworldwide
II. Endogenousglucocorticoids15
A. Hypothalamic-pituitary-adrenalaxis
1. Hypothalamussecretescorticotropin-releasinghormone(CRH)
2. CRHstimulatesreleaseofcorticotropinfromanteriorpituitary
3. Corticotropininducessynthesisandsecretionofcortisolbyadrenalcortex
Klembith|4
B.
C.
Glucocorticoidreceptor
1. Expressedinvirtuallyallcells
2. Steroidhormonereceptorfamily
3. Highaffinityforcortisol
4. Pleiotropiceffectsofglucocorticoidreceptorsonmultiplesignalingpathways
Cortisolanti-inflammatoryactionsbyinhibitingsynthesisofcytokinesandinflammatorymediatorsbyseveral
pathways(AppendixD)
1. Cortisol-glucocorticoidreceptorcomplexbindsglucocorticoid-responsiveelementsinthenucleusandfacilitates
orinhibitstranscription
a. InductionandactivationofannexinI
i. AnnexinIinhibitscytosolicphospholipaseA2α(cPLA2α)andblocksreleaseofarachidonicacidand
subsequentconversiontoeicosanoids(prostaglandins,thromboxanes,prostacyclins,andleukotrienes)
b. Inductionofmitogen-activatedproteinkinase(MAPK)phosphatase1
i. InactivatesJunN-terminalkinaseandpreventskinasecascade
(i) Inhibitstranscriptionofinflammatoryandimmunegenes
ii. MayinhibitcPLA2αbyblockingitsphosphorylationbyMAPKs
c. Cortisol-glucocorticoidreceptorcomplexdirectlyinterfereswithc-Jun-mediatedtranscriptionthrough
protein-proteininteractions
2. Interactionbetweencortisol-glucocorticoidreceptorcomplexandothertranscriptionfactorsregulateother
glucocorticoid-responsivegenes
a. Inhibitnuclearfactor-κB(NF-κB)transcriptionactivity
i. Blocksproductionofcytokines,chemokines,cell-adhesionmolecules,complementfactors
ii. RepressionofNF-κB-inducedtranscriptionofcyclooxygenase-2(COX-2)
b. Occursatlowercortisollevels
3. Glucocorticoidsignalingthroughmembrane-associatedreceptorsandsecondmessengers
III. Exogenousglucocorticoids
A. Comparisonofavailableglucocorticoids
Table2.Glucocorticoidrelativepotenciesanddoses19,20
Glucocorticoid
EquivalentDose*(mg)
Short-acting
Hydrocortisone
20
(cortisol)
Cortisoneacetate
25
Intermediate-acting
Prednisone
5
Prednisolone
5
Methylprednisolone
4
Triamcinolone
4
Long-acting
Dexamethasone
0.75
Betamethasone
0.75
*Oralorintravenous(IV)administration
RelativeAntiInflammatoryActivity
RelativeMineralocorticoid
(sodium-retaining)Activity
1
1
0.8
0.8
4
4
5
5
0.8
0.8
0
0
30
25
0
0
B.
C.
Numerousindications
Mechanismofaction
1. Sameasendogenouscortisol
D. Glucocorticoiddosingandpharmacokinetics(AppendixE)
E. Discontinuation19
1. Gradualwithdrawalbytaperingdosetopreventadrenalsuppression
a. Long-termtherapy
b. Highdoses(>20mg/dayofprednisoneorequivalentfor>3weeks)
F. Drug-druginteractions19
1. Immunosuppressants
2. Non-steroidalanti-inflammatorydrugs(NSAIDs)
3. Warfarin
Klembith|5
G.
4. Fluoroquinolones
5. Liveandinactivatedvaccines
6. Salicylates
7. Antidiabeticagents
8. Antacids
Adverseeffectsfromhigh-doseorprolongedglucocorticoidtherapy15,19
1. Hyperglycemia
2. Osteoporosis
3. Hypertension
4. Immunosuppression(increasedincidenceofsecondaryinfection,maskacuteinfection,prolongorexacerbate
viralinfections,limitresponsetoinactivatedvaccines)
5. Psychiatricdisturbances(severedepression,euphoria,insomnia,moodswings,personalitychanges,psychosis)
6. Growthretardationinchildren
7. Inhibitionofwoundrepair
8. Myopathy
9. Increasedintraocularpressure,open-angleglaucoma,andcataracts
10. Pepticulcer(withpossibleperforationandhemorrhage)
IV. ClinicalQuestion
A. DoestreatmentwithadjunctivecorticosteroidsimproveclinicaloutcomesinpatientswithCAP?
Klembith|6
LITERATUREREVIEW
Table3.SummaryofearlytrialsofadjunctivecorticosteroidtherapyinCAP
Study,Year StudyDesign
N
Sample
Primary
Corticosteroid
(Location)
Outcome
AgentandDuration
Confalonieri, Randomized, 46
SevereCAPin
PaO2:FiO2
Hydrocortisone200
200521
double-blind,
ICUtreatment
mgIVbolus,then10
placebomg/hourfor7days
(Italy)
controlled,
multicenter
Garcia-Vidal, Retrospective, 308
Hospitalized
30-day
Methylprednisolone
200722
observational
patientswith
mortality
(mediandose45.7
severeCAP(PSI
mg/dayor
(Spain)
IVorV)
equivalent)
Snijders,
Randomized, 213
Hospitalized
Clinicalcure
Prednisolone40mg
201023
double-blind,
patientswith
atday7
orallyorIVdailyfor
placeboCAP
7days
(Netherlands) controlled
Results
SignificantimprovementinPaO2:FiO2byday8andhospital
mortalitywithhydrocortisone(enrollmentsuspendedat
interimanalysis)
• Significantincreasedsurvivaltohospitaldischargein
hydrocortisonegroup(p=0.009)
• Mortalitywassimilarinbothgroups(5%nocorticosteroids
and7%corticosteroids)
• Steroidshadaprotectiverole(OR0.287,95%CI0.113-0.732)
• Severityofpneumoniaindependentfactorassociatedwith
increasedmortality(OR2.923,95%CI1.262-6.770)
• Nodifferenceinclinicalcureatday7
• DeclineinCRPlevelsfasterinprednisolonegroupuntilday7;
CRPhigheratday14
• Morelatefailuresinnon-severeCAPinprednisolonegroup
• Nodifferenceinadverseevents
Meijvis,
Randomized, 304
Hospitalized
Lengthof
Dexamethasone5mg • Statisticallysignificantdifferenceinmedianlengthofhospital
201124
double-blind,
patientswith
hospitalstay IVfor4days
stayby1day
placeboconfirmedCAP
• Nodifferenceinsecondaryoutcomesofhospitalmortalityand
(Netherlands) controlled
(excludedif
ratesofadmissiontoICU
directICU
• GreaterdeclineinCRPandIL-6concentrationsin
admission)
dexamethasonegroupinfirst4days
• Hyperglycemiamorecommonindexamethasonegroup
Nie,201225
Meta-analysis 1001 Hospitalized
Mortality
Hydrocortisone,
• Corticosteroidsdidnotsignificantlyreducemortality(PetoOR
of9RCTs
patientswith
prednisolone,
0.62,95%CI0.37-1.04)
CAP
dexamethasone,
• Subgroupanalysisbyseverity(4trials,N=214):survival
methylprednisolone
benefitinsevereCAP(PetoOR0.26,95%CI0.11-0.64)
• Subgroupanalysisdurationofcorticosteroids:significant
Duration1-9days
reductioninmortalityinprolonged(>5days)treatment
• Increasedriskofhyperglycemia
• Potentialpublicationbias
Cheng,
Meta-analysis 264
Hospitalized
Hospital
Hydrocortisone,
• Corticosteroidssignificantlyreducedhospitalmortality(Peto
201418
of4RCTs
patientswith
mortality(or prednisolone,and
OR0.39,95%CI0.17-0.90)
severeCAP
atlongest
methylprednisolone
• Qualityofevidencelowanddowngradedforinconsistencyand
follow-up
imprecision
time)
• Resultsshouldbeinterruptedwithcaution
• Moderateheterogeneityamongresults(I2=46%)
OR–oddsratio;CI–confidenceinterval;CRP–C-reactiveprotein;IL–interleukin;RCT–randomizedcontrolledtrial
•
Klembith|7
TorresA,SibilaO,FerrerM,etal.Effectofcorticosteroidsontreatmentfailureamonghospitalizedpatientswith
severecommunity-acquiredpneumoniaandhighinflammatoryresponse.JAMA.2015;313(7):677-86.26
Objective
Toassesstheeffectofcorticosteroidsinpatientswithseverecommunity-acquiredpneumoniaandhigh
inflammatoryresponse
StudyDesign Multicenter,randomized,double-blind,placebo-controlledtrial
Population
InclusionCriteria:
ExclusionCriteria:
• Aged18yearsorolder
• Priortreatmentwithsystemiccorticosteroids
• Clinicalsymptomssuggesting
• Nosocomialpneumonia
CAP(cough,fever,pleuritic
• Severeimmunosuppression(HIVinfection,immunosuppressive
chestpain,dyspnea)
conditionormedications)
• Newchestradiographic
• Preexistingmedicalconditionwithlifeexpectancy<3months
infiltrate
• Uncontrolleddiabetesmellitus
• MetsevereCAPcriteria
• Majorgastrointestinal(GI)bleedingwithin3months
(definedbymodifiedATS
• Conditionrequiringacutetreatmentwith>1mg/kg/day
criteriaorPSIriskclassV)
methylprednisoloneorequivalent
• C-reactiveprotein(CRP)level
• H1N1influenzaApneumonia
>150mg/Latadmission
Outcomes
• Primaryoutcome:rateoftreatmentfailure(early,late,oratbothtimes)
o Earlytreatmentfailure:clinicaldeteriorationwithin72hoursoftreatment(developmentofshock,
needforinvasivemechanicalventilationnotpresentatbaseline,ordeath)
o Latetreatmentfailure:radiographicprogression(increaseof≥50%ofpulmonaryinfiltrates
comparedwithbaseline),persistenceofsevererespiratoryfailure(pO2/FiO2<200mmHg,with
respiratoryrate≥30breaths/mininpatientsnotintubated),developmentofshock,needforinvasive
mechanicalventilationnotpresentatbaseline,ordeathbetween72and120hoursaftertreatment
initiation
• Secondaryoutcomes:timetoclinicalstability,lengthofICUandhospitalstays,in-hospitalmortality
• Adverseevents:hyperglycemia,superinfection,GIbleeding,delirium,acutekidneyinjury,acutehepatic
failure
Methods
• ThreeSpanishteachinghospitals–June2004toFebruary2012
• Randomized1:1toeithermethylprednisolone0.5mg/kgIVbolusevery12hours(N=61)orplacebo
(N=59)for5days
• Interventionstartedwithin36hoursofhospitaladmission
• AntibiotictreatmentaccordingtoIDSA/ATSCAPguidelines
• Laboratoryassessmentatpresentation:renalandliverfunctions,electrolytes,bloodglucose,CRP,
hematology,arterialbloodgases
• Biomarkerexamination:interleukin(IL)-6,IL-8,IL-10,procalcitonin,andCRPlevelsobtainedonfirstday
andafter3daysand7daysoftreatment
Statistics
• Two-sidedtypeIerrorof0.05and80%powertodetectabsolute20%reductionintreatmentfailureused
todeterminesamplesizeof120
• Pre-specifiedinterimanalysisplannedat50%ofpatientaccrual
• Efficacydataanalyzedforbothintention-to-treatandper-protocolpopulations
• Sensitivityanalysisofprimaryoutcomebylogisticregressionmodels
• Primaryandsecondaryoutcomesanalyzedbothwithandwithoutanadjustmentforpotential
confounders
o Twopredefinedcovariates:yearofadmissionandthecenter
o Allvariablesforwhichtherewasimbalancebetweenthegroupsatbaseline(p<0.10)
• Statisticaltests:X2test,Fisherexacttest,ttest,nonparametricMann-Whitneytest,Kaplan-Meiermethod
(log-ranktest),Coxproportionalhazardregressionmodels,logisticregressionmodels
o Calculated95%confidenceintervals
o Alltests2-tailedandsignificancesetat0.05
Results
• 120patientsrandomizedand112(93%)completedstudy
• Baselinecharacteristicscomparable,except:
o LowerlevelsofprocalcitoninandIL-10atday1inmethylprednisolonegroup
o Lowerproportionofpatientswithsepticshockinmethylprednisolonegroup
Klembith|8
PrimaryOutcome
(Intention-to-treat)
Authors’
Conclusion
Critique
Application
Methylprednisolone
(N=61)
No.(%)
8(13)
6(10)
Placebo
(N=59)
No.(%)
18(31)
6(10)
Difference
BetweenGroups,
%(95%CI)
18(3to32)
0(-10to11)
P
Value
NNT
Treatmentfailure
0.02
6
Earlytreatmentfailure
0.95
(0-72h)
Earlymechanical 4(7)
5(8)
2(-8to11)
0.74
ventilation
Earlysepticshock 2(3)
2(5)
2(-5to9)
0.68
Death 2(3)
2(3)
0(-6to7)
>0.99 Latetreatmentfailure
2(3)
15(25)
22(10to34)
0.001 5
(72-120h)
Radiographic 1(2)
9(15)
14(4to23)
0.007 8
progression
Respiratoryfailure 1(2)
5(8)
7(-1to15)
0.11
Latemechanical 1(2)
4(7)
5(-2to12)
0.20
ventilation
Latesepticshock 0
4(7)
7(0to13)
0.06
Death 0
0
Posthocsub-analysis: 2(3)
8(14)
10(0to20)
0.04
10
latetreatmentfailure
excludingradiographic
progression
NNT–numberneededtotreat
Sensitivityanalysisofprimaryoutcomeusinglogisticregressionmodel
PrimaryOutcome UnadjustedORorHR
PValue
AdjustedORorHR
PValue
(95%CI)
(95%CI)
Treatmentfailure 0.34(0.14-0.87)
0.02
0.33(0.012-0.90)
0.03
Latetreatment
0.10(0.02-0.46)
0.003
0.09(0.02-0.47)
0.004
failure(72-120h)
Radiographic
0.09(0.01-0.76)
0.03
0.09(0.01-0.78)
0.03
progression
HR–hazardratio
• Significantdifferenceintimetotreatmentfailurebetweengroupsinfavorofmethylprednisolone(p=0.03)
• Secondaryclinicaloutcomesandadverseevents
o Nostatisticallysignificantdifferencesobserved
• Inflammatorymarkers
o Atday3,greaterreductioninlevelsofCRPandIL-10inmethylprednisolonegroup
o Atday7,greaterreductioninlevelsofCRPremainedinmethylprednisolonegroup
o Patientswithapersistentlyhighinflammatoryresponseatday7hadhigherpercentageoftreatment
failure(p=0.003)andin-hospitalmortality(p=0.042)
Theacuteadministrationofmethylprednisolonecomparedwithplacebodecreasedtreatmentfailureand
inflammatoryresponseinpatientswithsevereCAPandhighinitialinflammatoryresponse.Hypothesizethat
havinglesstreatmentfailurecouldleadtodecreasedmortalityinCAP.
Strengths:
Limitations:
• Studydesign
• Generalizability–limitedtoseverepneumoniawithhigh
inflammatoryresponse
• Intention-to-treat,per-protocol,
adjustmentforbaselineanalysis • Smallsamplesize
• AllsitesusedIDSA/ATS
• Singledose/durationofmethylprednisolonestudied
guidelineforantibiotictherapy
• Lowertreatmentfailureinplacebogroup(31%)comparedto
studyusedtocalculatesamplesize–lessstatisticalpower
• Evaluatedinflammatory
response
• Nolong-termfollow-up
CorticosteroidsmaydecreasetreatmentfailureinpatientswithsevereCAPandahighinflammatoryresponse.
TodetermineifcorticosteroidsshouldberoutinelyusedinpatientswithCAP,additionalwell-conductedRCTs
withlargersamplesizesshouldbeperformed.
Klembith|9
BlumCA,NigroN,BrielM,etal.Adjunctprednisonetherapyforpatientswithcommunity-acquiredpneumonia:a
multicentre,double-blind,randomised,placebo-controlledtrial.Lancet.2015;385:1511-8.27
Objective
Toassesswhethershort-termcorticosteroidtreatmentreducestimetoclinicalstabilityinpatientsadmitted
tothehospitalforcommunity-acquiredpneumonia
StudyDesign Double-blind,multicenter,randomized,placebo-controlledtrial
Population
InclusionCriteria:
ExclusionCriteria:
• Aged18yearsorolder
• ActiveIVdruguse
• HospitaladmissionwithCAP:
• Acuteburninjury
o Newinfiltrateonchestradiograph,and
• GIbleedingwithinpast3months
o Presenceof≥1ofthefollowingacute
• Knownadrenalinsufficiency
respiratorysignsandsymptoms:cough, • Conditionrequiring>0.5mg/kg/dayprednisoneor
sputumproduction,dyspnea,corebody
equivalent
temperature≥38.0°C,auscultatory
• Pregnancyorbreastfeeding
findingsofabnormalbreathingsounds
• Severeimmunosuppression(HIVandCD4count<350
orrales,leukocytecount>1000cells/μL
cells/μL,immunosuppressivetherapyaftersolid
or<4000cells/μL
organtransplantation,neutropenia<500cells/μL,
cysticfibrosis,activetuberculosis)
Outcomes
• Primaryendpoint:timetoclinicalstability(stablevitalsignsfor≥24hours:temperature≤37.8°C,heart
rate≤100beats/minute,systolicbloodpressure≥90mmHg[≥100mmHgifdiagnosedwith
hypertension]withoutvasopressorsupport,mentalstatusbacktobaseline,abilityfororalintake,
adequateoxygenationonroomair[pO2≥60mmHgorpulseoximetry≥90%)
• Secondaryendpoints:timetoeffectivehospitaldischarge,recurrenceofpneumonia,hospitalreadmission,ICUadmission,all-causemortality,durationoftotalandIVantibiotictherapy,diseaseactivity
scoresspecifictoCAP,incidenceofcomplicationsduetoCAP(acuterespiratorydistresssyndrome
[ARDS],empyema,persistenceofpneumonia),corticosteroidsideeffects(hyperglycemia,hypertension,
delirium,nosocomialinfections,weightgain)
Methods
• SeventertiarycarehospitalsinSwitzerland–December1,2009toMay21,2014
• Randomized1:1toreceiveeitherprednisone50mgorallydailyorplacebofor7days
o Variableblocksizesoffourtosixandpatientsstratifiedatthetimeofstudyentrybystudycenter
• AntibiotictherapyaccordingtoIDSA/ATSCAPguidelines
• Patientsassessedforclinicalstabilityevery12hoursduringhospitalstay
• Routinelaboratorytestsofinflammatorymarkers(procalcitonin,CRP,WBCcount)weredoneondays1,
3,5,7,andbeforedischarge
• Fourbloodglucosemeasurementsperday
• Follow-uptelephoneinterviewsforsecondaryoutcomesafterdischargedoneonday30
Statistics
• Calculatedneededsamplesizeof800patientsfollowedfor≥14daystoachievestatisticalpowerof85%
• UnadjustedHRand95%CIusingCoxproportionalhazardsregressionforprimaryendpoint
• Sensitivityanalysis:primaryoutcomeanalysisrepeatedonper-protocolpopulation,multivariableCox
proportionalhazardsmodelfittedwithtreatmentgroupandpre-specifiedpotentialconfounders(patient
ageandPSIscore)
• Pre-specifiedsubgroupanalysis:patientage,initialCRPconcentration,historyofCOPD,PSIclass,blood
culturepositivity
• Secondaryendpoints:calculatedunadjustedandadjusted(forpatientageandPSIscore)estimateofthe
effectsizeandcorresponding95%CIsusinglinear,logistic,orCoxproportionalhazardsregression
• Two-sided95%CIsandtwo-sided5%significancelevel
Results
• 802eligiblepatientsinitiallyenrolled:392prednisonegroupand393placebogroup
• Baselinecharacteristicswellbalanced(highburdenofcomorbidities:diabetes,COPD,chronicheart
failure,chronicrenalinsufficiency;approximatelyhalfpatientsinhigh-riskPSIclassesIVandV)
Outcome
Prednisone
Placebo
HR,OR,orDifference
PValue
(N=392)
(N=393)
(95%CI)
Primaryendpoint
Timetoclinicalstability
3.0(2.5-3.4)
4.4(4.0-5.0)
HR:1.33(1.15to1.50) <0.0001
(days),intention-to-treat
Timetoclinicalstability
3.0(2.5-3.2)
4.4(4.0-5.0)
HR:1.35(1.16to1.56) <0.0001
(days),per-protocol
Klembith|10
Secondaryendpoints
Timetoeffectivehospital
discharge(days)
Recurrentpneumonia
Hospitalre-admission
ICUadmission
TimetoICUadmission(days)
TimeinICU(days)
6.0(6.0-7.0)
7.0(7.0-8.0)
HR:1.19(1.04to1.38)
0.012
23(6%)
32(9%)
16(4%)
1(1-1)
3(2-4)
18(5%)
28(8%)
22(6%)
1(1-1)
3(1-12)
0.42
0.64
0.32
0.33
0.96
16(4%)
9.0(7.0-11.0)
13(3%)
9.0(7.0-12.0)
4.0(3.0-6.0)
5.0(3.0-7.0)
59(41-78)
58(40-74)
CAPscore*atday30(points) 83(67-88)
84(72-89)
OR:1.30(0.69to2.44)
OR:1.14(0.67to1.93)
OR:0.72(0.37to1.39)
HR:0.73(0.38to1.38)
Difference:-0.2
(-8.7to8.2)
OR:1.24(0.59to2.62)
Difference:-0.47
(-1.21to0.27)
Difference:-0.89
(-1.57to0.20)
Difference1.00
(-5.23to7.23)
Difference-1.00
(-4.38to2.38)
All-causemortality
Totaldurationofantibiotic
treatment(days)
Intravenousantibiotic
treatment(days)
CAPscore*atday5(points)
Authors’
Conclusion
Critique
Application
0.57
0.22
0.011
0.75
0.56
Dataaremedian(interquartilerange[IQR])ornumber(%)
*Disease-specificscoreforCAPrangesfrom0to100,0markingtheworstscore
• Noevidenceofeffectmodificationindifferentpre-specifiedsubgroups
• CRPconcentrationssignificantlylowerinprednisonegroupthaninplacebogroupondays3,5,and7
Complicationsandadverseeventsuntilday30
Outcome
Prednisone
Placebo
ORorDifference
PValue
(N=392)
(N=393)
(95%CI)
ComplicationsduetoCAP
11(3%)
22(6%)
0.49(0.23to1.02)
0.056
Weightchange(kg)
-1.0
-1.0
Difference:0.34
0.46
(-3.0to1.0)
(-3.0to0.4)
(-0.56to1.25)
Adverseeventscompatible
96(24%)
61(16%)
1.77(1.24to2.52)
0.0020
withcorticosteroids,any
In-hospitalhyperglycemia
76(19%)
43(11%)
1.96(1.31to2.93)
0.0010
needinginsulintreatment
Otheradverseevent,any
20(5%)
34(9%)
0.57(0.32to1.00)
0.052
Dataaremedian(IQR)ornumber(%)
• Numberneededtoharm(NNH)foranyadverseeventscompatiblewithcorticosteroidsandNNHforinhospitalhyperglycemia:13
• Otheradverseeventscompatiblewithcorticosteroidswererareandsimilarbetweengroups
o Ratesofnewneedforinsulintreatmentatday30werelowinbothgroups
Findingssupportthehypothesisthatadministrationofcorticosteroidsmodulatestheimmuneresponseand
therebyshortenstimetoclinicalstabilityandlengthofhospitalstay.Resultsconfirmdataofvariousclinical
trials,systematicreviews,andmeta-analysesshowingabeneficialeffectofcorticosteroidsinCAP.
Strengths:
Limitations:
• Studydesign
• Limitedgeneralizabilitytoonlyhospitalizedpatients
• Largestandmostconclusiverandomized
• Notpoweredformortality
placebo-controlledtrialtodate
• Slightlysmallersamplesizethanpredicted
• AllseverityclassesofCAPincluded
• Limitationsofprimaryendpointoftimetoclinical
stability(combinedendpointincludingseveral
• Sensitivityanalysis
parameters)
• 30-dayfollow-up
• Corticosteroid-inducedhyperglycemiamayhaveledto
• Oralprednisone–easeofadministration
un-blinding
Corticosteroidsappeartoreducethetimetoclinicalstabilityandmayimprovetheclinicalcourseofdiseasein
patientshospitalizedwithCAP.Hyperglycemiaisthemostcommonadverseeventassociatedwithshort-term
corticosteroidtreatment.
Klembith|11
SiemieniukR,MeadeOM,Alonso-CoelloP,etal.Corticosteroidtherapyforpatientshospitalizedwithcommunityacquiredpneumonia:asystematicreviewandmeta-analysis.AnnInternMed.2015;163(7):519-28.28
Objective
Toexaminetheeffectofadjunctivecorticosteroidtherapyonmortality,morbidity,anddurationof
hospitalizationinpatientswithcommunity-acquiredpneumonia
StudyDesign Systematicreviewandmeta-analysisofrandomizedcontrolledtrials
Population
InclusionCriteria:
ExclusionCriteria:
• AdultswithCAPassignedtooralorIVcorticosteroid • Ventilator-associatedpneumonia,aspiration
therapyversusplaceboornotreatment
pneumonia,orPneumocystisjirovecii
pneumonia
• Studiesreportedon≥1outcomeofinterest
• StudieslimitedtopatientswithCOPD
Outcomes
All-causemortality,needformechanicalventilation,ICUadmission,developmentofARDS,durationof
hospitalization,timetoclinicalstability
Methods
• PreviousCochranereviewwithsimilarinclusioncriteriaidentifiedstudiesuptoDecember201029
• MEDLINE,EMBASE,andtheCochraneCentralRegisterofControlledTrialssearchedfromJanuary1,2010
toMay24,2015usingtheMedicalSubjectHeadingterms“pneumonia”and“corticosteroids”
• Ifstudyreportedoutcomesatmorethanonetimepoint,datawasabstractedclosestto30daysfrom
randomization
• GradingofRecommendationsAssessment,Development,andEvaluation(GRADE)systemusedtoassess
certaintyofevidenceforeachoutcomeandforentirebodyofevidence
Statistics
• Random-effectsmodels(Mantel-Haenszelriskratiosandmeandifferences)
• Nonparametricdataconvertedtomeansandstandarddeviations
• Sensitivityanalysis:omittingstudiesinwhichmeanswereestimatedfrommediansandomittingone
studythatwasstoppedearlyforalargeeffect
• HeterogeneityassessedusingvisualinspectionoftheresultsandtheI2statistic
• 95%confidenceintervalscalculated
Results
• ThirteenRCTsidentified(ninestudiesnotincludedinthepreviousreview)
• Samplesizesrangedfrom30-784hospitalizedpatients
• Corticosteroids:dexamethasone,prednisone,prednisolone,methylprednisolone,orhydrocortisone
• Durationoftreatmentrangedfromonedoseto10days
• Follow-uprangedfromin-hospitalto60daysfromenrollment
• Studiesoftenexcludedpatientsathighriskforadverseeffectsfromcorticosteroids(GIhemorrhagewithin
3months,immunosuppression,pregnantwomen)
Outcome
Corticosteroids
Control
RR
I 2
Certaintyof NNT
(n/N)
(n/N)
(95%CI)
(%)
Evidence
All-causemortality 7.9%(79/997)
5.3%
0.67
6
Moderate
(12studies,N=1974)
(52/977)
(0.45-1.01)
Mechanical
3.1%(17/550)
5.7%
0.45
0
Moderate
39
ventilation
(29/510)
(0.26-0.79)
(5studies,N=1060)
ICUadmission
5.3%(25/476)
7.6%
0.69
0
Moderate
(3studies,N=950)
(36/474)
(0.46-1.03)
ARDS
0.42%(2/473)
3.0%
0.24
0
Moderate
39
(4studies,N=945)
(14/472)
(0.10-0.56)
RR–riskratio
Outcome
Corticosteroids
Control
MeanDifference,
I 2
Certaintyof
days(95%CI)
(%)
Evidence
Durationof
-2.96
94
hospitalization
(-5.18to-0.75)
(9studies,N=1644)
Durationof
7.9days
9.1days
-1.00
0
High
hospitalization
(-1.79to-0.21)
(3studiesatlowrisk
ofbias,N=1288)
TimetoClinical
3.5days
4.7days
-1.22
38
High
Stability
(-2.08to-0.35)
(5studies,N=1180)
Klembith|12
Authors’
Conclusion
Critique
Application
Subgroupanalysisbypneumoniaseverity
Outcome
Corticosteroids
Control
RR
I2
NNT
(n/N)
(n/N)
(95%CI)
(%)
All-causemortality
Severepneumonia 7.4%(16/215)
22%(38/173)
0.39(0.20-0.77) 0
7
(6studies,N=388)
Notsevere 4.7%(36/762)
5.0%(41/824)
1.00(0.79-1.26)
0
pneumonia
(6studies,N=1586)
Mechanicalventilation
Severepneumonia 11.1%(15/135) 18.9%(18/95)
0.54(0.50-0.58) 0
13
(3studies,N=230)
Notsevere 0.48%(2/415)
2.7%(11/415)
0.18(0.08-0.43) 0
45
pneumonia
(2studies,N=830)
Adverseevents
Outcome
Corticosteroids
Control
RR
I2
(n/N)
(n/N)
(95%CI)
(%)
Hyperglycemiarequiring
15.2%(119/784)
8.7%(65/750) 1.49(1.01-2.19)
6
treatmenta
(6studies,N=1534)
Gastrointestinal
1.1%(7/628)
1.7%(10/595) 0.82(0.33-1.62)
0
hemorrhage
(7studies,N=1223)
Severeneuropsychiatric
1.8%(11/602)
1.3%(8/615)
1.65(0.88-3.08)
0
complications
(4studies,N=1217)
Rehospitalization
7.2%(39/543)
6.3%(35/546) 1.12(0.59-2.13)
0
(2studies,N=1089)
aHighcertaintyofevidence
• NNHforhyperglycemiarequiringtreatment:16
• Subgroupanalyses:riskofbias,yearofpublication,severityofpneumoniaatenrollment,durationof
corticosteroidtherapydidnotshowaconsistentinteractionacrossoutcomes
• Sensitivityanalyses:omissionofonestudythatwasstoppedearlyforbenefithadnoappreciableeffecton
theresults;omissionofstudiesinwhichmeanswereestimatedfrommedianvaluesforcontinuous
outcomehadnegligibleeffectontheresults
Resultsprovidehigh-qualityevidenceforthebenefitsofadjunctivecorticosteroidsinCAPanddecision
makersshouldstronglyconsidertheuseofcorticosteroidsinpatientshospitalizedwithCAP,particularlyin
thosewhoaremoreseverelyaffected.Overallcertaintyofavailableevidenceratedashighforthebenefitof
adjunctivecorticosteroids.
Strengths:
Limitations:
• Assessedeligibilityandrisk • Useofvariouscorticosteroids,routesofadministration,doses,and
ofbiasinduplicate
treatmentduration
• Rigorousliteraturesearch • Generalizability
• AppliedGRADEsystemto
• Someoutcomeswithsmallnumberofevents(needformechanical
evaluatecertaintyof
ventilation,admissiontoICU,ARDS)
evidence
• Publicationbiascouldnotberuledout
• Subgroupandsensitivity
• Highdegreeinheterogeneityinprimaryanalysisofdurationof
analyses
hospitalization
• “Rapidmeta-analysis”methodnewandnotyetvalidated
CorticosteroidsmaybenefitseveraloutcomesinCAP,withthemajoradverseeventinshort-termtreatment
beinghyperglycemia.LargerRCTscouldimprovecertaintyofthebenefitofadjunctivecorticosteroidsinCAP.
Additionaltrialsareneededtodetermineoptimalcorticosteroid,dose,durationoftreatment,andtheideal
patientpopulation.
Klembith|13
FUTURESTUDIES
I.
ExtendedSteroidinCAP(e)(ESCAPe)30
A. Objective:todetermineifprovidingearlytreatmentwithmethylprednisolonewillimprovesurvivalincriticallyill
patientswithsevereCAP
B. Primaryoutcome:all-causemortalityat60days
C. Intervention:methylprednisolone40mg/dayfor7days,then20mg/dayfor7days,then6daysoftaperingdose(12
mg/dayand4mg/day)
D. Currentlyrecruitingparticipants
1. Estimatedcompletiondate:January2018
II. Santeon-CAP;DexamethasoneinCommunity-acquiredPneumonia31
A. Objective:toinvestigatethebeneficialeffectsofadjunctivedexamethasoneinpatientshospitalizedforCAPwithan
aimtoassesswhichpatientsbenefitthemostfromtreatment
B. Primaryoutcome:lengthofhospitalstay
C. Intervention:dexamethasone6mgdailyfor4days
D. Currentlyrecruitingparticipants
1. Estimatedcompletiondate:December2015
III. CorticosteroidTherapyforSevereCommunity-AcquiredPneumonia32
A. Objective:toassesstheefficacyofadjunctivemethylprednisoloneinpatientswithCAP
B. Primaryoutcome:all-causemortalityat30days
C. Intervention:methylprednisolone80mg/dayfor3days,then40mg/dayfor3days
D. Currentlyrecruitingparticipants
1. Estimatedcompletiondate:May2017
IV. Community-AcquiredPneumonia:EvaluationofCorticosteroids(CAPE_COD)33
A. Objective:todetermineifcorticosteroidsimprovesurvivalincritically-illpatientswithsevereCAP
B. Primaryoutcome:all-causemortalityat28days
C. Intervention:hydrocortisone200mg/daybycontinuousIVinfusionfor4or7days,then100mg/dayfor2or4days,
andthen50mg/dayfor2or3days(durationchosenuponpatientinitialimprovement)
D. Notyetopenforrecruitment
1. Estimatedcompletiondate:December2018
V. CorticosteroidsinCommunity-acquiredPneumonia34
A. Objective:todeterminetheefficacyoftheadditionofcorticosteroidtherapytoantibioticsinchildrenhospitalized
withCAP
B. Primaryoutcome:lengthofhospitalstay
C. Intervention:dexamethasone0.6mg/kg/dayormethylprednisolone1mg/kg/day
D. Notyetopenforrecruitment
1. Estimatedcompletiondate:March2017
CONCLUSIONANDRECOMMENDATIONS
I. Shouldadjunctivecorticosteroidsbeusedinthetreatmentofcommunity-acquiredpneumonia?
A. NumerousstudiesinvestigatingthepotentialbenefitofadjunctivecorticosteroidtherapyinthetreatmentofCAP
1. Mostaresmall,singlesitestudies
2. Variousoutcomesstudied
3. Variousanti-inflammatoryagents,doses,anddurationoftreatment
4. Manystudiesshowedabenefitwithcorticosteroids
a. Limitedstudiespoweredtoshowmortalitybenefit
5. Hyperglycemiamostcommonadverseeffectobserved
6. Limitationswithearliermeta-analyses
a. MortalitybenefitonlyinsubgroupanalysisofsevereCAP(N=214)25
i. Possiblepublicationbias
b. Reductioninmortalityinmeta-analysisofonlyfourtrialsandqualityofevidencedown-gradeddueto
moderateheterogeneity18
i. Resultsshouldbeinterruptedwithcaution
Klembith|14
B.
RecentRCTsandmeta-analysisconfirmbeneficialeffectsofcorticosteroidsasadjunctivetreatmentinCAPwith
limitedadverseevents
1. Positiveoutcomes
a. Decreaseintreatmentfailure
b. Decreasetimetoclinicalstabilityby1day
i. Maytranslatetodecreasedlengthofhospitalstay
(i) Economicbenefit
(ii) Patientatdecreasedriskofnosocomialinfectionsanddeepveinthrombosis
2. Mortalitybenefitobservedinmeta-analysissubgroupanalysisofpatientswithsevereCAP
II. Additionalareasofresearch
A. Specificpopulationwithpotentialforthemostbenefitfromcorticosteroidtherapy
1. Pneumoniaseverity
2. Outpatient
3. Elderly
B. Optimalcorticosteroidagent,dose,anddurationoftreatment
III. Clinicalrecommendations
A. FurtherstudiesareneededbeforecorticosteroidsshouldbebroadlyrecommendedasadjunctivetreatmentofCAP
B. AdjunctivecorticosteroidsshouldbeconsideredinpatientshospitalizedwithsevereCAP
1. PSIriskclassIVandVorCURB-65score≥2
2. Prednisone50mgorallydailyormethylprednisolone0.5mg/kgIVevery12hours
3. Treatmentdurationof5-7days
C. Evaluatepatient-specificrisksversusbenefitsofcorticosteroidtherapy
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Table4.Abbreviations
ARDS
Acuterespiratorydistresssyndrome
BTS
BritishThoracicSociety
BUN
Bloodureanitrogen
CAP
Community-acquiredpneumonia
CI
Confidenceinterval
COPD
Chronicobstructivepulmonarydisease
COX-2
Cyclooxygenase-2
cPLA2α
CytosolicphospholipaseA2α
CRH
Corticotropin-releasinghormone
CRP
C-reactiveprotein
ED
Emergencydepartment
ERS/ESCMID
EuropeanRespiratorySociety/EuropeanSocietyofClinicalMicrobiologyandInfectiousDiseases
GI
Gastrointestinal
GRADE
GradingofRecommendationsAssessment,Development,andEvaluation
HIV
Humanimmunodeficiencyvirus
HR
Hazardratio
ICU
Intensivecareunit
IDSA/ATS
InfectiousDiseasesSocietyofAmerica/AmericanThoracicSociety
IL
Interleukin
IQR
Interquartilerange
IV
Intravenous
MAPK
Mitogen-activatedproteinkinase
Klembith|16
MDR
NF-κB
NICE
NNH
NNT
NSAID
OR
PaO2/FiO2
pO2
PSI
RCT
RR
US
WBC
Multi-drugresistant
Nuclearfactor-κB
NationalInstituteforHealthandCareExcellence
Numberneededtoharm
Numberneededtotreat
Non-steroidalanti-inflammatorydrug
Oddsratio
Arterialoxygenpressure/fractionofexpiredoxygen
Partialpressureofoxygen
PneumoniaSeverityIndex
Randomizedcontrolledtrial
Riskratio
UnitedSates
Whitebloodcell
APPENDICES
AppendixA:ClinicalIndicationsforExtensiveDiagnosticTesting9
Indication
Blood
Sputum
culture
culture
ICUadmission
X
X
Failureofoutpatientantibiotictherapy
X
Cavitaryinfiltrates
X
X
Leukopenia
X
Activealcoholabuse
X
X
Chronicsevereliverdisease
X
Severeobstructive/structurallung
X
disease
Asplenia(anatomicorfunctional)
X
Recenttravel(withinpast2weeks)
PositiveLegionellaUATresult
X
PositivepneumococcalUATresult
X
X
Pleuraleffusion
X
X
UAT–urinaryantigentest
AppendixB:PneumoniaSeverityIndexforCommunity-AcquiredPneumonia11
RiskFactor
Points
Demographics
Men
Age(years)
Women
Age(years)–10
Nursinghomeresident
+10
Comorbidities
Neoplasm
+30
Liverdisease
+20
HeartFailure
+10
Stroke
+10
Renalfailure
+10
Physicalexam
Alteredmentalstatus
+20
Respiratoryrate≥30breaths/min
+20
Systolicbloodpressure<90mmHg
+20
Temperature<35°Cor≥40°C
+15
Pulse≥125beats/min
+10
Legionella
UAT
X
X
X
Pneumococcal
UAT
X
X
X
X
X
Other
X
-
X
X
-
X
X
X
X
X
Klembith|17
Laboratoryandradiographicfindings
ArterialpH<7.35
+30
Bloodureanitrogen>30mg/dL
+20
Sodium<130mmol/L
+20
Glucose≥250mg/dL
+10
Hematocrit<30%
+10
Partialpressureofarterialoxygen<60mmHg
+10
Pleuraleffusion
+10
AppendixC:EmpiricalAntimicrobialTreatmentforCAP9
PatientCharacteristics
Outpatientandpreviouslyhealthyandnouseof
antibioticsinlast3months
Outpatientwithpresenceofcomorbidities(chronic
heart,lung,liver,orrenaldisease;diabetes;alcoholism;
malignancies;asplenia;immunosuppressingconditions;
useofantibioticswithinpast3months)
Outpatientinregionswith>25%ofinfectionswithhighlevel(MIC≥16µL/mL)macrolide-resistantS.
pneumoniae
Inpatient,non-ICU
Inpatient,ICU
PointTotal
<51
51-70
71-90
91-130
>130
RiskClass
I
II
III
IV
V
Recommendations
Macrolide
Alternative:doxycycline
Respiratoryfluoroquinolone(levofloxacin,moxifloxacin)
Beta-lactamplusmacrolide
•
•
•
•
Considerrespiratoryfluoroquinoloneorbeta-lactamplus
macrolide
• Respiratoryfluoroquinolone
• Beta-lactamplusmacrolide
Betalactam(cefotaxime,ceftriaxone,orampicillin-sulbactam)
pluseitherazithromycinorrespiratoryfluoroquinolone
The new england journal of medicine
AppendixD:GlucocorticoidAnti-InflammatoryMechanismsofAction15
CH2OH
Cytokines
Bacteria
Viruses
Free radicals
Ultraviolet radiation
HO
C O
OH
O
Cortisol
IkB
IkB kinase
Repression by means of negative
glucocorticoid-responsive elements
Corticotropin-releasing hormone
Pro-opiomelanocortin
Cytokines
Osteocalcin
Cytokine receptors
Proliferin
Chemotactic proteins
Keratins
Adhesion molecules
Interleukin-1b
Collagenases
Matrix metalloproteinases
c-Jun
Fos
Glucocorticoid
receptor
NF-kB
MAPK
phosphatase I
Jun N-terminal
kinase
Cytokines
Growth factors
Mitogens
Bacteria
Viruses
Ultraviolet radiation
Annexin I
Cytokines
Cytokine receptors
Chemotactic proteins
Adhesion molecules
Cytokines
Hormones
Mitogens
Endotoxin
Antigen
MAPKs
Phospholipids
cPLA2a
COX-2
MAPK-interacting
kinase
Arachidonic acid
5-LOX
Calcium kinase II
Calcium/calmodulin–
dependent kinase II
Calcium
Minor pathways
Prostaglandins
Leukotrienes
Inflammation
Core pathways
Enzyme
Protein kinase
Inflammatory
transcription factor
Protein
phosphatase
Inhibitory protein
Figure 4. Partial Molecular Architecture Underlying the Glucocorticoid-Induced Antagonism of Inflammation.
Inflammatory pathways are characterized by positive feedback loops (i.e., cytokines activate NF-kB, which in turn stimulates the synthesis of more
cytokines) and by redundancy (i.e., cytokines also activate c-Jun–Fos). The glucocorticoid receptor inhibits these pathways at multiple points by
directly blocking the transcription of inflammatory proteins by NF-kB and activator protein 1 and by inducing the expression of antiinflammatory
proteins such as IkB, annexin I, and MAPK phosphatase I. 5-LOX denotes 5-lipoxygenase, and COX-2 cyclooxygenase 2. Red lines denote in-
Klembith|18
AppendixE:GlucocorticoidPharmacology19
Glucocorticoid
Dosing
Hydrocortisone
Cortisoneacetate
Prednisone
Prednisolone
Methylprednisolone
Dexamethasone
15-240mgQ12h
(Nodosageadjustments)
25-300mg/day(PO)
(Nodoseadjustments,usewithcautionin
renalandhepaticimpairment)
5-60mgdaily
(Nodoseadjustments)
5-60mgdaily
(Nodosageadjustments,usewithcaution
inrenalimpairment)
Oral:2-60mg/day
IM(sodiumsuccinate):10-80mg/day
IM(acetate):10-80mgQ1-2weeks
IV(sodiumsuccinate):10-40mgover
severalminutesandrepeatedIVorIM
atintervalsdependingonclinical
response
(Nodosageadjustments,usecautionin
renalfailure)
• Oral,IM,IV:0.75-9mg/dayQ6-12h(in
divideddoses)
• Intra-articular,intralesional,soft
tissue:0.4-6mg/day
(Nodosageadjustments,usewithcaution
inrenalimpairment)
•
•
•
•
Routesof
administration
PO,IM,IV
PO,IM
PO
PO,IM,IV,intraarticular,
intradermal,soft
tissueinjection
PO,IM,IV
Pharmacokinetics
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
PO,IM,IV,intraarticular,
intradermal,soft
tissueinjection
•
•
•
•
Comments
Absorption:rapid
Metabolism:hepatic(minorsubstrateCYP3A4,Pglycoproteinsubstrate)
Half-life:8-12hours
Excretion:urine
Absorption:readily
Distribution:muscles,liver,skin,intestines,kidneys
Metabolism:hepatictoactivemetabolite
hydrocortisone(cortisol)
Bioavailability:interindividualvariability:43.7%
Half-lifeelimination:0.5hours
Excretion:urineandfeces
Absorption:50-90%
Metabolism:hepatictoprednisolone(minorCYP3A4
substrate,weak/moderateCYP2C19inducer)
Half-life:2-3hours
Excretion:urine
Metabolism:primaryhepatic(minorCYP3A4
substrate),alsometabolizedinmosttissues
Half-lifeelimination:3.6hours
Excretion:primarilyurine
Distribution:0.7-1.5L/kg
Metabolism:minorCYP3A4substrate,weakCYP2C8
inhibitor
Half-lifeelimination:3-2.5hours(reducedinobese)
Excretion:reducedinobese
Off-labelseptic
shockindication
Absorption:oral61-86%
Metabolism:hepatic(majorCYP3A4substrate,Pglycoproteinsubstrateandinhibitor,
weak/moderateCYP2A6,CYP2B6,CYP2C9inducer,
weakCYP3A4inducer,P-glycoproteinandUGT1A1
inducer
Half-lifeelimination:oral~4hours;IV1-5hours
Excretion:urine
Off-labelCOPD
exacerbation
indication
Off-labelCOPD
exacerbation
indication
Off-labelCOPD
exacerbation
indication
Klembith|19