Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia “ What is the study design (randomized trial, retrospective/prospective Cohort, case-control, case report or case series)?

Answer the following questions for article #1 titled:

“Empirical Anti-MRSA vs Standard Antibiotic Therapy and Risk of 30-Day Mortality in Patients Hospitalized for Pneumonia “

What is the study design (randomized trial, retrospective/prospective Cohort, case-control, case report or case series)?

What is the study hypothesis?

What is the primary outcome? Is it a clinical endpoint or a biomarker?

What is the intervention group and what is the control group?

Looking at table 1, are the groups are imbalanced, if there is imbalance, what did the authors do to account for this imbalance and lower bias?

In your opinion what is the major limitation for this article

Answer the following questions for article #2 titled:

“Spinal tuberculosis among human immunodeficiency virus–negative patients in a Kenyan tertiary hospital: a 5-year synopsis”

What is the study design (randomized trial, Cohort, case-control, case report or case series)?

What is the intervention group and what is the control group?

In your opinion what is the major limitation for this article

Answer the following questions for article #3 titled:

“Long-term symptoms of COVID-19 in children”

What is the study design (randomized trial, Cohort, case-control, case report or case series)?

What is the intervention group and what is the control group?

Answer the following questions for articles #4 & 5 titled:

“Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results”

and

“Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial”

Look carefully at the inclusion and exclusion criteria for both studies, what is the difference between the two studies, what are the advantages and disadvantages of both

Look at the primary outcome for both studies and compare between them. Which outcome do you think is more clinically relevant.

Answer the following questions for article # 6

“Effect of Piperacillin-Tazobactam vs Meropenem on 30-Day Mortality for Patients With E coli or Klebsiella pneumoniae Bloodstream Infection and Ceftriaxone Resistance”

What is the primary outcome for the study?

What is the study hypothesis?

Is the study blinded?

What is the intervention group? What is the control group?

EmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskof30-DayMortalityinPatientsHospitalizedforPneumoniaBarbaraEllenJones,MD,MSc;JianYing,PhD;VanessaStevens,PhD;CandaceHaroldsen,MPH;TaoHe,MS;McKennaNevers,MPH;MatthewA.Christensen,MD;RichardE.Nelson,PhD;GregoryJ.Stoddard,MS;BrianC.Sauer,PhD;PeterM.Yarbrough,MD;MakotoM.Jones,MD,MSc;MatthewBidwellGoetz,MD;TomGreene,PhD;MatthewH.Samore,MDIMPORTANCEUseofempiricalbroad-spectrumantibioticsforpneumoniahasincreasedowingtoconcernforresistantorganisms,includingmethicillin-resistantStaphylococcusaureus(MRSA).Theassociationofempiricalanti-MRSAtherapywithoutcomesamongpatientswithpneumoniaisunknown,evenforhigh-riskpatients.OBJECTIVETocompare30-daymortalityamongpatientshospitalizedforpneumoniareceivingempiricalanti-MRSAtherapyvsstandardempiricalantibioticregimens.DESIGN,SETTING,ANDPARTICIPANTSRetrospectivemulticentercohortstudywasconductedofallhospitalizationsinwhichpatientsreceivedeitheranti-MRSAorstandardtherapyforcommunity-onsetpneumoniaintheVeteransHealthAdministrationhealthcaresystemfromJanuary1,2008,toDecember31,2013.Subgroupsofpatientsanalyzedwerethosewithinitialintensivecareunitadmission,MRSAriskfactors,positiveresultsofaMRSAsurveillancetest,andpositiveresultsofaMRSAadmissionculture.Primaryanalysiswasaninverseprobabilityoftreatment–weightedpropensityscoreanalysisusinggeneralizedestimatingequationregression;secondaryanalysesincludedaninstrumentalvariableanalysis.StatisticalanalysiswasconductedfromJune14toNovember20,2019.EXPOSURESEmpiricalanti-MRSAtherapyplusstandardpneumoniatherapyvsstandardtherapyalonewithinthefirstdayofhospitalization.MAINOUTCOMESANDMEASURESRiskof30-dayall-causemortalityafteradjustmentforpatientcomorbidities,vitalsigns,andlaboratoryresults.SecondaryoutcomesincludedthedevelopmentofkidneyinjuryandsecondaryinfectionswithClostridioidesdifficile,vancomycin-resistantEnterococcusspecies,orgram-negativebacilli.RESULTSAmong88605hospitalizedpatients(86851men;medianage,70years[interquartilerange,62-81years]),empiricalanti-MRSAtherapywasadministeredto33632(38%);8929patients(10%)diedwithin30days.Comparedwithstandardtherapyalone,inweightedpropensityscoreanalysis,empiricalanti-MRSAtherapyplusstandardtherapywassignificantlyassociatedwithanincreasedadjustedriskofdeath(adjustedriskratio[aRR],1.4[95%CI,1.3-1.5]),kidneyinjury(aRR,1.4[95%CI,1.3-1.5]),andsecondaryCdifficileinfections(aRR,1.6[95%CI,1.3-1.9]),vancomycin-resistantEnterococcussppinfections(aRR,1.6[95%CI,1.0-2.3]),andsecondarygram-negativerodinfections(aRR,1.5[95%CI,1.2-1.8]).Similarassociationsbetweenanti-MRSAtherapyuseand30-daymortalitywerefoundbyinstrumentalvariableanalysis(aRR,1.6[95%CI,1.4-1.9])andamongpatientsadmittedtotheintensivecareunit(aRR,1.3[95%CI,1.2-1.5]),thosewithahighriskforMRSA(aRR,1.2[95%CI,1.1-1.4]),andthosewithMRSAdetectedonsurveillancetesting(aRR,1.6[95%CI,1.3-1.9]).Nosignificantfavorableassociationwasfoundbetweenempiricalanti-MRSAtherapyanddeathamongpatientswithMRSAdetectedonculture(aRR,1.1[95%CI,0.8-1.4]).CONCLUSIONSANDRELEVANCEThisstudysuggeststhatempiricalanti-MRSAtherapywasnotassociatedwithreducedmortalityforanygroupofpatientshospitalizedforpneumonia.Theseresultscontributetoagrowingbodyofevidencethatquestionsthevalueofempiricaluseofanti-MRSAtherapyusingexistingriskapproaches.JAMAInternMed.2020;180(4):552-560.doi:10.1001/jamainternmed.2019.7495PublishedonlineFebruary17,2020.Editorialpage485SupplementalcontentAuthorAffiliations:Authoraffiliationsarelistedattheendofthisarticle.CorrespondingAuthor:BarbaraEllenJones,MD,MSc,DivisionofPulmonaryandCriticalCare,VeteransAffairsSaltLakeCityHealthCareSystem,50NMedicalDr,Wintrobe701,SaltLakeCity,UT84132([email protected]).ResearchJAMAInternalMedicine|OriginalInvestigation552(Reprinted)jamainternalmedicine.com©2020AmericanMedicalAssociation.Allrightsreserved.

PneumoniaistheleadingcauseofdeathfrominfectionintheUnitedStates,1andtimelyempiricalantibiotictherapyagainstthemostlikelypathogensisacorner-stoneofcare.However,causativepathogensarerarelyidentified,2leavinguncertaintyinthechoiceofempiricalan-tibiotictherapy.Forpatientshospitalizedforcommunity-onsetpneumonia,thisuncertaintyhasbeenmagnifiedbytheemergenceofresistantorganisms,chieflymethicillin-resistantStaphylococcusaureus(MRSA)andPseudomonasaeruginosa.Theconceptofhealthcare–associatedpneumo-nia,intendedtoassistcliniciansinriskassessment,3likelycon-tributedtotheoveruseofbroad-spectrumantibiotics.4,5Con-sequently,althoughfewerthan5%ofhospitalizedpatientshaveresistantorganismsdetected,morethanone-thirdre-ceivebroad-spectrumantibiotics.6Effortstoenhanceclinicalpredictionofresistantorgan-ismshaveresultedinseveralnewpromisingresults.7-10ForpatientsatriskofMRSAinfection,theuseofmoleculardiag-nostictestingwiththenasalpolymerasechainreaction(PCR)surveillancetesthasalsobeenproposedasapotentialtooltostratifypatients.11-13However,nosinglestrategyhasprovedtosubstantiallyenhancedecisionaccuracy,7andnewclinicalpracticeguidelinesemphasizetheneedforvalidationoftheseapproaches.14Somestudieshavesuggestedthatempiricalbroad-spectrumtherapymaybeharmful.15,16Itisthusun-clearwhichpatientsbenefitsufficientlyfromempiricaltreat-mentwithbroad-spectrumagentstowarrantsuchtherapy.Theprimaryobjectiveofthisstudywastoevaluate30-dayriskofdeathinpatientshospitalizedforpneumoniawhowerereceivingempiricalanti-MRSAtherapyplusguideline-concordant(ie,standard)antibioticscomparedwiththosere-ceivingstandardtherapyaloneamonggroupsofpatientswhomaywarranttherapy.TheVeteransHealthAdministrationcom-prisesalargeintegratedhealthcaresystemwithasharedelec-tronichealthrecordandclinicaldatarepositoryformorethan5millionveteransat140medicalcenters.Previousstudieshavereportedsubstantialvariationinthedecisiontouseempiri-calanti-MRSAtherapyacrossandwithinfacilities17andyear6thatwasunexplainedbydifferencesinpatientcharacteris-tics.Weleveragedthisvariationtoexaminerisksof30-daymor-talityamongallpatientsaswellassubgroupsthatmayex-pectgreaterbenefitfromanempiricalanti-MRSAstrategy,includingthoseinitiallyadmittedtotheintensivecareunit(ICU),thosewithahistoryofMRSAinfectionorcolonizationorotherclinicalriskfactors,thosewithMRSAdetectedonre-sultsofnasalPCR,andthosewithMRSAdetectedbyculturewithin2daysofadmission.MethodsStudyDesign,Setting,andParticipationWeconductedaretrospectivecohortstudyofallhospitaliza-tionsforcommunity-onsetpneumoniaintheVeteransAf-fairs(VA)healthcaresystemfromJanuary1,2008,toDecem-ber31,2013(Figure1),usinganexistingdatasetthatcontainedextensivelyvalidatedclinicaldata18anddemonstratedsuffi-cientvariationintreatment17toallowforcomparativeeffec-tivenessresearch.Weidentifiedhospitalizationsinacutein-patientwardswithaprincipalInternationalClassificationofDiseases,NinthRevision(ICD-9)codeforpneumoniaorsec-ondaryICD-9codeforpneumoniawithaprincipalICD-9codeforsepsisandrespiratoryfailure,acase-findingapproachthathasbeenfoundtoberesilienttovariationindiagnosticcoding.17,19Patientswereexcludediftheywerenotadminis-teredanantimicrobialwithinthefirstcalendardayofhospi-talization,werehospitalizedwithpneumoniainthepreviousmonth,orweretransferredfromotheracutecarefacilities.Thestudywasreviewedandapproved,andwaiversofconsentweregrantedonthebasisofinfeasibilityandminimalriskofharmtoparticipants,bytheUniversityofUtahInstitutionalRe-viewBoardandtheResearchandDevelopmentCommitteeoftheVASaltLakeCityHealthCareSystem.StudyDataandMeasurementsTheprimaryexposureofinterestwastreatmentwithanti-MRSAtherapy(vancomycinhydrochlorideorlinezolid)plusguideline-recommendedstandardantibiotics(β-lactamandmacrolideortetracyclinehydrochloride,orfluoroquinolone)14,20vsstandardtherapyalone.Becausemanypatientsreceivedanti-MRSAtherapywithoutstandardantibiotics,wealsoevaluatedthisstrategyasanadditionaltreatmentgroup.Toconductananalysisfromobservationaldatasimilartoanintention-to-treatclinicaltrial,21,22weclassifiedallpatientsaccordingtothetreatmenttheyreceivedonthefirstcalendardayofhospital-ization.MedicationadministrationwascapturedusingtheVAstandardizedbarcodemedicationadministrationdata,whichwaspreviouslyvalidatedagainstmanualmedicalrecordre-viewtoaccuratelyrepresentempiricaltherapy.18Theprimaryoutcomeofinterestwasall-causemortalitywithin30daysofhospitalization.DeathdatawereobtainedfromtheVAVitalStatusfile.Patientdemographics,clinicalriskfactorsforresistantorganisms,andfeaturesassociatedwithillnessseveritywereextractedandcuratedforeachhospital-izationusingapreviouslyvalidatedapproach.18Comorbidi-tiesincludedage,sex,renaldisease,liverdisease,congestiveheartfailure,cerebrovasculardisease,neoplasticdisease,im-munocompromise(includingHIV,solidorgantransplant,neu-tropenia,andimmunosuppressivetherapy),residenceataKeyPointsQuestionWhatistheassociationofempiricalanti–methicillin-resistantStaphylococcusaureustherapywith30-daymortalityforpatientshospitalizedwithpneumonia?FindingsThisnationalcohortstudyof88605hospitalizationsforpneumoniathatuseddetailedclinicaldatatoemulateaclinicaltrialdidnotfindamortalitybenefitofempiricalanti–methicillin-resistantSaureustherapyvsstandardantibioticsforanygroupofpatientsexamined,eventhosewithriskfactorsformethicillin-resistantSaureus.MeaningThisstudycontributestoagrowingbodyofevidencesuggestingthatempiricalanti–methicillin-resistantSaureustherapyusingexistingriskapproachesmaynotbebeneficialtomostpatientshospitalizedwithpneumonia.EmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumoniaOriginalInvestigationResearchjamainternalmedicine.com(Reprinted)JAMAInternalMedicineApril2020Volume180,Number4553©2020AmericanMedicalAssociation.Allrightsreserved.

nursinghome,woundcare,numberofhospitalizationdaysinthepast60days,antibiotictherapyinthepast60days,his-toryofMRSAcolonizationorinfectioninthepastyear,andre-ceiptoftubefeeding.Acuteillnessseverityfeaturesincludedvitalsignsandlaboratorytestresultsroutinelycollectedfrompatientswithpneumonia.Weextractedthefirstlaboratorytestresults(bloodureanitrogen,creatinine,glucose,potassium,sodium,whitebloodcellcount,hematocrit,plateletcount,al-bumin,bilirubin,arterialpH,arterialPaO2,lactate,andtro-ponin)between12hoursbeforeand24hoursafteradmis-sion.Becausethepatient’sinitialtrajectory,bestreflectedbychangingvitalsigns,caninfluenceboththeinitialtreatmentdecisionandfinaloutcome,weextractedtheworstvitalsigns(minimumandmaximumheartrate,minimumsystolicbloodpressure,maximumrespiratoryrate,andminimumoxygensaturation)within12hourspriortothetimeoftreatmentas-signment(antibioticadministration).Missingvitalsigns,whichoccurredinlessthan5%ofallcases,weretreatedasmissingatrandomandimputedwithmedianvalues.Allmissinglabo-ratorytestvalueswereimputedwithnormalvalues;wealsocreatedindicatorvariableswhenlaboratorytestvaluesweremissingthathadmorethan5%prevalenceofmissingnessinthepopulation(albumin,bilirubin,lactate,arterialpH,andtro-ponin).WeextractedMRSAcultureandPCRsurveillancedataoccurringwithinthefirst2calendardaysandyearpriortotheadmission.WedefinedaclinicallyrelevantpositiveMRSAcultureasoneoccurringwithinthefirst2calendardaysfromthedayofadmissionfrombloodorarespiratorysource(spu-tum,endotrachealaspirate,bronchoalveolarlavage,orpleura),aspreviouslydescribed.17StatisticalAnalysisStatisticalanalysiswasconductedfromJune14toNovember20,2019.Ourprimaryanalysiswasaninverseprobabilityoftreatmentpropensityscore–weightedanalysisthatestimatedthemeantreatmenteffectfortheentirepopulationofthe3de-finedempiricaltreatments—standardtherapy,anti-MRSAtherapyplusstandardtherapy,andanti-MRSAtherapywith-outstandardtherapy—on30-daymortalityaftercontrollingforpatientcharacteristicspotentiallyassociatedwithboththepro-pensityoftreatmentandtheriskof30-daymortality.Toimple-mentthisapproach,wefirstcomputedpropensityscoresforthe2anti-MRSAtreatmentsbasedon41patientcharacteristicsascovariates,includingallextractedcomorbidities,vitalsigns,andlaboratorytestvaluesmentionedabove.Thepropensityscoreswereestimatedbyapplyinggeneralizedboostedmachine-learningmodelsasdescribedbyMcCaffreyetal23tominimizethemaximumstandardizedmeandifferencesinthecovari-atesbetweenthe3treatmentgroupsusingthetwangpackageintheRstatisticalcomputingenvironment.24Thedistribu-tionsofpropensityscoresinthe3treatmentgroupswerevisu-allyinspectedforthedegreeofcommonsupportbetweenpa-tientspriortoweighting(Figure2).Thebalanceofcharacteristicsbetweentreatmentgroupsafterweightingwasconsideredad-equateifstandardizeddifferenceswerelessthan0.2(Figure3).Wethenfitaninversepropensityscore–weightedregressionwithgeneralizedestimatingequationthataccountedforclusteringofpatientswithinfacilityusingindependentworkingcovari-ancematricesundermodifiedPoissonregressionmodels25toestimatepopulation-averageadjustedriskratios(aRRs)of30-daymortalityforthe2anti-MRSAtreatmentgroupscom-paredwithstandardtherapyasthecontrolgroup.Wehereaf-teruseweightedpropensityscoreanalysistorefertothisfullsequenceofanalyses.SubgroupAnalysesToexploreassociationsbetweentreatmentanddeathfordif-ferentpatientgroups,weappliedthesameweightedpropen-Figure1.StudyPopulation128 748Hospitalizations for pneumonia at VA medical centers, 2008-2013112 857Hospitalizations after exclusions88 605In final study population54 973Received empirical standard therapya13 528Received empirical anti-MRSA therapy plus standard therapy20 104Received empirical anti-MRSA therapy and no standard therapy15 891Excluded413881943559Transferred from hospitalWith pneumonia in previous 28 daysAt outlier facility24 252With no empirical regimen with standard regimen or anti-MRSAtherapyMRSAindicatesmethicillin-resistantStaphylococcusaureus;VA,VeteransAffairs.aStandardantibioticsweredefinedaseitheraβ-lactamplusmacrolideortetracycline,orarespiratoryfluoroquinolone(moxifloxacinorlevofloxacin).β-Lactamsincludednonpseudomonals(ampicillin,amoxicillin,ampicillin-sulbactam,amoxicillin-clavulanate,cefuroxime,cefotaxime,ceftriaxone,ceftizoxime,cefixime,cefpodoxime,ceftibuten,cefdinir,orertapenem)orantipseudomonals(piperacillin-tazobactam,ticarcillin-clavulanate,ceftazidime,cefepime,meropenem,doripenem,orimipenem).ResearchOriginalInvestigationEmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumonia554JAMAInternalMedicineApril2020Volume180,Number4(Reprinted)jamainternalmedicine.com©2020AmericanMedicalAssociation.Allrightsreserved.

sityscoreanalysisto4subgroupsofpatientswhomightwar-rantempiricalanti-MRSAtreatmentowingto(1)initialadmissiontotheICU,(2)clinicalriskforMRSAdetection,(3)positiveinitialresultsofMRSAPCRsurveillancescreen-ing,and(4)positiveresultsofaclinicalcultureforMRSA(de-tectedonresultsofbloodorrespiratoryculturewithin48hours).WedefinedclinicalriskforMRSAasahistoryofMRSAinfectionorcolonizationinthepastyearoratleast2ofthefol-lowing:previoushospitalization,nursinghomeresidence,andpreviousintravenousantibiotictherapy,whichwasbasedonapreviousexaminationoftheseriskfactorsintheVApopulation17aswellasarevalidationinthestudycohort(eAp-pendix4intheSupplement).SecondaryAnalysesEvenaftercontrollingformeasuredpatientcharacteristicsintheweightedpropensityscoreanalysis,itispossiblethatre-sidualconfoundingowingtounmeasuredpatientcharacter-istics(ie,mentalstatusorradiographicfindings)maybiasourestimatesoftheassociationofanti-MRSAtherapywithmor-tality.Inparticular,physiciansmayhavedisproportionatelyassignedanti-MRSAtherapytopatientswhomtheyper-ceivedtobeatgreaterriskforinfectionanddeath;thisper-ceptionmayhavebeeninfluencedbyfactorsunavailableintheelectronichealthrecord.Inviewofthisrisk,wecapitalizedonthevariationinpracticepatternsforuseofanti-MRSAtherapyacrossfacilitiesandoverdifferentyearsthatwasunex-plainedbypatientcharacteristicsorprevalence6,17,26toper-formaninstrumentalvariableanalysis.Theproportionofhos-pitalizationswithempiricalanti-MRSAtherapyforeachfacilityandyearwastreatedasaninstrumenttoevaluatetheasso-ciationofempiricalanti-MRSAtherapywith30-daymortal-ity.Weimplementedtheinstrumentalvariableanalysisusinga2-stageresidualinclusionapproach.27,28WealsoadjustedforFigure3.PatientCharacteristicsBeforeandAfterInverseProbabilityofTreatmentWeighting0.80.60.40.20.10Absolute Standardized Difference, Maximum PairwiseUnweightedWeightedPrevious inpatient daysMissing lactic acidHematocritMissing pH arterialAlbuminLactic acidAntibiotics in last 60 daysNeoplastic diagnosisMRSA colonizedBUNNursing home residentBalanceplotofpatientcharacteristicsforprimaryanalysisbeforeandafterinverseprobabilityoftreatmentweightingusing41patientcharacteristics.Dotsrepresentthemaximumofpairwiseabsolutestandardizedmeandifferencebetween3treatmentgroupsforeachofthecovariates.Foreachvariable,linesconnectdotsforthesamevariablewithandwithoutweighting.BUNindicatesbloodureanitrogen.Figure2.RelativeDistributionofPropensityScoresforTreatmentWithAnti–Methicillin-ResistantStaphylococcusaureus(MRSA)Therapy10.07.55.02.50DensityPropensity Score for Anti-MRSA Therapy Plus Standard AntibioticsAnti-MRSA therapy without standard antibioticsStandard antibiotics without anti-MRSA therapyAnti-MRSA therapy plus standard antibiotics1.0000.250.500.7586420DensityPropensity Score for Anti-MRSA Therapy Without Standard Antibiotics1.0000.250.500.75Relative distributions of propensity scores anti-MRSA therapy plus standardantibioticsARelative distributions of propensity scores anti-MRSA therapy withoutstandard antibioticsBConditionaldensitycurvesdemonstratingrelativedistributionsofpropensityscoresfortreatmentwithanti-MRSAtherapywithandwithoutstandardantibiotics.EmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumoniaOriginalInvestigationResearchjamainternalmedicine.com(Reprinted)JAMAInternalMedicineApril2020Volume180,Number4555©2020AmericanMedicalAssociation.Allrightsreserved.

patientcharacteristicsascovariatestocontrolforconfound-ingatthefacilityandyearlevel.Althoughresidualconfound-ingisalsopossibleforinstrumentalvariableanalysis,theinstrumentalvariableanalysisshouldavoidthetypeofcon-foundingthatresultsfromuseofanti-MRSAtherapyforindi-vidualpatientswhoareperceivedtobeatgreaterrisk.Afulldescriptionofthisanalysis,includingassessmentsofitsun-derlyingassumptions,28,29isavailableineAppendix2,eTable2,eFigure6,andeAppendix3intheSupplement.SensitivityAnalysisIncorporatingAntipseudomonalAntibioticsBecausereceiptofempiricalanti-MRSAtherapyoftencoin-cideswithreceiptofantipseudomonaltherapy,whichmayalsohaveanassociationwithoutcomes,weestimatedtheasso-ciationofanti-MRSAtherapyandantipseudomonaltherapyseparatelywith30-daymortalitybyapplyingaweightedpro-pensityscoreanalysistocomparepatientsreceivinganti-MRSAtherapyalone,antipseudomonaltherapyalone,andnoanti-MRSAorantipseudomonaltherapyas3treatmentgroups.Theanalysisissimilartotheprimaryanalysisexceptthatweaddedreceiptofstandardtherapyasacovariateintheout-comemodel.StatisticalanalyseswereperformedusingSAS,version9.2(SASInstituteInc),Stata,version16.0(StataCorpLLC),andR(RFoundationforStatisticalComputing;http://cran.r-project.org)software.ExaminationofSecondaryOutcomesTheweightedpropensityscoreanalysiswasappliedtothefollowingsecondaryeventsoccurringbetween48hoursand30daysafterhospitalization:kidneyinjury(definedasanincreaseincreatinineof0.3mg/dL[toconverttomicro-molesperliter,multiplyby88.4]or50%frominitialcreati-ninelevel),incidentorrecurrentClostridioidesdifficileinfec-tion(detectionoftoxinwithoutpreviouspositivetestresultsfortoxininthepast14days),anddetectionofvancomycin-resistantEnterococcussppandgram-negativerodsinbloodorurinecultures.ResultsAtotalof88605hospitalizationsforpneumoniawerestud-ied(Figure1),witha30-dayall-causemortalityof10%(n=8929).Empiricalanti-MRSAtherapywasadministeredto33632patients(38%).Ofthese,13528receivedempiricalanti-MRSAtherapyplusstandardantibiotics,20104receivedem-piricalanti-MRSAtherapywithoutstandardantibiotics,and54973receivedempiricalstandardguideline-recommendedtherapyalone(Table1).20Patientsreceivingempiricalanti-MRSAtherapydemon-stratedagreatercomorbidityburden(renaldisease,29%vs25%;congestiveheartfailure,35%vs30%;neoplasticdis-ease,34%vs3%;andnursinghomeresidents,9%vs3%),moreriskfactorsforMRSA(7%vs2%withhistoryofMRSAinfection,36%vs12%withprevioushospitalization,and42%vs29%withpreviousantibiotics),andgreaterillnessseverity(medianPneumoniaSeverityIndex,124[interquar-tilerange,95-156]vs103[interquartilerange,81-131])aswellasworseoutcomes(16%vs6%for30-dayall-causemortal-ity)comparedwithpatientsreceivingstandardtherapyalone(Table1).20However,thedistributionofpropensityfortreatmentdemonstratedsufficientoverlapbetweenthetreatmentgroups(Figure2A),andweightingresultedinsuf-ficientbalanceinpatientcharacteristicsforall3pairwisecomparisons(Figure2B).Empiricalanti-MRSAtreatmentwassignificantlyassoci-atedwithgreater30-daymortalitycomparedwithstandardtherapyalone,withapropensityscore–weightedaRRof1.4(95%CI,1.3-1.5)forempiricalanti-MRSAtreatmentplusstan-dardtherapyand1.5(1.4-1.6)forempiricalanti-MRSAtreat-mentwithnonstandardtherapy(Table2).Thecorrespondingpropensityscore–weightedmarginalprobabilitiesof30-daymortalitywere11.6%forempiricalanti-MRSAtreatmentplusstandardtherapyand12.7%forempiricalanti-MRSAtreat-mentwithnonstandardtherapycomparedwith8.6%forstan-dardtherapyalone.SubgroupAnalysesAmongallhospitalizations,14370patients(16%)wereini-tiallyadmittedtotheICU,19045(22%)hadclinicalriskfac-torsforMRSA,2775(3%)hadpositivePCRresults,and2154(2%)hadMRSAdetectedbyclinicalculture.Sufficientcom-monsupportresultedinadequatebalanceinpatientcharac-teristicsafterweightingforallsubgroups(eAppendix1;eTable1;andeFigures1,2,3,4,and5intheSupplement).Wefoundasignificantincreasein30-daymortalityasso-ciatedwithempiricalanti-MRSAtherapyplusstandardtherapycomparedwithstandardtherapyaloneamongpatientsadmittedtotheICU(aRR,1.3;95%CI,1.2-1.5),withahighclinicalriskforMRSA(aRR,1.2;95%CI,1.1-1.4),andwithpositiveresultsofsurveillancePCR(aRR,1.6;95%CI,1.3-1.9)butnosignificantdifferenceinriskof30-daymortal-ityforpatientswithpositiveresultsofclinicalculture(aRR,1.1;95%CI,0.8-1.4[Table2]).Similarassociationswerefoundforthegroupreceivinganti-MRSAtherapywithoutstandardtherapy(Table2).InstrumentalVariableAnalysis,AnalysisofAntipseudomonalAntibiotics,andSecondaryOutcomesResultsofsecondaryanalysessuggestedsimilarassocia-tions.Intheinstrumentalvariableanalysis,wefoundasig-nificantassociationbetweenuseofanti-MRSAtherapyand30-daymortality(aRR,1.6;95%CI,1.4-1.9).Intheweightedpropensityscoreanalysisexaminingseparateassociationsofempiricalantipseudomonaltherapyfromanti-MRSAanti-biotics,wefoundboththerapiestobeseparatelyassociatedwithhigherriskof30-daymortalityaftercontrollingforstandardtherapy(anti-MRSAtherapy:aRR,1.2;95%CI,1.1-1.3;antipseudomonaltherapy:aRR,1.3;95%CI,1.2-1.4).Useofempiricalanti-MRSAtherapywasassociatedwithahigherriskofkidneyinjury(aRR,1.4;95%CI,1.3-1.5),Cdif-ficileinfection(aRR,1.6;95%CI,1.3-1.9),vancomycin-resistantEnterococcusspp(aRR,1.6;95%CI,1.0-2.3),andsecondarygram-negativeroddetection(aRR,1.5;95%CI,1.2-1.8).ResearchOriginalInvestigationEmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumonia556JAMAInternalMedicineApril2020Volume180,Number4(Reprinted)jamainternalmedicine.com©2020AmericanMedicalAssociation.Allrightsreserved.

Table1.PatientCharacteristicsandOutcomesbyTreatmentGroupCharacteristicValueaAllPatients(N=88605)StandardAntibioticsAlone(n=54973)bAnti-MRSATherapyPlusStandardAntibiotics(n=13528)WithoutStandardAntibiotics(n=20104)Age,median(IQR),y70(62-81)70(62-81)68(61-80)70(62-81)Femalesex1754(2)1711(3)279(2)354(2)Renaldisease23924(27)13594(25)3912(29)6418(32)Liverdisease2810(3)1393(3)548(4)869(4)Cerebrovasculardisease17048(19)9477(17)2767(20)4804(24)Congestiveheartfailure28679(32)16654(30)4721(35)7304(36)Neoplasticdisease25772(29)1393(3)4569(34)7602(38)Nursinghomeresident5879(7)1829(3)1179(9)2871(14)Woundcare3914(4)1407(3)959(7)1548(8)Immunocompromised1628(2)595(1)440(3)593(3)HistoryofMRSAInfection4168(5)1226(2)679(7)1408(9)Colonization6060(7)2317(4)884(9)1847(12)Previoushospitalizationin90d21082(24)6794(12)4804(36)9484(47)Previousantibioticsin60d31365(35)16067(29)5679(42)9619(48)Tubefeeding1108(1)375(1)218(2)515(3)PneumoniaSeverityIndex,median(IQR)c111(86-142)103(81-131)124(95-156)128(100-162)Heartrate,median(IQR),beatspermin100(86-113)98(85-110)104(90-118)102(88-116)Respiratoryrate,median(IQR),breathspermin22(20-24)22(20-24)22(20-28)22(20-26)Systolicbloodpressure,median(IQR),mmHg113(100-128)115(103-130)108(95-124)109(95-124)Maximumtemperature,median(IQR),°C37.3(36.8-38.2)37.3(36.9-38.4)37.4(38.9-38.4)37.4(36.8-38.3)Pulseoximetry<90%orarterialPaO2<60mmHg22201(25)9889(18)3908(29)3250(24)Albumin,median(IQR),g/dL3.2(3.0-3.6)3.7(3.2-4.5)3.3(2.7-4.1)3.4(2.8-4.0)Bilirubin,median(IQR),mg/dL0.7(0.5-0.9)0.9(0.6-1.0)0.8(0.5-1.0)0.8(0.5-1.0)Bloodureanitrogen,median(IQR),mg/dL20(14-29)19.9(14-27)22(15-34)22(15-33)Serumbicarbonate,median(IQR),mEq/L26(23-28)26(23-28)26(23-28)25(22.9-28.0)Creatinine,median(IQR),mg/dL1.1(0.9-1.5)1.1(0.9-1.5)1.2(0.9-1.7)1.2(0.9-1.7)Glucose,median(IQR),mg/dL122(103-156)121(102-154)123(103-160)123(103-159)Hematocrit,median(IQR),%37.1(33.0-41.1)38.4(34.4-41.8)35.1(30.7-39.3)36(31.7-40.1)Lactate,median(IQR),mEq/L1.0(1.0-1.0)1.0(1.0-1.0)1.0(1.0-1.1)1(1-1.3)ArterialpH7.4(7.4-7.4)7.4(7.4-7.4)7.4(7.4-7.4)7.4(7.4-7.4)Plateletcount,median(IQR),×103/μL216(164-281)219(168-275)223(159-296)214(156-285)Potassium,median(IQR),mEq/L4.1(3.7-4.4)4.0(3.7-4.4)4.1(3.8-4.5)4.1(3.7-4.5)Sodium,median(IQR),mEq/L137(134-139)137(134-139)137(133-140)136(133-139)Troponin,median(IQR),ng/mL0.03(0.03-0.04)0(0-0)0(0-0)0(0-0)Whitebloodcellcount,median(IQR),×103/μL11800(8500-16000)11500(8500-15400)12300(8400-17000)12300(8500-17200)Patientsubgroups,No.(%)ICUadmission14320(16)4774(9)4332(32)5214(26)MRSAriskfactors(historyorprevioushospitalization)19045(22)6331(12)4804(36)9484(47)MRSAsurveillancePCRpositive2775(3)1682(3)389(3)704(4)MRSAdetectedonclinicalculture2154(2)592(1)600(4)962(5)TreatmentpatternsTotalantibioticdays,median(IQR),d10(7-13)10(7-13)11(7-14)10(7-14)Totaldaysofanti-MRSAtherapy,median(IQR),d0(0-3)0(0-0)3(2-5)4(2-6)(continued)EmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumoniaOriginalInvestigationResearchjamainternalmedicine.com(Reprinted)JAMAInternalMedicineApril2020Volume180,Number4557©2020AmericanMedicalAssociation.Allrightsreserved.

DiscussionInthisnationalobservationalstudyofpatientshospitalizedforpneumoniausingdetailedclinicaldata,wewereunabletoestablishbenefitofempiricalanti-MRSAtherapy,evenwhenriskfactorsforMRSAwerepresentorclinicalseveritywar-rantedadmissiontotheICU.Thesefindings,whichwerero-busttomultiplemethodsofanalysis,contributetoagrowingbodyofevidencethatraisesquestionssurroundingwide-spreadempiricaluseofextended-spectrumantibioticsinpa-tientswithcommunity-acquiredpneumonia.15,16,30Thesefindingsshouldbeinterpretedcarefully.Estimatesoftreatmenteffects,whethergeneratedfromrandomizedtrialsorobservationalstudies,arepopulationmeans.Individualmembersofapopulationmayvarywidelyinoutcomesfromdifferenttreatments.Inthepatientcohortthatweanalyzed,itisplausiblethattherewereindividualswhowouldhaveex-periencedanetclinicalbenefitfromempiricalreceiptofananti-MRSAregimenandotherswhowouldhaveexperiencednetharm.Potentialsourcesofharmfromvancomycin,whichac-countedfor98%oftheanti-MRSAtherapyinourstudy,in-cluderenaltoxiceffects,allergy,andsuperinfection.16,31-33Inoursecondaryanalyses,anti-MRSAtherapywasassociatedwithincreasedriskofkidneyinjuryandsecondaryinfec-tions.Theinfluenceofthedecisiontotreatwithanti-MRSAtherapyonotherantibioticchoiceswasanotherpathwaythatlikelyhadanassociationwithoutcomes.OurevaluationofpatientswhoseadmissionculturesgrewMRSAwasnotatestofwhetherMRSAshouldbetreatedwhenitisisolated.Rather,ouranalysisaddressedonlytheques-tionofwhetherempiricaltherapyagainstMRSAwasbenefi-cialcomparedwithstandardempiricaltreatment.Thestrat-egyofaddinganti-MRSAtherapyonceresultsofcultureswerepositivewasnotspecificallyexamined.However,MRSAwasmostcommonlyisolatedfromsputum.Arecognizedlimita-tionofrespiratoryculturesisthattheyoftenreflectoropha-ryngealcolonization.34Thus,acontributingexplanationforourresultsisthatrespiratoryculturesmayhavepoorpositivepre-dictivevalueforMRSApneumonia.Thisfindingcallsintoques-tionwhetherrespiratoryculturesshouldbeusedasacrite-rionstandardforinfectioninpneumoniaandaddsurgencytotheneedforbetterdiagnostictoolstomorepreciselyidentifybacterialandviralcausesofpneumoniaandotherinfections.FuturestudiesshouldextendtheworkpresentedheretoexaminetreatmentdecisionsduringthepostempiricalTable2.AdjustedRiskRatiosfor30-DayMortalityAmongPrimaryandSubgroupInverseProbability–WeightedAnalysesGroupAdjustedRiskRatio(95%CI)Anti-MRSATherapyPlusStandardAntibioticsAnti-MRSATherapyWithoutStandardAntibioticsAllpatients1.4(1.3-1.5)1.5(1.4-1.6)PatientsadmittedtoICU1.3(1.2-1.5)1.4(1.2-1.5)HighclinicalriskforMRSA1.2(1.1-1.4)1.3(1.1-1.4)MRSAsurveillancePCRpositive1.6(1.3-1.9)1.8(1.4-2.3)MRSAculturepositive1.1(0.8-1.4)1.2(0.9-1.6)Abbreviations:ICU,intensivecareunit;MRSA,methicillin-resistantStaphylococcusaureus;PCR,polymerasechainreaction.Table1.PatientCharacteristicsandOutcomesbyTreatmentGroup(continued)CharacteristicValueaAllPatients(N=88605)StandardAntibioticsAlone(n=54973)bAnti-MRSATherapyPlusStandardAntibiotics(n=13528)WithoutStandardAntibiotics(n=20104)Empiricaltreatment,No.(%)β-Lactam63437(72)34412(63)11345(84)17679(88)Fluoroquinolone33304(38)25738(47)7566(56)0Macrolide35753(40)29414(54)5951(44)388(2)Antipseudomonaltherapy30243(34)3127(6)9877(73)17238(86)Outcomes30-dMortality,No.(%)8929(10)3261(6)2126(16)3542(18)Lengthofstay,median(IQR),d4(3-7)4(2-6)6(3-10)6(4-10)Readmissionin28d,No.(%)17682(20)9276(17)3099(23)5307(26)Abbreviations:ICU,intensivecareunit;IQR,interquartilerange;MRSA,methicillin-resistantStaphylococcusaureus;PCR,polymerasechainreaction.SIconversionfactors:Toconvertalbumintogramsperliter,multiplyby10.0;bilirubintomicromolesperliter,multiplyby17.104;bloodureanitrogentomillimolesperliter,multiplyby0.357;bicarbonatetomillimolesperliter,multiplyby1.0;creatininetomicromolesperliter,multiplyby88.4;glucosetomillimolesperliter,multiplyby0.0555;hematocrittoproportionof1.0,multiplyby0.01;lactatetomillimolesperliter,multiplyby0.111;plateletsto109perliter,multiplyby1.0;potassiumtomillimolesperliter,multiplyby1.0;sodiumtomillimolesperliter,multiplyby1.0;troponintomicrogramsperliter,multiplyby1.0;andwhitebloodcellsto109perliter,multiplyby0.001.aDataarepresentedasnumber(percentage)ofpatientsunlessotherwiseindicated.bStandardantibioticsweredefinedaseitheraβ-lactamplusmacrolideortetracycline,orarespiratoryfluoroquinolone(moxifloxacinorlevofloxacin).β-Lactamsincludednonpseudomonals(ampicillin,amoxicillin,ampicillin-sulbactam,amoxicillin-clavulanate,cefuroxime,cefotaxime,ceftriaxone,ceftizoxime,cefixime,cefpodoxime,ceftibuten,cefdinir,orertapenem)orantipseudomonals(piperacillin-tazobactam,ticarcillin-clavulanate,ceftazidime,cefepime,meropenem,doripenem,orimipenem).cPneumoniaSeverityIndexwasestimatedforeachpatientusingallfeaturesextractablefromtheelectronichealthrecord,whichincludedallelementsexceptformentalstatusandpresenceofpleuraleffusiononresultsofchestimaging.20ResearchOriginalInvestigationEmpiricalAnti-MRSAvsStandardAntibioticTherapyandRiskofMortalityinPatientsWithPneumonia558JAMAInternalMedicineApril2020Volume180,Number4(Reprinted)jamainternalmedicine.com©2020AmericanMedicalAssociation.Allrightsreserved.

treatmentphase,suchasdeescalation,3,35aswellasdosingandtherapeuticdrugmonitoring,whichwerenotexaminedinourstudy.Validapproachescandrawcausalinferencesaboutse-quentialdecisionsthatusetime-varyinginformation,suchassequentialmultipleassignmentrandomizedtrials36andob-servationalstudiesofdynamictreatmentregimens.37Identi-fyingoptimalantibioticdecision-makingstrategiesforpa-tients—includinghowbesttointegrateinformationfromresultsofculturesandmoleculardiagnosticteststomakesubse-quentdecisionsaboutantibioticsafterempiricaltherapy—meritsfurtherresearch.LimitationsThisobservationalstudyhaslimitations.Whileourlargepopu-lationsize,variation,anddetailedclinicaldataallowedustocompareoutcomesforpatientswithsimilarmeasuredillnessseverity,andwhiletheinstrumentalanalysisshouldprovidesomeprotectionagainstbiasbyunmeasuredseverity,re-sidualconfoundingisstillpossible.Inoursecondaryanaly-sis,antipseudomonaltherapywasfoundtobeassociatedwith30-daymortality.Thisfindingwarrantsfurtherinvestigationasmaybesuggestedbytheaddedassociationofconcomitanttherapy.Ourcase-findingapproachiswidelyusedbutreliedondiagnosiscodesassignedattheendofthehospitalization;whileadequateprecisionhasbeenfoundinthisapproach,38wemayhaveincludedsomepatientswhodidnotinitiallyre-ceiveadiagnosisofpneumonia.Wecapturedallantibioticsad-ministeredinthehospital,butanestimated2%ofpatientsinourpopulationreceivedadifferentantibioticintheemer-gencydepartment.18Ourpopulationisdisproportionatelymale,andalthoughnodifferencesinantibioticeffectshavebeenreported,womenhavedifferentoutcomepatternsfrommeninpneumonia.39Similarly,ourpopulationhadaninsuf-ficientnumberofpatientsreceivinglinezolidtocompareitsseparateeffects.ConclusionsCliniciansareconstantlyseekinginnovationsthatmightprom-isebetteroutcomesforourpatients.However,oureagernesstoimproveoutcomes,particularlyforcriticallyillpatients,makesussusceptibletoadoptpracticesthatmayhaveplausibilityandpromisebutlacksignificantevidenceorvalidation.40-43Onceadopted,thesepracticesbecomenormsthatpersistdespitecautionarystudies.Withamortalityratethathasnotsubstan-tiallyimprovedindecades,thethreatofresistantorganisms,andtheemphasisontimelyantibioticsinsepsis,itisnotsur-prisingthatthestrategyofearlybroad-spectrumantibioticsforpneumoniahasbecomethenorm.Theunderlyingassump-tionofthisapproachisthatthebenefitofmorepotentanti-bioticsduringtheempiricalphaseexceedstheharms.Ourstudyquestionsthisassumption.Wehopethatnewerdiag-nosticapproaches44-46andmoreevidenceinformingantimi-crobialdecisionswillenhanceourabilitytoaccuratelytreatourpatients.Inthemeantime,administrationofempiricalanti-MRSAtherapyforpneumoniausingcurrentapproachesshouldbereconsidered,eveninhigh-riskpatients.ARTICLEINFORMATIONAcceptedforPublication:December23,2019.PublishedOnline:February17,2020.doi:10.1001/jamainternmed.2019.7495AuthorAffiliations:DivisionofPulmonaryandCriticalCare,VeteransAffairsSaltLakeCityHealthCareSystem,SaltLakeCity,Utah(B.E.Jones);UniversityofUtah,SaltLakeCity(B.E.Jones,Stevens,Nelson,Sauer,Yarbrough,M.M.Jones,Samore);DivisionofEpidemiology,UniversityofUtah,SaltLakeCity(Ying,Haroldsen,He,Nevers,Stoddard,Greene);DivisionofEpidemiology,VeteransAffairsSaltLakeCityHealthCareSystem,SaltLakeCity,Utah(Stevens,Sauer,M.M.Jones,Samore);DivisionofInternalMedicine,UniversityofUtah,SaltLakeCity(Christensen);DepartmentofHealthEconomicsandEpidemiology,VeteransAffairsSaltLakeCityHealthCareSystem,SaltLakeCity,Utah(Nelson);DepartmentofInternalMedicine,VeteransAffairsSaltLakeCityHealthCareSystem,SaltLakeCity,Utah(Yarbrough);DivisionofInfectiousDisease,VeteransAffairsGreaterLosAngelesHealthcareSystem,LosAngeles,California(Goetz).AuthorContributions:DrB.E.Joneshadfullaccesstoallthedatainthestudyandtakesresponsibilityfortheintegrityofthedataandtheaccuracyofthedataanalysis.Conceptanddesign:B.E.Jones,Ying,Stevens,Sauer,M.M.Jones,Greene,Samore.Acquisition,analysis,orinterpretationofdata:B.E.Jones,Ying,Stevens,Haroldsen,He,Nevers,Christensen,Nelson,Stoddard,Sauer,Yarbrough,Goetz,Greene,Samore.Draftingofthemanuscript:B.E.Jones,Stevens,Nevers,Christensen,M.M.Jones.Criticalrevisionofthemanuscriptforimportantintellectualcontent:B.E.Jones,Ying,Stevens,Haroldsen,He,Nelson,Stoddard,Sauer,Yarbrough,Goetz,Greene,Samore.Statisticalanalysis:B.E.Jones,Ying,Stevens,Nevers,Nelson,Stoddard,Sauer,M.M.Jones,Greene,Samore.Obtainedfunding:Samore.Administrative,technical,ormaterialsupport:B.E.Jones,Stevens,Christensen,Sauer.Supervision:Greene.ConflictofInterestDisclosures:DrB.E.JonesreportedreceivinggrantsfromtheCentersforDiseaseControlandPreventionandVeteransAffairsHealthServicesResearchandDevelopmentduringtheconductofthestudy.MsNeversreportedreceivinggrantsfromtheCentersforDiseaseControlandPreventionduringtheconductofthestudy.DrSauerreportedreceivinggrantsfromtheVeteransAffairsduringtheconductofthestudy.DrGreenereportedreceivingpersonalfeesfromJanssenPharmaceuticals,DURECTCorporation,andPfizerIncandgrantsfromAstraZenecaandCSLoutsidethesubmittedwork.Nootherdisclosureswerereported.REFERENCES1.CentersforDisease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ClinicalStudySpinaltuberculosisamonghumanimmunodeÞciencyvirusÐnegativepatientsinaKenyantertiaryhospital:a5-yearsynopsisPhilipM.Mwachaka,BSc(Hons),MBChB*,SimeonS.Ranketi,BSc(Hons),MBChBIVstudent,ObonyoG.Nchafatso,BSc(Hons),MBChB,BenM.Kasyoka,MBChBIVstudent,JuliusG.Kiboi,MBChB,MMed(Surg)DepartmentofHumanAnatomy,SchoolofMedicine,UniversityofNairobi,00100GPO,Nairobi,KenyaReceived16August2010;revised21December2010;accepted26January2011AbstractBACKGROUNDCONTEXT:Spinaltuberculosis(TB)accountsformorethanhalfofallcasesofskeletalTB.AlthoughKenyahasoneofthehighestburdensofTB,dataonspinalTBinthiscoun-tryremainscarce.PURPOSE:Tohighlighttheclinicalpresentationandmanagementofthisconditioninoursetup.STUDYDESIGN:Retrospectivestudy.SETTING:KenyattaNationalHospitalinKenya.PATIENTSAMPLE:Onehundredtwenty-ninepatients.OUTCOMEMEASURES:PatientsÕconditionafterinterventionanddurationofhospitalstay.METHODS:Thisstudyinvolvedreviewofpatientsadmittedtoourhospitalbetween2004and2009withadiagnosisofspinalTB.RESULTS:Themostcommonpresentingcomplaintswerebackpainin100patients(77.5%)andlimbweaknessin94patients(72.9%),whereasthemostfrequentphysicalexaminationÞndingwasgibbusdeformityin85patients(65.8%).Most(79patients,61.2%)hadseveremotorandsensoryimpairmentgradedaseitherAmericanSpinalInjuryAssociation(ASIA)AorASIAB.Imagingrevealedmultiplevertebraediseasein90patients(79.6%).Ofthese,themostcommonwastwovertebraediseasein77patients(68.1%).Allpatientsweremanagedusinganti-TBdrugsandanal-gesics;however,33(25.6%)requiredadjunctiveoperativemanagement.Meanhospitalstaywas53.3days.Markedclinicalimprovementwasseenin91patients(70.0%)within6monthsoftreatment.CONCLUSION:PatientswithspinalTBinoursettingtendedtopresentlateandwithadvanceddisease.Therefore,ahighindexofsuspicionshouldbemaintainedandappropriatechemotherapystartedasearlyaspossible.2011ElsevierInc.Allrightsreserved.Keywords:Spinaltuberculosis;Presentation;Management;KenyaIntroductionTuberculosis(TB)causes2millionto3milliondeathsannuallyworldwide[1Ð4].AccordingtotheWorldHealthOrganizationÕsGlobalTBReport2009,Kenyaranks13thinthelistof22high-burdenTBcountriesintheworldandhastheÞfthhighestburdeninAfrica[5].Inthatreport,Kenyahadmorethan132,000newTBcasesandaninci-dencerateof142newsputumsmearÐpositivecasesper100,000peopleperyear.Itwasalsoreportedthatthean-nualmortalityrateassociatedwithTBinthecountrywas26per100,000amonghumanimmunodeÞciencyvirus(HIV)Ðnegativepatientsand39per100,000inHIV-positiveindividuals.Tuberculosisusuallystartsinthelungsbutcanbedis-seminatedhematogenouslytootherpartsofthebody,suchasthemusculoskeletalsystem[2,3].SpinalTBisthecom-monestformofskeletalTB[1Ð4].SpinalTBposesagreatchallengetophysiciansowingtoitsnonspeciÞcandwidespectrumofclinicalpresentationsandthusoftenresultsFDAdevice/drugstatus:notapplicable.Authordisclosures:none.*Correspondingauthor.SchoolofMedicine,UniversityofNairobi,POBox9712,00100GPO,Nairobi,Kenya.Tel.:(254)72-335-3913.E-mailaddress:[email protected](P.M.Mwachaka)1529-9430/$-seefrontmatter2011ElsevierInc.Allrightsreserved.doi:10.1016/j.spinee.2011.01.033TheSpineJournal11(2011)265Ð269

indelayindiagnosisifahighindexofsuspicionisnotmaintained[6,7].Second,neuralinvolvementmayoccurinupto50%ofpatientsandcancauseirreversibledamageifnotpromptlyandadequatelytreated[1,8,9].Thereispau-cityofdataregardingspinalTBinKenya,despitethefactthatthecountryhasoneofthehighestTBburdensinAfrica[5].Thisstudyaimedathighlightingtheclinicalpresenta-tionandmanagementofpatientswithspinalTBpresentingataKenyantertiaryhospital.PatientsandmethodsCasesofspinalTBwereidentiÞedretrospectivelybyexaminingrecordsofpatientsadmittedtoKenyattaNationalHospital,inKenya,withadiagnosisofspinalTBbetweenJanuary1,2004,andDecember31,2009.Ken-yattaNationalHospitalisoneofthetwomajorteachingandreferralhospitalsinKenya.ApprovaltoconductthestudywasgrantedbytheKenyattaNationalHospitalEthicsResearchBoard.Atotalof129patientÞleswereexamined.InformationretrievedincludedpatientsÕbiodata,HIVsta-tus,clinicalpresentation,investigationsperformed,numberandtypeofvertebraeinvolvedbasedonimagingresults,treatmentinterventions,andoutcome.MotorandsensoryimpairmentswereclassiÞedaccordingtotheAmericanSpi-nalInjuryAssociation(ASIA)Impairmentscale.ResponsetotherapywasclassiÞedaseitherimprovementorworsen-inginclinicalpresentationofthepatientwithin6monthssinceinstitutionofthetherapy.Datacollectedwereana-lyzedusingtheStatisticalPackageforSocialSciencesforWindowsversion17.0(SPSSInc.,Chicago,IL,USA).ResultsPatientdataOfthe129patientsreviewed,68(52.7%)weremaleand61(47.3%)werefemale.Theyoungestpatientwas3yearsold,whereastheoldestwas81yearsold(mean,33.5616.2years).Mostpatientswereinthethirdandfourthdecadesoflife.ThedistributionofpatientsaccordingtoagegroupisshownintheFigure.AllpatientsstudiedwereHIVnegative.ClinicalpresentationBackpainwasthemostcommonpresentingsymptomasshowninTable1.Inadditiontobackpain,sixpatientshadpainelsewhere.Ofthesepatients,two(1.7%)hadlowerbackandabdomenpain,two(1.7%)hadbackpainandchestpain,one(0.83%)hadbackpainandhippain,andone(0.83%)hadbackpainandlowerlimbpain.Lowerlimbweaknesswasre-portedby90patients(70.3%),whereasupperlimbwasin-volvedintwopatients(2.1%).Gibbusdeformitywasnotedin85patients(65.8%),whereas15patients(11.6%)hadky-phoscoliosis.SensoryandmotorimpairmentsaccordingtotheASIAscalewereasfollows:ASIAA,48patients(37.2%);ASIAB,31patients(24.0%);ASIAC,26patients(20.2%);ASIAD,14patients(10.9%);andASIAE,10pa-tients(7.7%).Inaddition,tendernessatthebackwaselicitedin48patients(37.2%).InvestigationsperformedPlainradiographsofthespinewerethemostfrequentlyperformedinvestigationsin126patients(97.7%),followedbymagneticresonanceimaging(MRI)scansin58patients(45%).OthertestsdoneweresputumsmearsforacidfastFigure.Distributionofpatientsaccordingtoagegroups.ContextKenyahasanexceptionallyhighburdenoftuberculosisinfection,andmuchofthisisassociatedwithHIVim-munosuppression.Whilethisassociationhasbeenthesubjectofconsiderableresearch,thereislittlemoderndataavailableonspinaltuberculosisinHIV-negativepatients.ContributionTheauthorspresentdatafromasinglelargetertiarycen-terfroma5-yearperiodandnotethatthevastmajorityofpatientspresentedwithadvanceddiseaseofthespine.Three-quartershadseverebackpainorweakness,andtwo-thirdshadgrosskyphosisorneurologicimpairment.Mostpatientsrespondedtochemotherapeuticorsurgicalinterventionwithimprovement.ImplicationThesedatahighlightthatspinaltuberculosisisnotlimitedtopatientswithHIVinfection.Limitedresources,poornu-trition,concomitantdisease,andlimitedaccesstoroutinehealthcarenegativelyimpactpatientswithspinaldisordersglobally.Thesefactorsperpetuatetheprevalenceofseriousspinalinfections.PatientsoftenpresentlateinthecourseoftheirdiseaseandwithagreaterlikelihoodofsigniÞcantmorbidityandmortality.Effortstoaddresstheseissues,whileongoingandadmirable,arecurrentlyinsufÞcient.—TheEditors266P.M.Mwachakaetal./TheSpineJournal11(2011)265–269

bacilliin16patients(12.4%),computedtomographyscansin14patients(10.9%),bacterialculturesandsensitivitytestsin13patients(10.1%),andMantouxtestin13patients(10.1%).Inaddition,25patients(19.4%)hadchestradio-graphstakentovisualizepulmonaryTB.Inaddition,histo-logicalstudieswereperformedin33biopsiedspecimens(25.6%)obtainedduringsurgery.VertebralinvolvementThenumberandlevelofvertebrainvolvedinthediseaseprocessasseeninimagingmodalitiesusedweredocu-mentedin113patients.Thediseaseprocessfrequentlyinvolvedtwovertebraein77patients(68.1%).Thetotalnumberofvertebraeinvolvedintheremainingpatientswasasfollows:onevertebrain23patients(20.4%),threevertebraein6patients(5.3%),andfourvertebraein4patients(3.5%),whereas5,8,and11vertebraediseasewasreportedinonepatienteach.Inthelatter,thevertebraethatwereinvolvedincludedT7ÐL5.ThedistributionofthediseaseaccordingtovertebralcolumnissummarizedinTable2.Inallagegroups,mostpatients(43.4%)hadlesionsinthethoracicvertebrae.Involvementofboththoracicandlumbarvertebraewasobservedin10patients(8.8%),whereasthreepatients(2.7%)hadlumbosacralinvolvement.MostcommonlyaffectedvertebrawasT9in25individuals(22.1%)fol-lowedbyL1in22patients(Table3).ManagementandclinicaloutcomeMedicalmanagementthatinvolvedadministrationofanti-TBdrugs,analgesics,andphysiotherapywasthemainstayofthetreatmentinall129patients(100%).Theanti-TBdrugregimeninvolvedrifampicin,isoniazid,pyrazi-namide,andethambutolduringtheinitial8-weekintensivephase,followedbyrifampicinandisoniazidinthecontinu-ationphase.Therapywasgivenforanaverageof9months.Lumbarcorsetswereusedby22patients(17.1%).Thirty-threepatients(25.6%)requiredsurgicalinterven-tion,whichinvolvedcorddecompressionandstabilizationofthespine.Indicationsforsurgeryincludedlackofresponsetomedicaltherapyandworseningofspinaldefor-mity.Themeandurationofhospitalstaywas53.3days(range1Ð285days).Patientswhorequiredsurgerystayedlongerfor92.95days(standarddeviation83.0days)com-paredwiththosewhoweremanagedconservatively,62.55days(standarddeviation74.9days).Inaddition,patientswhopresentedwithASIAAhadthelongestmeanhospitalstayof56.9days(range1Ð285days),whereasthosewithASIAEhadtheshorteststayof30.03days(range3Ð107days).Markedclinicalimprovementintermsofsignsandsymptomswasseenin91patients(70.0%)overa6-monthperiodfollowinginstitutionoftreatment.Threepatients(2.3%)hadcomplicationofdeepvenousthrombosis,andanadditional12patients(9.3%)werelosttofollow-up.Twenty-fourpatients(18.4%)developedparaplegia.Atthetimeofpresentation,thesepatientswerenotedtohaveseveremotorandsensoryimpairmentsasfollows:ASIAA,10patients(55.6%);ASIAB,4patients(22.2%);andASIAC,4patients(22.2%).Table2VertebralinvolvementVertebraeAgegroup,n(%)Total0Ð10y11Ð20y21Ð30y31Ð40y41Ð50y51Ð60y61Ð70yO70yCervicalÑ1(7.69)5(11.6)ÑÑ1(10.0)ÑÑ7(6.2)Thoracic2(40.0)8(61.5)13(30.2)10(50.0)4(33.3)5(50.0)6(85.7)1(33.3)49(43.4)Lumbar2(40.0)3(23.1)21(48.8)6(30.0)4(33.3)3(30.0)1(14.3)2(66.7)42(37.2)Thoracolumbar1(20.0)Ñ3(7.0)2(10.0)4(33.3)ÑÑÑ10(8.8)LumbosacralÑ1(7.7)Ñ1(5.0)Ñ1(10.0)ÑÑ3(2.7)SacralÑÑÑ1(5.0)ÑÑÑÑ1(0.9)CoccygealÑÑ1(2.3)ÑÑÑÑÑ1(0.9)Total5(100)13(100)43(100)20(100)12(100)10(100)7(100)3(100)113(100)Table1ClinicalpresentationofspinaltuberculosisPresentingcomplaintn%Backpain10077.5Limbweakness9472.9Urinary/fecalincontinence4031.0Nightsweats2720.9Backswelling2418.7Weightloss97.0Cough97.0Table3Top10vertebraeinvolvedinthediseaseVertebraeFrequency%T92522.1L12219.5L32118.6L42118.6L52017.7T102017.7T81916.8L51614.2T111210.6T12119.7T6119.7267P.M.Mwachakaetal./TheSpineJournal11(2011)265–269

DiscussionSpinalTB,alsoknownasPottdisease,resultsfromaninfectionofthevertebraebytheMycobacteriumtubercu-losisbacteria.Theorganismmaystaydormantintheskeletalsystemforanextendedperiodbeforethediseasecanbedetected[2,4].Thus,spinalTBisachronicandslowlyprogressivediseasewithawidespectrumofclin-icalpresentations.Inthepresentstudy,morementhanwomenhadspinalTB.Similarandhigherincidenceratioshavebeenreportedinotherstudies[10Ð12].Somestudieshave,however,reportedafemalepredominance[13Ð15].Themeanageofpatientsinourstudywas33.5years,withthepeakprevalenceinthe20-to30-yearagegroup.Ameanageof35.1to39yearshasbeenreportedinprevi-ousstudies[9,16,17].StudiesinIran,Pakistan,andSouthAfricahavereportedapeakprevalenceagegroupof20to40years[11,14,18].IntheSouthAfricanstudy,mostpatients(57.4%)wereagedbetween20and40years.Pres-enceofunidentiÞedriskfactorsclusteredtothisagegroupmightaccountforthisuniquepatternobserved.EffortsshouldbeintensiÞeddirectedtowardidentifyingthesefac-torsasthisisthemosteconomicallyactivegroupandthusposesasigniÞcanthealthburden.SpinalTBhasawidespectrumofclinicalpresentationsasdepictedinthepresentstudy,withbackpainandlowerlimbweaknessbeingtheleadingsymptoms.Thisisconcor-dantwithmostpreviousstudies[11,12,18Ð20].Neurologi-caldeÞcitsoccurbecauseofkyphoticdeformity,spinalabscess,and/orgranulationtissuecompressingthespinalcordorcaudaequina[6].Inourstudy,mostpatientspre-sentedwithspinaldeformities,whichcouldhaveledtothemajorneurologicaldeÞcitssuchasparaplegianotedinsomecases.Furthermore,mostpatientspresentedlateasevidencedbytheprofoundmotorandsensorydeÞcitsasshownbypoorASIAgrades.BecausespinalTBdoesnotusuallypresentwiththeconstitutionalsymptomsofpulmonaryTBofcough,weightloss,fever,andnightsweats,andalsobecausetheneurologicaldeÞcitsarelatemanifestationsofthediseaseprocess,ahighindexofsus-picionisimportantinestablishingthediagnosis[1,3,6].Diagnosticroleofdifferentimagingmodalitieshasbeenwidelydiscussedintheliterature[21,22].TheMRIandcomputedtomographyscansarecrucialtodetectearlyTBbeforeenoughbonydamageisdonetobecomeevidentonplainradiographs[6,9].ThecomputedtomographyandMRIscanscanalsohelpindecidingthemodeoftreatment(surgicalornonsurgical)andthekindofapproach(anteriororposterior)ifsurgicaltreatmentisoptedfor[6,18].Althoughplainradiographsofthespinehaveanumberoflimitations,theywerethemaininvestigativetoolinourstudy(97.7%),probablybecausetheyarecheaperthanotherimagingmodalities.Thoracicvertebraewerethemostfrequentlyaffectedbythedisease.TheseÞndingsconcurwithreportsfromotherstudies[9,14,15,18].Thehighfrequencyofthoracicverte-brainvolvementisattributabletohematogenousseedingofMycobacteriumfromthelungs.InvolvementofmultiplevertebraeasseeninourpatientshasalsobeenreportedbyDharmalingam[3]andHadadietal.[23].ThegoalsofmanagementofspinalTBaretoeradicatetheinfection,topreventortreatneurologicaldeÞcits,tocorrectspinaldeformities,toachievenormalsagittalcon-toursofthespinalcolumn,andtoachieveunrestrictedmobilizationandnormalizationofpatientsÕdailyactivitiesassoonaspossible[24].TreatmentofspinalTBdependsonseverityandextentofneuralinvolvementandvertebraldamage.Intheabsenceofmajorneurologicalinvolvementanddeformity,thepatientistreatedconservativelywithastandardanti-TBdrugregimen[6,9,18,24,25].Abraceorcollarisalsoadvisedifthediseaseinvolvesthecervicalorlumbarregionsorthethoracolumbarjunction[6].Useofabraceorcollarwasmodestinourpatientpopulationprob-ablybecauseofitshighcost.Inthepresentstudy,about25%ofthepatientsrequiredsurgicalintervention.UsuallytheindicationsforsurgeryarefewandspeciÞc.TheyincludeneurologicaldeÞcit,spi-naldeformitywithinstability,severeorprogressivekypho-sis,retropulsedbonefragmentsinthecanal,largeabscesscausingrespiratoryembarrassment,andnoresponsetomedicaltherapy[6,25].Surgicalinterventionmaybelim-itedtodebridementorradicalresectionwithautograftingandinstrumentation[4].Short-termcourseofanti-TBdrugsisusuallygiventopatientsaftersurgery[24,26].Thedura-tionofthechemotherapyis,however,controversial[6].ImportantdifferentialsforspinalTBincludepyogenicandfungalinfections,sarcoidosis,metastasis,andlymphoma[27].WhereasimagingmodalitiesareoflimitedcapacitytodistinguishthemfromspinalTB,slowprogressionandchro-nicityaresuggestiveofspinalTB[11,27].WhenindoubtofthediagnosisofspinalTBsuchaswhenthereispoorre-sponsetomedicaltherapy,abiopsyisrecommended[11].Cultureandsensitivitytestsshouldalsobeperformedinun-responsivecasestoruleoutmultidrugresistanceTB.Inconclusion,spinalTBisacurablecondition;however,delayindiagnosisandtreatmentcausessigniÞcantmorbid-ityanddisability.Inresource-limitedsettingswhereidealimagingmodalitiessuchasMRIscansareexpensive,ahighindexofsuspicionshouldalwaysbemaintainedandappro-priatemedicaltherapywithanti-TBdrugsinstitutedasearlyaspossible.References[1]TurgutM.Spinaltuberculosis(PottÕsdisease):itsclinicalpresenta-tion,surgicalmanagement,andoutcome.Asurveystudyon694patients.NeurosurgRev2001;24:8Ð13.[2]AlmeidaA.Tuberculosisofthespineandspinalcord.EurJRadiol2005;55:193Ð201.[3]DharmalingamM.Tuberculosisofthespine:theSabahexperience.Epidemiology,treatmentandresults.Tuberculosis(Edinb)2004;84:24Ð8.268P.M.Mwachakaetal./TheSpineJournal11(2011)265–269

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