therapeu7c drug monitoring (tdm) of the beta-lactam ...hu)ner, von dach, renzoni et al. int j...

angela.hu)[email protected]

Dr.AngelaHu)nerDivisionofInfec7ousDiseasesGenevaUniversityHospitals

31May2018

Therapeu7cdrugmonitoring(TDM)ofthebeta-lactaman7bio7cs:

it’sabout7me

OR…


Dr.AngelaHu)nerDivisionofInfec7ousDiseasesGenevaUniversityHospitals

31May2018

The ofbeta-lactamtherapy

Nofinancialconflictofinterest

Possibleintellectualconflictofinterest:

Workingonbeta-lactamTDMforafewyearsnow…

Outline:beta-lactamTDM

•  WhyperformTDMofbeta-lactaman7bio7cs•  Whoshouldundergobeta-lactamTDM•  Howshouldbeta-lactamTDMbedone•  Wherebeta-lactamTDMisbeingdone•  Whataretheoutstanding/understudiedissues•  Notcovered:con7nuousversusintermi)ent

infusion

RATIONALE

TARGETPOPULATIONS

PRACTICALASPECTS

CURRENTSITUATION

CURRENTISSUES

Whyperformbeta-lactamTDM?Aclinicalcase(I)

•  32year-oldmanwithnopastmedicalhistoryadmi)edtotheintensivecareunitwithpolytraumafromamotorvehicleaccident– Mul7plesurgeries,longintuba7on

•  Day10:ven7lator-associatedpneumoniadiagnosed–  Extended-spectrumbeta-lactamase+Klebsiellapneumoniaegrowsfrombroncho-alveolarlavagecultures

–  Imipenem500mgqidbegun

RATIONALE TARGETPOPULATIONS CURRENTSITUATIONPRACTICALASPECTS CURRENTISSUES

•  Pa7entremainsfebrile,Klebsiellapersistsintrachealaspirates

•  Onday5ofimipenemtherapy,crea7nineclearanceiscalculated:305ml/min

•  Thenextmorning,bloodisdrawnforatroughlevelofimipenem:thedrugisundetectable(<0.5mg/L)…

Whyperformbeta-lactamTDM?Aclinicalcase(II)


Thepharmacokine7cindices

T>MICbeta-lactamsvancomycin

Cmax/MICaminoglycosidesfluoroquinolonesdaptomycinmetronidazole

AUC/MIClinezolid7gecycline

Tradi7onalcategoriza7on:

(It’sabout7me!)


Thepharmacokine7cindices

T>MICbeta-lactamsvancomycinAUC/MICbeta-lactamsvancomycinlinezolid7gecyclineaminoglycosidesfluoroquinolonesdaptomycinmetronidazole

Maybesomethingmorelikethis:

(LAGOM?)


Augmentedrenalclearance(oranincreasedvolumeofdistribu7on)

Augmentedrenalclearance:glomerularhyperfiltra7on,byconsensus>130ml/min


•  Weneedtodobe)erforourindividualpa7ents–  Mortalityofsepsiss7llunacceptablyhighin2018–  Popula7onsarechanging(obesity,dialysis/CRRT,immunosuppression)

•  Preservingwhatwes7llhave:asasocietyweareinafinemess

An7bacterialresistance Us! An7bio7cpipeline

Afinemess

Brun-Buissonetal,IntensCareMed2004

Ra7onalefornowmeasuringlevelsofan7bio7cswe’dusedblindlyfor20years


Ra7onaleformeasuringlevelsofan7bio7cswe’dusedblindlyfor20years

•  Thatdryan7bio7cpipeline

Newsystemican7bacterialagentsapprovedbytheUSFDAper5-yearperiod.

Boucheretal.ClinInfDis2013


Whoneedsbeta-lactamTDM?

•  Thecri7callyill– Post-trauma,post-opera7ve,burn,ECMOpa7ents– Hyperdynamicpathophysiologicstates:

•  Augmentedrenalclearanceàearlyelimina7on•  Capillaryleaksyndromeàincreased&changingvolumesofdistribu7on(Vd)

Thesepa:entslooknothinglikethephaseI,healthyvolunteerswhosebeta-lactamconcentra:onsinformapproveddosingregimens


Robertsetal.IntJAn:microbAg2010Oct;36(4):332-9

•  Pa7entremainsfebrile,Klebsiellapersistsintrachealaspirates

•  Onday5ofimipenemtherapy,crea7nineclearanceiscalculated:305ml/min

•  Thenextmorning,bloodisdrawnforatroughlevelofimipenem:thedrugisundetectable(<0.5mg/L)

•  Anintermediatelevel(t3h)is0.88mg/L…

Whoneedsbeta-lactamTDM?Aclinicalcase(III)



•  Prospec7veobserva7onalstudyof100ICUpa7ents–  aged18-60years,severeinfec7on,crea7nineclearance≥60ml/min

•  Primaryoutcome:clinicalresponseatday30–  (inrela7ontolevelsofoneof4measurablebeta-lactams)

•  Secondaryoutcomes:incidenceofARC,incidenceof“subthreshold”beta-lactamconcentra7ons

Hu)ner,vonDach,Renzonietal.IntJAn:microbAg2015;45(4):385-92


•  Meanage45years

•  Mediancrea7nineclearance144ml/min–  64%hadARCatinclusion

•  Mosthadimipenem(>piperacillin/tazobactam>meropenem>cefepime)




Oddsra7oforundetectableimipenemlevelsifaugmentedrenalclearancepresent=3.3(95%CI1.1-9.9)

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meanimipenemconcentra7ons,studypa7ents

meanreportedimipenemconcentra7ons,healthyvolunteers

OurICUpa7entsvs.healthyvolunteersmg/L




Whoelseneedsbeta-lactamTDM?

•  Pa7entsondialysisorcon7nuousrenalreplacementtherapy– TDMforbothexposure&safety

•  Obesepa7ents– Wideinter-individualvariability,increasedVd

•  Elderlypa7ents–  Impairedabsorp7on,reducedproteinbinding,wideinter-individualvariability

Hu)neretal.JAn:microbChemother2015;70(12):3178-83


Beta-lactamTDM:morecommonlytoensureexposurebutalsotoprotectagainsttoxicity

•  Beta-lactamsknownfortheirrela7velylowtoxicityEXCEPTcefepime…

Huwyleretal.ClinMicrobiolInfect2017;23:454-59


Whoelseneedsbeta-lactamTDM?

Huwyleretal.ClinMicrobiolInfect2017;23:454-59

•  Pa7entsoncefepimeformorethanafewdays•  Pa7entswithrenalinsufficiencyoncefepimeforanyperiodof7me

•  Troughlevelsshouldprobablybe≤20mg/L


Howshouldbeta-lactamTDMbedone?

Logis7cs•  Quickly–  (Almostnever)

•  Inastandardized/validatedfashion–  (Currentlyallin-house)

•  Cheaply–  (Depends)

•  Thoroughlyàintandemwithtargetorganism’sMIC!–  (Rarely)

Wongetal.JAn:microbChemother2014;69(5):1416-23


Howisbeta-lactamTDMcurrentlydone?

Assays•  Eitherhigh-performanceliquidchromatographywithultravioletdetec7on(HPLC/UV)or

•  Liquidchromatography–tandemmassspectrometry(LC–MS/MS)

•  Rarely,microbiologicassay•  Mostcentersmeasuretotal(free+protein-bound)levels,thoughweshouldbegoingforfreelevels–  Especiallyforhighlyprotein-bounddrugslikeflucloxacillin(95%)andceyriaxone(60%)!

Wongetal.JAn:microbChemother2014;69(5):1416-23Wongetal.An:microbAgChemother2013;57(12):6165-70


WhatshouldbethePKtargets?

Wongetal.JAn:microbChemother2014;69(5):1416-23Mulleretal.Drugs2018;78(4):439-451

Efficacy/exposuretargets•  Mostcommontargetis100%fT>MIC–  Pragma7sm/feasibilityversusPKinforma7ongathering

•  YoumaynothavetheMIC–  ConsiderEUCASTbreakpoints

•  Mayneedtoadjustdependingonsiteofinfec7on,drug’sproper7es



Hu)ner,vonDach,Renzonietal.IntJAn:microbAg2015;45(4):385-92Mulleretal.Drugs2018;78(4):439-451

Toxicitythresholds•  “Workisongoing.”(=Wedon’treallyknow.)–  Evenforcefepime(thatwasjustonesmallretrospec7vestudy!)

•  Weknowthereisalotofvariabilityforsomean7bio7cs–  piperacillin,amoxicillin,flucloxacillin

•  Somean7bio7csdon’tseemtohave(discernibly)concentra7on-dependenttoxicity–  Theexampleofimipenem…



Bricheuxetal.UnderreviewatClinMicrobiolInfect

Toxicitythresholds•  Of300pa7entsinGenevaundergoingimipenemTDM,8(3%)hadtoxicityconsideredlikelyrelated–  Norealdifferencesinimipenemlevels(median5.2mg/lversus4.8mg/l,p=0.78)ordura7onoftherapy(9vs10days)

–  Everyonehadlowlevels!

Beta-lactamTDM:currentstatus


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Probablyabout40centersdoingbeta-lactamTDM

OngoingPlanned

Onlyaroughes7mate



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Intensivists Intensivists+infec7ousdiseasesspecialists

à

Outstandingissue#1:Doesbeta-lactamTDMimproveclinicaloutcomes?

•  Weknowitimprovespharmacologicoutcomes–  Simeetal.Cantherapeu7cdrugmonitoringop7mizeexposuretopiperacillininfebrileneutropenicpa7entswithhaematologicalmalignancies?Arandomizedcontrolledtrial.JAn:microbChemother2015;70(8):2369-75

–  Pateletal.Therapeu7cdrugmonitoringofbeta-lactaman7bio7csinburnspa7ents--aone-yearprospec7vestudy.TherDrugMonit2012;34(2):160-4

•  Butwecan’teasilyshowdifferencesinclinicaloutcomes

–  Norandomizedtrialhasyetshownsuperioroutcomes•  Ge~nghardertodo(localculturechanges,clinicalequipoiselost)

–  Thatpa7entwithKlebsiellapneumonia…


Clinicalcase:ouryoungman(IV)

•  Day6ofimipenemtherapy:spontaneousimprovementbeforeanydosechange– Defervescence,weaningfromven7lator

•  Day10:infec7onfullyresolved,imipenem500mgqiddiscon7nued

•  Day12:transferredtothefloor




•  Primaryoutcome:clinicalresponse– Pa7entswithlowimipenemlevelsdidnothavemorefailure!•  Failurein18/98(18%),nodifferenceinimipenemlevels•  Augmentedrenalclearancewasactuallyprotec7ve—oramarkerofsomethingprotec7ve

•  Thereareotherstudieslikethis…– Difficultpopula7ontostudy(polypharmacy,differingcomorbidi7es&severi7es,diagnosesunclear,etc.)

•  Point-prevalencestudyofintermediate(50%fT>MIC)&trough(100%fT>MIC)beta-lactamserumconcentra7ons

•  384pa7entsacross68ICUs–  Of248pa7entstreatedforinfec7on,16%didnotachieve50%fT>MIC&were32%lesslikelytohaveposi7veclinicaloutcome(OR0.68,95%CI0.52-0.91,P=.009)

•  +Associa7onbetweenposi7veclinicaloutcomeandanincreasing100%fT>MICra7o(OR1.56,95%CI1.15-2.13,P=0.03)


RobertsJAetal.ClinInfectDis2014;58:1072–83

(Bestevidence–buts7llnotenough)

Outstandingissues:Doesbeta-lactamTDMimproveotheroutcomes?

Whataboutecologicoutcomes?



7681907676

2016:

EmergenceofPseudomonasaeruginosaresistanceinpa:entswithimipenemtherapeu:cdrugmonitoring

LaurianeLenggenhager,MohamedAbbas,CarolinaFankhauser,BenediktHu)ner,StephanHarbarth,AngelaHu)ner

Background:An7bio7coverusedrivesan7bio7cresistance.Resistancetocarbapeneman7bio7csamongPseudomonasaeruginosastrainsappearstoberisinginstepwiththeirincreaseduse.Weexaminedthetransi7onfromimipenemsuscep7bilitytoresistanceamongP.aeruginosastrainsdetectedinhospitalisedpa7ents,exploringimipenemdura7onandplasmaconcentra7onsdeterminedbytherapeu7cdrugmonitoring(TDM)asriskfactors.Material/methods:Inthissingle-centreretrospec7vecohortstudy,weincludedalladultpa7entswhowerehospitalizedbetweenJanuary2013andJuly2016,underwentanyimipenemTDM,andhadatleastoneP.aeruginosa-posi7veclinicalculture.Theprimaryoutcomewasemergenceofanimipenem-resistantP.aeruginosa(IRP)strain.Totalimipenemplasmaconcentra7onsweremeasuredbyhigh-performanceliquidchromatographywithultravioletdetec7on.ComparisonsbetweengroupsusedtheChi2orFisherexacttestforcategoricaldataandanindependentStudent'st-testforcon7nuousdata;medianswerecomparedusingtheMann-Whitneytest.Associa7onwithP-values≤0.05wereconsideredsta7s7callysignificant.Results:Weiden7fied67adultpa7entswithimipenemTDM(mediannumberofmeasurements1,range1-6)andatleastonespecimenyieldingP.aeruginosa(median2,IQR1-4).Most(49/67,73%)weremale;meanagewas63years(SD±16).Aslightmajority(34/67,51%)weresurgicalpa7entsandnearlyhalf(32/67,48%)werehospitalizedintheintensivecareunit….

Pa7entsinwhomIRPemergedhadsignificantlymoredaysofimipenemtherapythanthosewhosestrainsremainedsensi7ve(median11days[IQR5-10]vs.5[IQR3-7],P=.044).Theytrendedtowardlowerimipenemlevels(meanminimumconcentra:on3.97mg/l[SD±3.85]vs.5.31mg/l[SD±5.36])…

Lenggenhageretal.ECCMID2017



Otheroutstandingissues

•  Nocommercialbeta-lactamassay

•  MICsaredifficulttoperform

•  Therapeu7crangeshavenotbeendefined

•  Technicalissues– stability

Wheremoreworkisneeded

•  TDMisn’ttheinterven7on;it’stheguide

•  Moreneedstobedoneforthegroup–  Effectsofop7mizeddosing±shorterdura7onsonresistancedevelopment

•  Moreneedstobedonefortheindividual–  Theapproachof“Gohardandgohome”/“Hithardandhitfast”hasnotbeenstudiedinarandomizedtrial…


Afinalcase

•  55year-oldmanwithcoarcta7onoftheaorta– S.sanguinisendocardi7sin2007•  Mechanicalvalvereplacement

•  Admi)edinAprilwithfeverandchills– S.aureusendocardi7s– Treatedwithflucloxacillin2gq4h(12g/day)•  Nolevelsdrawn•  Crea7nineclearance160ml/min

– Febrile&bacteremicfor48hours– Endofday2:changeinmentalstatus


Afinalcase(II)

•  55year-oldmanwithcoarcta7onoftheaorta– Day3:lumbarpuncture•  30WBC(87%neutrophils),4RBCs•  Glucose2mmol/l,protein0.45g/l•  PCR+forMSSA•  Culturelaterposi7veforMSSA


Isflucloxacillinapprovedformeningi7stherapy?

www.compendium.ch


DoesflucloxacillinpenetratetheCSFornot?


Thepa7ent’sfreeflucloxacillinconcentra7onsinplasmaandCSFwere7.5mg/Land0.3mg/L,respec7vely.

Chewetal.IntJAn:microbAg2016;29:229-31


“Nonetheless,astudyperformedinNewZealanddemonstratedcurein24of30casesofMSSAmeningi:susingi.v.flucloxacillinatdosesrangingbetween8gand12gq24h….However,one-thirdofthesubjectswerechildrenbelow15yearsofage.ThemajorityhadMSSAmeningi:srelatedtoneurosurgery,whichoXenoccurswithoutsignificantmeningealinflamma:onandwhichwouldbeexpectedtoreduceCSFpenetra:onofflucloxacillin.Thisstudy,however,wasasingle-centreretrospec:vecohortstudyinwhichmeasurementofdruglevelswasnotundertakenandtheresultsshouldbeviewedcau:ously…”

Chewetal.IntJAn:microbAg2016;29:229-31

Sca)eredepidemiologicevidencethatitworks,maybe80%ofthe7me(?)

“Requiresfurtherstudy”

•  Couldwedobe)er?

•  Arewefailingpa7entsinthecri7calearlydaysofinfec7on?

– TDMoftheseoldan7bio7csshouldguidetheirop7mizeduse


Conclusions•  Pharmacokine7cdatafromhealthyvolunteersarenotrepresenta7veofcri7callyill&otherpopula7ons

•  Beta-lactamTDMisatoolthat,intheindividualpa7ent,canhelpensureadequatean7bio7cexposureandprotectagainsttoxicity(e.g.,cefepime)–  Butlogis7c&technicalissuesneedaddressing

•  TDMistheguideandshouldbeusedtorevisitouroldassump7onsaboutdosingandpharmacokine7cs

•  Theremaybearoleforimprovingecologicoutcomesforthegroup–  Butmoredataareneeded


Thankyou!


AliceBricheux ElodievonDachLaurianeLenggenhager

DavidTonoli AbderrahimKarmime PierreLescuyer

therapeu7c drug monitoring (tdm) of the beta-lactam ...hu)ner, von dach, renzoni et al. int j...

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