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Primarybloodstreaminfectionasanindication:RegulatoryperspectiveFDA/IDSA/ISAPWorkshopApril15,2004DavidRoss,M.D.,Ph.D.1OutlineRegulatoryhistoryDefininganti-infective(AI)indicationsPrimarybloodstreaminfectionasanAIindication2Bloodstreaminfection(BSI):history10drugsindicatedforbacteremiaorsepticemiaAlllabeledpriorto1992LabelingbasedonvariableorunspecifiedclinicalmanifestationsindifferentstudiesIncludesbacteremiaassociatedwithfocalinfectionandbacteremiaofunknownoriginPatientspooledfromtrialsofotherindications39/93Anti-InfectiveDrugsACmeetingBacteremiadidnotaffectoutcomeinalargeNDAdatasetBacteremiaisduetoinfectionataprimarysiteBacteremicSIRSpatientsformaheterogeneouspopulationUnclearifbacteremicSIRSpatientsweresickerthannonbacteremicpatients49/93ACconclusionsBacteremialessimportantthansiteofinfectionforclassifyinginfectionsStudyof‘bacteremicsepsis’asaseparateindicationnotfeasiblegivenheterogeneityofpatientpopulationLabelingshouldincludebacteremiainthecontextofsite-specificinfections,e.g.,“pneumoniawithassociatedbacteremia”5ReconsideringBSIasanindicationIncreasedincidenceofBSI:withresistantpathogens(e.g.,VRE,MRSA)withoutidentifiableprimarysourceIssuesinmeasuringdrugeffectinBSI...PatientheterogeneityDifferencesinnaturalhistoryfordifferentpathogensDifferencesinpathogenepidemiology/virulenceNeedtodefineanidentifiableclinicalsyndrome ...beforeconsideringasanindication6Doesbacteremiaequaldestiny?28yofemalewithpatchyinfiltrateinonelobe.Nocomorbidities.HR80,RR16.SCx

→

S.pneumoniaeBCx→

S.pneumoniae.Mortalityrisk<0.1%52yomalewithmultilobarpneumonia.Chronicrenalfailure,uncontrolledDMHR130,RR35.Intubated.SCx

→

S.pneumoniaeBCx→negativeMortalityrisk27%

7NotallbacteremiasarethesameA76yonursinghomeresidentwasadmittedforalteredmentalstatus,hypotension,hypo-thermia,obtundation,andneckstiffness.ACXRshowedbi-lateralinfiltrates.AnLPshowed4,218WBC/μL(89%segs)andglucoseoflessthan20mg/dL.BloodandCSFCxgrewMRSA. DespiteMICUtransfer,therapywithvancomycinandrifampin,andaggressivesupportivecare,thepatientdeterioratedanddied11daysafteradmission.A67yoMwithchronicrenalfailurereceivinghemodialysisviaanarteriovenousgraftwasadmit-tedforfeverto38.0°C;thepatientwasotherwisewell.Nomurmurwasfoundandthegraftwasnon-tender.Thefeverresolvedandvancomycinwasstarted.BCxgrewMRSA.Therewasnofurtherfeverorothersx.ArepeatBCxwaspositive.Atransesophageal

echocardio-gramwasnegative,aswasaDopplerultrasoundofthegraft.Thepatientreceived4weeksofIVvancomycinanddidwell.RepeatBCxwerenegative.8Site-basedanti-infective(AI)indication“Infectionataspecifiedbodysiteduetoaspecified,susceptiblemicroorganism”.(PointstoConsider,1992)AccountsfordifferencesindrugefficacyforinfectionsatdifferentsitesAllowsdemonstrationofefficacyfromadequateandwell-controlledstudiesAllowsdescriptionofdrugeffectinlabeling9EssentialsofanAIindicationMustbearecognizeddiseaseorcondition,oranimportantmanifestationofadiseaseDefinablesyndromewithspecificclinicalmanifestations,diagnosticcriteria,andtherapeuticrequirementsDrugtreatmenteffectdemonstrableviaadequateandwell-controlledtrialsusingclinicallyrelevantendpointsDescribableinlabeling10AIindicationsvs.non-indicationsAIindicationsUrinarytractinfectionOsteomyelitisBacterialmeningitisStreptococcalpharyngitisCommunity-acquiredpneumoniaProphylaxisagainstpost-operativeinfectionNon-indicationsDysuriaElevatedESRComathroatcultureforGASPleuriticchestpainDecreaseinskincolonization11CAPUTIBacteremiaMeningitisEndocarditisComplicatedIABDOsteomyelitisSSTI12BSIvs.bacteremiaCandidalBSI(candidemia)AcceptedAIindicationFrequentlyprimaryBSI(noidentifedunderlyinginfection)DefinableclinicalsyndromeEscherichiacolibacteremiaNotacceptedAIindicationVirtuallyneverprimaryBSIVarietyofpotentialunderlyinginfections(e.g.,GI,GU)Varietyofclinicalmanifestations13BSIvs.(pseudo)bacteremiaPeripheralBCx(n=1408)CatheterBCx(n=1408)pvalueTrueBSI13.7%14.4%0.59Contamination1.8%3.8%0.001Indeterminate0.9%1.6%0.09Negative83.6%80.1%0.02EvertsRJetal.JClinMicrobiol.2001;39:3393-339414BacteremiaasasurrogateendpointChaissonRetal.Ann.Intern.Med.1994;121:905-11Clarithromycindose500mgbid1000mgbid2000mgbidBacterialloadat2weeks(cfu/mL)1453425Mortalityat12weeks5.7%25.5%28.0%15QuestionsIsthereadistinctpatientpopulationwithprimarybacterialBSIthatcanbeidentifiedatthetimeofrandomizationintoaclinicaltrial?Ifyes,howshouldpatientswithbacterialBSIwhodemonstrateevidenceofmetastaticinfectionpost-randomizationbeclassifiedwithregardtoa)whethertheBSIwasprimaryorsecondaryatthetimeofrandomization;b)outcome?W