1
ConsiderationsforEffectSitePharmacokineticstoEstimateDrugExposure:
ConcentrationsofAntibioticsintheLung
KeithA.Rodvold1,WilliamW.Hope2SaraE.Boyd2,3
1CollegesofPharmacyandMedicine,UniversityofIllinoisatChicago,Chicago,Illinois,USAand
2AntimicrobialPharmacodynamicsandTherapeutics,DepartmentofMolecularandClinical
Pharmacology,UniversityofLiverpool,Liverpool,UnitedKingdom
3DivisionofInfectiousDiseases&Immunity,ImperialCollegeLondon,London,UnitedKingdom
JournalSubmission:CurrentOpinioninPharmacology
Runningtitle:Intrapulmonaryconcentrationsofantibiotics
Keywords:Antibiotics,epithelialliningfluid,bronchoalveolarlavage,microdialysis
Addresscorrespondenceto:
KeithA.Rodvold,Pharm.D.FCCP,FIDSA
UniversityofIllinoisatChicago,CollegeofPharmacy
833SouthWoodStreet,Room164,m/c886
Chicago,Illinois60612USA
Phone: 312-996-3341
Fax: 312-413-1797
Email: [email protected]
2
ABSTRACT
Bronchoalveolarlavage(BAL)andmicrodialysishavebecomethemostreliableandrelevant
methodsformeasuringlungconcentrationsofantibiotics,withthemajorityofBALstudiesinvolving
eitherhealthyadultsubjectsorpatientsundergoingdiagnosticbronchoscopy.Emphasisontheamount
ofdrugthatreachesthesiteofinfectionisincreasinglyrecognizedasnecessarytodeterminewhethera
doseselectionwilltranslatetogoodclinicaloutcomesinthetreatmentofpatientswithpneumonia.
Observedconcentrationsand/orparametersofexposure(e.g.,area-under-the-curve)needtobe
incorporatedwithpharmacokinetic-pharmacodynamicindicessothatrationaldoseselectioncanbe
identifiedforspecificpathogensandtypesofpneumonicinfection(community-acquiredversushospital-
acquiredbacterialpneumonia,includingventilator-associatedbacterialpneumonia).Whilehaving
measuredplasmaorlungconcentration-timedatafromcriticallyillpatientstoincorporateinto
pharmacokinetic-pharmacodynamicmodelsisveryunlikelyduringdrugdevelopment,itisessentialthat
altereddistribution,augmentedrenalclearance,andrenalorhepaticdysfunctionshouldbeconsidered.
Notably,thenumberofpublishedstudiesinvolvingmicrodialysisandintrapulmonarypenetrationof
antibioticshasbeenlimitedandmainlyinvolvebeta-lactamagents,levofloxacin,andfosfomycin.
Opportunitiestomeasureinhigh-resolutioneffectsitespatialpharmacokinetics(e.g.withMALDI-MSIor
PETimaging)andinvivocontinuousdrugconcentrations(e.g.withaptamer-basedprobes)nowexist.
Goingforwardthesestudiescouldbeincorporatedintoantibioticdevelopmentprogramsfor
pneumoniainordertofurtherincreasetheprobabilityofcandidatesuccess.
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INTRODUCTION
Anadequatedrugconcentrationatthesiteofaninfectioncontinuestohaveanimportantrolein
ourabilitytounderstandthepharmacokinetic-pharmacodynamic(PK-PD)relationshipsofantibiotics[1].
Duringthepast50years,numerousstudieshavebeenconductedtomeasuretissue,cellorfluid
concentrationsofantibioticsinthelung[2,3,4••,5,6••,7•,8••].Variousmethodsandsamplingsites
havebeenused.Nevertheless,noclearconsensusexistsontheoptimalapproachformeasuringthe
concentrationsofantibioticsinthelung[3,4••,5,6••,7•,9].Methodsthatinvolvemeasuringthe
concentrationsofantibioticswithinspecificsubcompartmentsofthelungprovideimportantinsights
intoantimicrobialefficacy.Bronchoalveolarlavage(BAL)andmicrodialysisarecurrentlythemost
reliableandrelevantmethodsformeasuringlungconcentrationsofantibiotics[4••,5,7•,8••].This
reviewwillfocusonhumanstudiesthathaveusedthesetwotechniquestomeasureintrapulmonary
concentrationsofantibiotics.
INTRAPULMONARYPENETRATION
Avarietyofmethodologieshavebeenusedformeasuringconcentrationsofantibioticsand
determiningtheirdistributionpatternsinthelungs[6••,8••].Eachhasitsadvantages,potential
limitations,andmethodologicalissues.Historically,anti-infectivedrugconcentrationsweremeasuredby
obtaininglungtissueduringasurgicalprocedure.Althoughthisisoneoftheoldestmethodsfor
measuringdrugconcentrationsinthelung,whole-tissueconcentrationsmaybedifficulttointerpret[9].
Themajordrawbackofdrugconcentrationsreportedfromwholelungtissue,bronchialtissuesand/or
secretionsistheassumptionthatantibioticsareuniformlydistributedwithinalllungcompartments(e.g.
extracellular,intracellular,interstitium).Themeasureddrugconcentrationwillthereforerepresenta
mixturefromallcompartmentsinsteadofthedrugconcentrationattheclinicallyrelevantsiteof
infection.Currently,thetwopreferredmethodsformeasuringantibioticconcentrationsinthelungare
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BALandmicrodialysis.BronchoscopywithBALcandetermineconcentrationsinboththeepithelial
liningfluid(ELF)andalveolarmacrophages(AM),whereasmicrodialysismeasuresconcentrationsinthe
interstitialfluidofthelung[4••,8••].TheELFistherelevantsitefortheextracellularrespiratory
pathogensthatarecausativeinacutebacterialpneumoniaandinfectiveexacerbationofchronic
bronchitis.Theselowerrespiratorytractinfectionsmayprogresstoinvolvetheinterstitialfluidofthe
lung.Incontrast,infectionscausedbyintracellularpathogenssuchLegionellapneumophilaand
ChlamydophilapneumoniaeexistwithinAM.
AssessmentofAntimicrobialDrugConcentrationsinLungs
Moststudiesthatmeasuredrugconcentrationsataninfectionsiteoftenplacetoomuchemphasis
onthevalueofthepenetrationratio.Unfortunately,ratiosareusedtoclaimthatspecificantibiotics
maybebetterfortreatingpneumonia.Theratioofsite-to-plasmaconcentrationsprovidesanimportant
pharmacologicalcharacteristic.However,inisolationitisnotadequatetodeterminewhetheranagent
willbeeffectiveattreatingpulmonaryinfectionandalsodoesnotidentifyhowmuchdrugneedstobe
administered.
Penetrationratioschangeasafunctionoftimebecauseconcentrationsinplasmaandatthesiteof
infectiondemonstratesystemhysteresis(e.g.,increasesanddecreasesatdifferentratesfromeach
other).Suchtime-dependencylimitstheinterpretabilityofmeasuresfromasinglesamplingtimeand
thetruepenetrationofadrugintothelung.Toovercomethislimitation,samplesshouldbecollected
fromapopulationofpatientsthroughoutthedosinginterval(eventhoughanindividualpatientonly
contributesasinglelungconcentration).Inaddition,anoverallmeasureofdrugexposure(i.e.thearea-
under-the-curve[AUC])ineachcompartmentshouldbecalculatedandusedtodeterminethe
penetrationratio.
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Theamountofdrugthatreachesthesiteofinfectionisanimportantdeterminantofdoseselection.
Observedconcentrationsand/ormeasuresofdrugexposure(e.g.,area-under-the-curve,AUC)are
fundamentaltorationaldoseselectionforspecificpathogensandpneumonicdiseases(e.g.community-
acquired[CABP]versushospital-acquired[HABP]bacterialpneumonia,includingventilator-associated
bacterialpneumonia[VABP]).
Thefollowingaspectsinstudydesignarecriticalforapreciseestimateofdrugexposureandto
supportclinicaldoseandcandidateregimenselectionfornewagents:(i)investigatingregimensthatare
mostlikelytobeprogressedtosubsequentclinicaltrials;(ii)ensuringserialsamplingfromplasma
throughoutthedosingintervalinindividualpatients;(iii)samplingfromthelungthatcoversthedosing
intervalatapopulationlevel(becauseeachpatientcanonlycontributeasinglelungconcentration);(iv)
determiningconcentrationratiosfromrobustestimatesofAUCinplasmaandtherelevantpulmonary
subcompartment;(v)consideringplasmaproteinbindingwithbothunboundandtotaldrug
concentrationsinplasmaandusingthesedatatobetterunderstandpenetrationcharacteristics;(vi)
usinganalyticalproceduresthatarebothsensitiveandspecificforplasmaandeffectsite
concentrations;(vii)correctingfordilutionfromsampling(i.e.BAL)withureaestimationbeingthemost
commonlyusedprocedure;(viii)translatingeffectsiteexposuresusingnon-clinicalPK-PDtargets,for
examplerelatinghumanELFexposuretoELFPK-PDtargetsfromhighlypredictivemurinemodelsof
pneumonia;and(ix)performingPK-PDmodellingandsimulationtoassessandpredicttheperformance
ofvariouscandidateregimens.
BronchoalveolarLavage(BAL)Studies
BronchoscopywithBALhasbecomeareliabletechniqueformeasuringconcentrationsofantibiotics
inELF.Duringthepasttwodecades,severalgroupsofinvestigatorshaveusedthismethodtodetermine
drugpenetrationintoELFandtocompareplasmaandELFconcentrationsofantibiotics[4••,10].Using
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BALstudiestoassessELFconcentrationshasbecomeanimportantcomponentofantibacterialdrug
developmentprogramssincethemajorityofpneumonicinfectionsarecausedbyextracellular
pathogens[11••,12].Table1providesanupdateonpublishedstudiesevaluatingplasmaandELF
exposuresofantibioticsthathaverecentlybeenapprovedorarecurrentlyindevelopment[13-25].We
directthereadertoourpreviousreviewpublicationsregardingdataforotheranti-infectiveagentsas
wellasadetaileddescriptionofusingbronchoscopyandBALformeasuringELFdrugconcentrationsand
determiningintrapulmonarypenetration[4••,5].
HealthySubjects.ThemajorityofBALstudieshaveinvolvedeitherhealthyadultsubjectsor
patientsundergoingdiagnosticbronchoscopy(Table1)[4••,13-25].Afewstudieshavetargetedolder
outpatientsorpatientswithaclinicaldiagnosisofmildtomoderatechronicbronchitis,chronic
obstructivepulmonarydisease,orcommunity-acquiredbacterialpneumonia[4••].Acomparisonof
thesepatientswithmildtomoderaterespiratorytractinfectionsand/orinflammatoryprocesseshas
suggestedthatELFconcentrationsweresimilarinmagnitudeandtimecoursetothoseobservedin
healthysubjects.Thus,antibacterialconcentrationsinELFfromhealthysubjectstendtoserveasan
estimateoftheaveragedrugexposureatextracellularsitesoflunginfection.
Pharmacokineticsandpharmacodynamicsareincreasinglyrecognizedtobeessentialtoolsinthe
developmentofnewantibioticsinordertomaximizetheprobabilitythattherightdoseforinfected
patientswillbestudiedfirsttime[1,11••].Anintrapulmonarypenetrationstudyinhealthysubjectscan
assistadrugdevelopmentprogrambydeterminingwhetherornotanantibioticpenetratesintolung,
andifitdoes,whetherconcentrationsoftheantibioticcanbeadequatelyachievedtotreatthetarget
pathogens.Thesetwoassessmentsareextremelyvaluableformakingearlierandbetter“go/nogo”
decisions,andtoestablishwhetheracandidateregimenissuitableforfurtherclinicalstudyorrequires
adaptationpriortoprogression.
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DesigninganappropriatedosageregimentotreatpatientswithCABPorHABPhasincreasingly
involvedtheincorporationofpreclinicalexposure-responserelationships,phase1clinicalpharmacology
doserangingstudies,andELFconcentration-timedatafromhealthysubjects[12].Computersimulations
usingpopulationPKmodelingcanbeperformedtoestimatetheproportionofpatientslikelytoreach
theprobabilityoftargetattainmentforthePK-PDindicesestablishedfromdynamicinvitro(e.g.,hollow
fibermodel)and/orinvivoanimalmodel(s).Thissupportsoptimaldoseselectionbytranslatingrelevant
non-clinicaleffectsiteexposuresthatareassociatedwithefficacytoclinicaldata.Forexample,ELFPK-
PDtargetsfrommurinelunginfectionmodelscanbeassessedtodetermineifthesetargetscan
consistentlybeachievedgivenhumanELFexposuresforaparticularagent.Variousdifferentdosing
regimensforthatagentcanbegeneratedandcomparedinordertomakeafinaldoseselectionbased
ontheprobabilitythatthemajorityofpatients(e.g.,≥90%)achievethedesiredPK-PDtarget
attainment.Conductinganintrapulmonarypenetrationstudyinhealthysubjectsduringaphase1
programcanacceleratedrugdevelopmentandminimizetheriskassociatedwithdoseselectionfor
clinicaltrialsofantibioticsforpneumonia.Delayinganintrapulmonarypharmacologystudyuntillate
phase2orduringphase3pivotalpneumoniastudiesisnowstronglydiscouragedtopreventinadequate
doseselectionforrespiratorytractinfections[12].
Ambroseandcolleagueshaveelegantlyreviewedthepharmacokinetic-pharmacodynamic
considerationsforHABPandVABPstudies[11••].Atleasttwopublishedstudieshaveillustratedthe
difficultiesinachievingdrugexposuresandtargetattainmentinVABPpatientsrelativetoHABPpatients
duringdrugdevelopmentprograms[11••,12,26,27].Toovercometheseissuesduringdrug
development,doseanddosingregimensshouldbeestablishedwithMonteCarlosimulationsandtarget
attainmentstudiesthatincorporateasmuchspecificinformationaspossibleforcriticallyillpatients
withHABPandVABP.Ideally,thisinformationwouldincludeawiderangeofdemographic
characteristicsandlaboratorydatathatreflectsthetargetpopulationofpatientswithpneumonia,lung
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penetrationandpharmacodynamicsattheinfectedsite,andMICdistributiondataofrecentbacterial
isolatesobtainedfromhospitalizedpatientswithpneumonia.MICdistributionsforEnterobacteriaceae
commonlyimplicatedinHABPandVABPcandiffersignificantly[11••].Therefore,abroadrangeof
microbiologicaldataencompassingbothclinicalentitiesshouldbeconsideredwhenassessingeffectsite
exposuresthatareimportantfornosocomialpneumonia.Whilehavingmeasuredplasmaorlung
concentration-timedatafromcriticallyillpatientstoincorporateintopharmacokinetic-
pharmacodynamicmodelsisveryunlikely,considerationsofaltereddistribution,augmentedrenal
clearance,andrenalorhepaticdysfunctionshouldbeconsidered[28,29].Differingvaluesofmeanor
medianpopulationpharmacokineticparametersaswellasthehighvariabilityassociatedwitheach
parametershouldalsobeconsideredforsubgroupsofpatientswithHABPandVABP.Thisapproachto
dosagedesignshouldlowertheriskoftreatmentfailuresduringaclinicaltrialprogramofseriouslyill
patientstreatedforVABPand/orHABP.Prospectivelycollectedpharmacokinetic-pharmacodynamic
dataduringpivotalclinicaltrialscanconfirmandre-evaluatetheadequacyoftheselecteddosing
regimentoachievedesiredefficacyandsafetymargins.
CriticallyIllPatients.ThereareonlyalimitednumberofBALstudiesinpatientswhowereinan
intensivecareunit,receivingmechanicalventilation,and/orbeingtreatedforseverepneumonia(Table
2)[30-48].Allofthestudiespublishedtodatewereconductedwithantibioticsthathadalreadyreceived
regulatoryapprovalandhadbeenusedinclinicalpracticeforseveralyears.Jamalandcolleagueshave
usedthesedatatoprovideclinicaldosingstrategiesforvariousantibioticdrugclassesbased
physiochemicalcharacteristics,pharmacodynamicsproperties,andrelativedegreeofELFpenetration
(Figure1)[10].
Oneofthemostrecentconcernsindrugdevelopmentprogramshasbeenwhetherhealthysubjects
adequatelyreflecttheintrapulmonaryconcentrationsobservedincriticallyillpatients.Itiswellknown
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thatawiderangeofinter-andintra-patientvariabilityisobservedinplasmadrugconcentrationsand
pharmacokineticparametersofcriticallyillpatients[49,50,51].Manyofthesepatientshaveadditional
variables(e.g.,augmentedrenalfunction,obesity,andhepaticorrenaldysfunction)alongwiththeir
potentiallylife-threateningpneumonicinfectionthatmaysubstantiallyaffectthedispositionof
antibiotics.Furthermore,criticallyillpatientsoftenreceivevarioustreatments(e.g.,intravenousfluid
resuscitation,drugtherapy,andcontinuousrenalreplacementtherapy)thatcanalterapparentvolume
ofdistributionand/orclearanceofantibiotics.Alterationsinpulmonarypermeability,dilutionof
intrapulmonaryconcentrationsduetoanincreasedvolume,and/ordisruptionintransportsystemsin
thelungsbecauseofinjuryorinfectionhavebeensuggestedasphysiologicalexplanationsforlower
intrapulmonaryconcentrationsinthecriticallyillpatient[37••].Regimensbasedonstudiesfrom
healthysubjectsornon-criticallyillpatientsmayleadtosuboptimalantibioticexposureinplasma
and/orlung.
Methodologicalissuesdifferbetweenstudiesconductedincriticallyillpatientsandhealthysubjects.
Incriticallyillpatients,theBALprocedureofteninvolvesmicrolavageorminilavage(e.g.20mLof0.9%
normalsalinesolutioninstilledasoneortwoaliquotspersamplingtime)[52].Thenumberofpatients
studied(n=8to12patients)isaboutone-thirdofthetypicalnumberstudiedinhealthyhuman
subjects.Samplingschemesareusuallylimitedtoeitherasetofpeakandtroughconcentrationsduring
anintermittentdosinginterval,orasinglesamplingtimeduringintermittentorcontinuousinfusion.
Rarelyaresamplescollectedoveranentiredosingintervalbecausestudiesoccurinanuncontrolled
environment.Despitedifferencesinstudyproceduresforcriticallyillpatients,thereportedmeanor
medianpenetrationratiosofELF-to-plasmaformostantibioticstendtobesimilar(e.g.,
aminoglycosides,linezolid)orhigher(e.g.,beta-lactams)thanthoseobservedinhealthysubjectsand
outpatients.However,antibioticconcentrationsdemonstrateasubstantialamountofvariabilityin
criticalillness,whichcanresultinalowerdrugexposureinplasmaandsubsequentlyatthesiteof
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infection(e.g.,lung).Forexample,theaverageratioofELF-to-unboundplasmaconcentrationsfor
piperacillinandtazobactaminhealthysubjectshasbeenreportedas38%and77%,respectively(Table
1)[17].Inseventeencriticallyillpatients,therespectivemedianratiosforthesetwodrugswere
reportedas49%(range:2%to516%)and121%(11%to381%)duringintermittentdosingand63%(29%
to117%)and138%(57%to326%)forcontinuousinfusion,respectively(Table2)[36,37••].Thewide
rangesaroundthesemedianvaluesillustratesmarkedpharmacokineticvariability,whichiscommonly
observedincriticallyillpatients.
Anintrapulmonarypharmacokineticstudyconductedincriticallyillpatientsduringthedevelopment
programforanewantibioticishighlydesirable.However,itisbothpracticallyandethicallychallenging
becauseoftheneedtoobtaininformedconsentfromindividualpatients.Apragmaticapproachcould
includeanoptionalBALcollectiondesignedaspartoftheresearchprotocolforpatientsenrolledinto
thesesafetyandefficacyclinicaltrials.However,datafromphase1ELFstudiescarriedoutinhealthy
volunteerswillallowfordoseandregimenselectiontobecompletedasoptimallyaspossiblepriorto
thesephase3studies.Appropriatetimingofdoseadministrationandsamplecollection(e.g.,both
plasmaandBALfluid)byexperiencedinvestigatorsisstillrequiredtoproviderobustandreliable
pharmacokineticdata.Additionalstudieswithconsiderationoftheseissuesaredesperatelywarranted
todeterminewhichunderlyingphysiologicalandpathologicalprocessesinpatientswithHABPandVABP
havethegreatestimpactonplasmaandlungconcentrations.Inaddition,definingrelationships
betweenpharmacokinetic-pharmacodynamicparameters,clinicalormicrobiologicaloutcomes,and
resistancesuppressionarelikelytobeassociatedwithahigherprobabilityoffavorabletherapeutic
responseintheseseriouslyillpatients.
Microdialysis
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Microdialysisisanadditionaltechniqueforestimatingintrapulmonarydrugconcentrations[7•,
8••].Thistechniqueallowsdirectmeasurementofunbounddrugconcentrationsintheinterstitialfluid
compartmentofthelung.Inadditiontomeasuringunbound,pharmacologicallyactivedrug
concentrationsintheinterstitium,microdialysisallowsforcontinuoussamplingofdrugconcentrations
inboththelungandplasmaofthesamepatients.However,theplacementofmicrodialysiscatheters
intothelunghaspracticaldifficultiesandthishaslimiteditsusetopatientsundergoingelectivethoracic
surgery.
Thenumberofpublishedstudiesinvolvingmicrodialysisandintrapulmonarypenetrationof
antibioticshasbeenlimitedandincludesbeta-lactamagents,levofloxacin,andfosfomycin(Table3)[53-
60].Antibioticpenetrationintointerstitialfluidtendstobelowerinpatientswithinfectionascompared
tohealthysubjects.Thesedifferencesmayberelatedtotheclinicalconditionandtreatmentof
intensivecarepatientswithsepticshock.Similartobronchoalveolarlavagestudiesincriticallyill
patients,microdialysisstudieshavebeenlimitedtoantibioticscurrentlyapprovedforclinicaluseand
notaspartofanantibacterialdrugdevelopmentprogram.
Futuretechnologiesforassessinglungpenetration
Opportunitiestomeasureinhigh-resolutioneffectsitespatialpharmacokinetics(e.g.withMALDI-MSIor
PETimaging)nowexist[61-63].Thesetoolsmaybeexploredtofurtherunderstandantibioticexposure-
responserelationshipswithinthelungsofhighlypredictiveanimalmodelsofpneumonia.Data
generatedmaythenbeusefullyappliedtohelppredictcandidatesuccessandfacilitatemore-informed
“go/no-go”decisionswhendecidingwhethertoprogressanewdrugfromthepreclinicaltotheclinical
arena.Furthermore,toolshavebeendevelopedtomeasurecontinuousinvivodrugconcentrationswith
aptamer-basedprobes,allowingforreal-timemeasurementofsmallmoleculesinanimalandhuman
studies[64-65].Thesetoolsholdthepotentialtoallowforbettertranslationfromanimaltohuman
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studiesandtofacilitatedetailedanalysesofpatientspecificpharmacokineticvariationinclinical
settings.Goingforwardthesenewtechnologiescouldalsobeincorporatedintoantibioticdevelopment
programsforpneumoniatofurtherincreasetheprobabilityofcandidatesuccess.
SUMMARY
Rationaldoseselectionofantibioticsforthetreatmentofbacterialpneumoniacontinuestobea
challenge.MeasurementofantibioticconcentrationsbytechniquessuchasBALandmicrodialysishave
becomereliableandconsistentindescribingtheamountofdrugexposureatsitesoflunginfection.
Effectsiteexposureremainsessentialtoincorporateintotheevaluationofspecificdosingregimens
designedtobeefficaciousagainstpotentialbacterialpathogensinpneumonia.Furtherstudiesare
warrantedincriticallyillpatientswithpulmonaryinfectionstoexploreimportantdifferencesinthe
pattern,timecourseandmagnitudeofintrapulmonaryconcentrationscomparedtohealthysubjects.In
addition,potentiallinksbetweenpharmacokinetic-pharmacodynamicindicesbasedonplasma
exposuresandclinicalorbacterialoutcomesinpneumoniawouldbevaluable.Thesedatacouldbeused
tooptimizeregimensfornewantibioticsinclinicaltrialsforefficacy,orfortheclinicalcareofseriouslyill
patientswithdrugsthatarecurrentlyavailable.
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18
19FIGURE1Strategiesfordefiningdosingofantibioticsforinfectionsinthelung[10]
20Table1Publishedstudiesonepithelialliningfluidconcentrationsofselectedantibioticsinhealthyadultsubjects
Antibiotic Dose PenetrationRatio(ELF-to-TotalPlasma)
PenetrationRatio(ELF-to-UnboundPlasma)
AUCELF(µg�h/mL)
AUCtotal-plasma(µg�h/mL)
Ceftaroline[13] 600mgq12h600mgq8h
18.0%17.7%
22.5%23.6%
8.099.36
45.0±7.3253.0±7.16
Imipenem[14] 250-500mgq6h 44% 55% N.R. N.R.
Meropenem-Vaborbactam[15]
2.0gq8h2.0gq8h
63%53%
65%79%
111.7105.1
186±33.6204±34.6
Ceftazidime-Avibactam[16]
2.0gq8h0.5gq8h3.0gq8h1.0gq8h
31.3%34.9%32.4%32.0%
N.R.N.R.N.R.N.R.
92.313.714724.8
29539.245477.6
Ceftolozane-Tazobactam[17]
1.0gq8h0.5gq8h
48%44%
59%N.R.
75.18.5
158.5±24.119.3.±2.9
Piperacillin-Tazobactam[17]
4.0gq6h0.5gq6h
26%54%
38%N.R.
94.524.7
357.3±65.946.1±8.7
Eravacycline[18] 1mg/kgq12h 132% 644% 4.93 4.56±0.94
Omadacycline[19] 100mgq12hx3,then100mgq24h 147% 184% 17.23 12.14±3.22
Tigecycline[19] 100mgx1,then50mgq12h 171% 659% 3.16 2.20±0.42
Tedizolid[20] 200mgQ24h 433% 4120% 109.3 25.13±5.78
Nafithromycin[21] 800mgq24h 1380% N.R. 224.1 16.2
Solithromycin[22] 400mgq24h 1030% N.R. 80.3 7.92±4.39
Lafamulin[23] 150mgx1 75% 570% 3871 4985
GSK1322322[24] 1.5g12h 120% 350% 78.9 66.7
GSK2251052[25] 1.5g12h 53.4% 59.3% 29.4 55.1
Datapresentedasmeanormean±SD;N.R.,notreportedPenetrationratiowasdeterminedinallstudiesbytheratioofAUCELF/AUCplasma
21Table2Reportedpenetrationofselectedantibioticsintoepithelialliningfluidofcriticallyillpatients
AntibioticClass Antibiotic Dosing MeanPenetrationRatio Interpretation,CommentsAminoglycoside
Tobramycin[30]Tobramycin[31]Tobramycin[32]Gentamicin[33]Netilmicin[34]
7-10mg/kgIVoncedailyConcentration-adjusteddosing150mgIMsingledose300mgIMoncedailyx4days240mgIVoncedaily450mgIVsingledose
~12%(range:0.8%-12.8%)0.5-hour:30±3%2.0-hour:42±16%4.0-hour:64±37%8.0-hour:153±76%140±80%160±60%1.0-hour:30±5%2.0-hour:85±10%4.0-hour:114±26%6.0-hour:74±18%1.0-hour:35%2.0-hour:78%3.0-hour:177%4.0-hour:145%
Singlesamplingtimeat30minutesafterendof30-minuteinfusionSinglesamplingtimeat6hoursafterendof30-minuteinfusionPenetrationratiosbasedonreportedmeanconcentrationsinplasmaandliningfluidinoriginalreport
Beta-lactambeta-lactamaseinhibitorcombinationproduct
Piperacillin-tazobactam[35]Piperacillin-tazobactam[36]
4.5gIVq8hNo/MildRenalFailure:13.5g/24hoursIVcontinuousinfusion18g/24hoursIVcontinuousinfusionModerate/AdvancedRenalFailure:13.5g/24hoursIVcontinuousinfusion18g/24hoursIV
P:56.8±33.6%T:91.3±27.7%MedianP:46%(IQR:29%-62%)MedianT:85%(IQR:68%-132%)MedianP:43%(IQR:30%-65%)MedianT:84%(IQR:50%-105%)MedianP:39%(IQR:31%-48%)MedianT:49%(IQR:39%-69%)MedianP:85%(IQR:60%-96%)
Penetrationratio(ELF/Plasmatotal)determinedatsinglesamplingtimePenetrationratio(ELF/Plasmatotal)determinedatsinglesamplingtime
22
Piperacillin-tazobactam[37••]
continuousinfusion4.5gIVq8horq12h
MedianT:65%(IQR:63%-80%)MedianP:49.3%(range:2.0%-515.9%)MedianT:121.2%(range:11.0%-391.3%)
PenetrationratiodeterminedasAUCELF/AUCunbound=plasma
Carbapenem Meropenem[38]Meropenem[39•]Ertapenem[40]Ertapenem[41]
2gor500mgIVasa3-hinfusionq8hor1gIVasa0.5-hinfusionq8h1gIVasa0.5-hinfusionq8h1gIVasa3-hinfusionq8h1gIVasa1-hinfusiononcedaily1gIVasa1-hinfusiononcedaily
81.6%±223%Median:25.42%20%29%Median32%(IQR:28-46%)1.0-hour:6.19%±11.0%3.0-hour:6.85%±6.45%5.0-hour:9.40%±10.7%
PenetrationratiodeterminedasAUCELF/AUCtotal-plasma
PenetrationratiodeterminedasAUCELF/AUCtotal-plasma
PenetrationdeterminedbyELF/Cunbound-plasmawhereCiseitherat1-,12-or24-haftertheendofinfusion
PenetrationdeterminedbyELF/Ctotal-plasmawhereCiseitherat1-,3-or5-haftertheendofinfusion
Cephalosporin Cefepime[42]Ceftazidime[43]
2gasa0.5-hinfusionfollowedby4g/24hoursIVcontinuousinfusion2gasa0.5-hinfusionfollowedby4g/24hoursIVcontinuousinfusion
104%±8.9%20.6%±8.9%
PenetrationdeterminedbyELF/Ctotal-plasmawhereCiseitherat8:00am,12:00pmor6:00pmafter2daysofIVcontinuousinfusionPenetrationdeterminedbyELF/Ctotal-plasmawhereCiseitherat8:00am,12:00pmor6:00pmafter2daysofIVcontinuousinfusion
Fluoroquinolone Levofloxacin[44] 500mgIVq24h500mgIVq12h
Peak:131%±31%Trough:118%±36%Peak:127%±46%Trough:112%±40%
Eachpatienthadtwostandardizedbronchoalveolarmicrolavageprocedures
Glycopeptide Vancomycin[45] Dose-adjusted(plasmatroughconcentrationof
24.6%(range:19.2%-42.6%)14%(range:2.3%-28.5%)
VancomycinpenetrationhigherinpatientswhenELFalbuminvalues≥3.4mg/mL
23
15-20mg/L) thanwithnormalvalues<3.4mg/mL(p<0.02)
Oxazolidinone Linezolid[46]Linezolid[47]Linezolid[48]
600mgIVq12h1200mg/24hours(50mg/h)IVcontinuousinfusion600mgIVq12h(IIGroup)1200mg/24hours(50mg/h)byIVcontinuousinfusion(CIGroup)
Peak:105%±34%Trough:104%±28%Median97%(IQR:80-108%)IIGroup:Median80%(IQR:56.6-130.5%)CIGroup:Median106%(IQR:71.6-116%)
EachpatienthadtwostandardizedbronchoalveolarmicrolavageproceduresPenetrationdeterminedbyELF/serumCssorAUCratiosCriticallyillobese(BMI≥30kg/m2)adults;PenetrationratiosbasedonMonteCarlosimulationforIIgrouphadamedianof87.1%(IQR:78.7-95.4%)comparedtoCIgrouphadamedianof98.8%(IQR:93.8-104.3%)
24Table3Publishedstudiesonmicrodialysisandlungpenetrationofselectedantibioticsinpatients
Antibiotic Dose PenetrationRatio AUClung(µg�h/mL) AUCplasma(µg�h/mL)
Cefpirome[53] 2g Mean:67% Mean±SEM:261±24 Mean±SEM:174±15
Cefpirome[54] 30mg/kgMedian:46%(range:32-98)*Median:63%(range:19-155)#
Median:206(range:49-379)*Median:182(range:80-382)# Median:291(range:133-713)
Piperacillin-Tazobactam[55]
4.5g Piperacillin:Mean±SD:63%±29%Tazobactam:Mean±SD:193%±156%
Piperacillin:Mean±SD:288.0±167.0Tazobactam:Mean±SD:45.7±44.8
Piperacillin:Mean±SD:470.0±142.0Tazobactam:Mean±SD:36.2±26.0
Meropenem[56] 1g Mean±SD:41%±21% Mean±SD:36.2±17.9 Mean±SD:95.4±46.6
Levofloxacin[57] 500mg Median:60%(range:40-90) Median:18.6(range:10.1-33.6) Median:32.6(range:24.3-44.2)
Levofloxacin[58] 500mg Mean:67% Median:37.8(range:33.0-39.3) Median:56.3(range:41.8-89.6)
Levofloxacin[59] 500mgMedian:30%(range:10-70)‡Median:70%(range:40-80)†
Median:15.7(range:2.7-24.3)‡Median:72.2(range:22.2-95.8)†
Median:77.2(range:53.5-95.2)‡Median:82.5(range:66.3-106.7)†
Fosfomycin[60] 4gMean±SD:53%±31%*Mean±SD:63%±31%#
Mean±SD:315.1±151.2*Mean±SD:367.6±111.9# Mean±SD:665.9±179.5
PenetrationratiowasdeterminedinallstudiesbytheratioofAUCinterstitialfluid/AUCplasma
*infectedlung#uninfectedlung‡ patients undergoing coronary artery bypass with cardiopulmonary bypass † patientsoperatedwiththeoff-pumpcoronaryarterybypassgraftingtechnique.