considerations for effect site pharmacokinetics to estimate...
TRANSCRIPT
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.
3
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
4
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.
5
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
6
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.
7
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
8
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
9
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
10
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
11
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
12
studiesandtofacilitatedetailedanalysesofpatientspecificpharmacokineticvariationinclinical
settings.Goingforwardthesenewtechnologiescouldalsobeincorporatedintoantibioticdevelopment
programsforpneumoniatofurtherincreasetheprobabilityofcandidatesuccess.
SUMMARY
Rationaldoseselectionofantibioticsforthetreatmentofbacterialpneumoniacontinuestobea
challenge.MeasurementofantibioticconcentrationsbytechniquessuchasBALandmicrodialysishave
becomereliableandconsistentindescribingtheamountofdrugexposureatsitesoflunginfection.
Effectsiteexposureremainsessentialtoincorporateintotheevaluationofspecificdosingregimens
designedtobeefficaciousagainstpotentialbacterialpathogensinpneumonia.Furtherstudiesare
warrantedincriticallyillpatientswithpulmonaryinfectionstoexploreimportantdifferencesinthe
pattern,timecourseandmagnitudeofintrapulmonaryconcentrationscomparedtohealthysubjects.In
addition,potentiallinksbetweenpharmacokinetic-pharmacodynamicindicesbasedonplasma
exposuresandclinicalorbacterialoutcomesinpneumoniawouldbevaluable.Thesedatacouldbeused
tooptimizeregimensfornewantibioticsinclinicaltrialsforefficacy,orfortheclinicalcareofseriouslyill
patientswithdrugsthatarecurrentlyavailable.
13
REFERENCESandRECOMMENDEDREADINGS
Papersofparticularinterest,publishedwithintheperiodofreview,havebeenhighlightedas:
• ofspecialinterest
•• ofoutstandinginterest
1. OnufrakNJ,ForrestA,GonzalezD.Pharmacokineticandpharmacodynamicsprinciplesofanti-infectivedosing.ClinTher2016,38:1930-1947.
2. BaldwinDR,HoneybourneD,WiseR.Pulmonarydispositionofantimicrobialagents:methodologicalconsiderations.AntimicrobAgentsChemother1992,36:1171-1175.
3. BaldwinDR,HoneybourneD,WiseR.Pulmonarydispositionofantimicrobialagents:invivoobservationsandclinicalrelevance.AntimicrobAgentsChemother1992,36:1176-1180.
4. RodvoldKA,GeorgeJM,YooL.Penetrationofanti-infectiveagentsintopulmonaryepithelialliningfluid:focusonantibacterialagents.ClinPharmacokinet2011,50:637-664.
•• Comprehensivereviewofbronchoalveolarlavagestudiesandthedatageneratedupto2011forintrapulmonarypenetrationofantibiotics.
5. RodvoldKA,YooL,GeorgeMJ.Penetrationofanti-infectiveagentsintopulmonaryepithelialliningfluid:focusonantifungal,antitubercularandmiscellaneousanti-infectiveagents.ClinPharmacokinet2011,50:689-704.
6. BambergerDM,FoxworthJ,KallenbergerMA,PepitoBS,GerdingDN.Extravascularantimicrobialdistributionandtherespectivebloodandurineconcentrationsinhumans.In:AntibioticsinLaboratoryMedicine,6thedition.EditedbyAmsterdamD.WoltersKluwerHealth;2015:678-780.
•• Comprehensivereviewoftypesofextravascularsites,methodologytostudydistributionofantibioticsinhumans,andaccuratedeterminationandinterpretationofdata.Extensiveuseoftablestosummarizeandillustrateconcentrationsofantibioticsinavarietyoftissuesandfluids.
7. ZeitlingerM,MullerM,JoukhadarC.Lungmicrodialysis:apowerfultoolforthedeterminationofexogenousandendogenouscompoundsinthelowerrespiratorytract(mini-review).AAPSJ2005,7:E600-608.
• Areviewthathighlightsthedifferencesbetweenbronchoalveolarlavageandmicrodialysisstudiesfordeterminingdrugconcentrationsinthelowerrespiratorytract.
8. DhananiJ,RobertsJA,ChewM,LipmanJ,BootsRJ,PatersonDL,FraserJF.Antimicrobialchemotherapyandlungmicrodialysis:areview.IntJAntimicrobAgents2010,36:491-500.
•• Areviewontheuseofmicrodialysisstudiestodetermineintrapulmonaryconcentrationsofantibioticsstudiesinpatients.
9. MoutonJW,TheuretzbacherU,CraigWA,TulkensPM,DerendorfH,CarsO.Tissueconcentrations:doweeverlearn?JAntimicrobChemother2008,61:235-237.
10. JamalJ-A,Abdul-AzizM-H,LipmanJ,RobertsJA.Definingantibioticdosinginlunginfections.ClinPulmonaryMed2013,20:121-128.
11. AmbrosePG,BhavnaniSM,Ellis-GrosseEJ,DrusanoGL.Pharmacokinetic-pharmacodynamicconsiderationsinthedesignofhospital-acquiredorventilator-associatedbacterialpneumoniastudies:lookbeforeyouleap!ClinInfectDis2010,51(S1):S103-s110.
•• AcriticalevaluationforwhydeterminingintrapulmonaryconcentrationsofantibioticsbeforestartingclinicaltrialsinpatientswithHABPandVABP.
12. AmbrosePG.Antibacterialdrugdevelopmentprogramsuccessesandfailures:apharmacometricexplanation.CurrOpinPharmacol2017;36:1-7.
14
13. RiccobeneTA,PushkinR,JandourekA,KnebelW,KharitonT.Penetrationofceftarolineintotheepithelialliningfluidofhealthyadultsubjects.AntimicrobAgentsChemother2016,60:5847-5857.
14. vanHasseltJG,RizkML,LalaM,Chavez-EngC,VisserSA,KerbuschT,DanhofM,RaoG,vanderGraafPH.Pooledpopulationpharmacokineticmodelofimipeneminplasmaandthelungepithelialliningfluid.BrJClinPharmacol2016,81:1113-1123.
15. WenzlerE,GotfriedMH,LoutitJS,DursoS,GriffithDC,DudleyMN,RodvoldKA.Meropenem-RPX7009concentrationsinplasma,epithelialliningfluid,andalveolarmacrophagesofhealthyadultsubjects.AntimicrobAgentsChemother2015,59:7232-7239.
16. NicolauDP,SiewL,ArmstrongJ,LiJ,EdekiT,LearoydM,DasS.Phase1studyassessingthesteady-stateconcentrationofceftazidimeandavibactaminplasmaandepithelialliningfluidfollowingtwodosingregimens.JAntimicrobChemother2015,70:2862-2869.
17. ChandorkarG,HuningtonJA,GotfriedMH,RodvoldKA,UmehO.Intrapulmonarypenetrationofceftolozane/tazobactamandpiperacillin/tazobactaminhealthyadultsubjects.JAntimicrobChemother2012,67:2463-2469.
18. ConnorsKP,HousmanST,PopeJS,RussomannoJ,SalernoE,ShoreE,RedicanS,NicolauDP.Phase1,open-label,safetyandpharmacokineticstudytoassessbronchopulmonarydispositionofintravenouseravacyclineinhealthymenandwomen.AntimicrobAgentsChemother2014,58:2113-2118.
19. GotfriedMH,HornK,Garrity-RyanL,VillanoS,TzanisE,ChitraS,ManleyA,TanakaSK,RodvoldKA.Comparisonofomadacyclineandtigecyclinepharmacokineticsintheplasma,epithelialliningfluid,andalveolarcellsinhealthyadultsubjects.AntimicrobAgentsChemother2017,62:e01135-17.
20. HousmanST,PopeJS,RussomannoJ,SalernoE,ShoreE,KutiJL,NicolauDP.Pulmonarydispositionoftedizolidfollowingadministrationofonce-dailyoral200-milligramtedizolidphosphateinhealthyadultsubjects.AntimicrobAgentsChemother2012,56:2627-2634.
21. RodvoldKA,GotfriedMH,ChughR,GuptaM,FriedlandHD,BhatiaA.Comparisonofplasmaandintrapulmonaryconcentrationsofnafithromycin(WCK4873)inhealthyadultsubjects.AntimicrobAgentsChemother2017,62:e01096-17.
22. RodvoldKA,GotfriedMH,StillJG,ClarkK,FermandesP.Comparisonofplasma,epithelialliningfluid,andalveolarmacrophageconcentrationsofsolithromycin(CEM-101)inhealthyadultsubjects.AntimicrobAgentsChemother2012,56:5076-5081.
23. ZeitlingerM,SchwameisR,BurianA,BurianB,MatznellerP,MullerM,WichaWW,StrickmanDB,PrinceW.Simultaneousassessmentofthepharmacokineticsofapleuromutilin,lefamulin,inplasma,softtissuesandpulmonaryepithelialliningfluid.JAntimicrobChemother2016,71:1022-1026.
24. NadererOJ,RodvoldKA,JonesLS,ZhuJZ,BowenCL,ChenL,DumontE.PenetrationofGSK1322322intoepithelialliningfluidandalveolarmacrophagesasdeterminedbybronchoalveolarlavage.AntimicrobAgentsChemother2014,58:419-423.
25. TeneroD,BowersG,RodvoldKA,PatelA,KurtineczM,DumontE,TomaykoJ,PatelP.IntrapulmonarypharmacokineticsofGSK2251052inhealthyvolunteers.AntimicrobAgentsChemother2013,57:3334-3339.
26. AwadSS,RodriguezAH,ChuangYC,MarjanekZ,PareigisAJ,ReisG,ScheerenTW,SanchezAS,ZhouX,SaulayM,EngelhardtM.Aphase3randomizeddouble-blindcomparisonofceftobiprolemedocarilversusceftazidimepluslinezolidforthetreatmentofhospital-acquiredpneumonia.ClinInfectDis2014,59:51-61.
15
27. KoffefMH,ChastreJ,ClavelM,RestrepoMI,MichielsB,KanigaK,CirilloI,KimkoH,RedmanR.Arandomizedtrialof7-daydoripenemversus10-dayimipenem-cilastatinforventilator-associatedpneumonia.CritCare2012,16:R218.
28. RobertsJA,LipmanJ.Optimaldoripenemdosingsimulationsincriticallyillnosocomialpneumoniapatientswithobesity,augmentedrenalclearance,anddecreasedbacterialsusceptibility.CritCareMed2013,41:489-495.
29. KatsubeT,WajimaT,IshibashiT,ArjonaFerreiraJC,EcholsR.Pharmacokinetic/pharmacodynamicsmodelingandsimulationofcefiderocol,aparenteralsiderophorecephalosporin,fordoseadjustmentbasedonrenalfunction.AntimicrobAgentsChemother2016,61:e01381-16.
30. BoselliE,BreilhD,DjabaroutiS,GuillaumeC,RimmeleT,GordienJ-B,XuerebF,SauxM-C,AllaouchicheB.Reliabilityofmini-bronchoalveolarlavageforthemeasurementofepithelialliningfluidconcentrationsoftobramycinincriticallyillpatients.IntensiveCareMed2007,33:1519-1523.
31. CarcasAJ,Garcia-SatueJL,ZapaterP,Frias-IniestaJ.Tobramycinpenetrationintoepithelialliningfluidofpatientswithpneumonia.ClinPharmacolTher1999,65:245-250.
32. MazzeiT,NoveilliA,DeLallaF,MiniE,PeritiP.Tissuepenetrationandpulmonarydispositionoftobramycin.JChemother1995,7:363-370.
33. PanidisD,MarkantonisSL,BoutzoukaE,KaratzasS,BaltopoulosG.Penetrationofgentamicinintothealveolarliningfluidofcriticallyillpatientswithventilator-associatedpneumonia.Chest2005,128:545-552.
34. ValckeY,VogelaersDP,ColardynFA,PauwelsRA.Penetrationofnetilmicinintothelowerrespiratorytractafteronce-dailydosing.Chest1992,101:1028-1032.
35. BoselliE,BreilhD,CannessonM,XuerebF,RimmeleT,ChassardD,SauxM-C,AllaouchicheB.Steady-stateplasmaandintrapulmonaryconcentrationsofpiperacillin/tazobactam4g/0.5gadministeredtocriticallyillpatientswithseverenosocomialpneumonia.IntensiveCareMed2004,30:976-979.
36. BoselliE,BreilhD,RimmeleT,GuillaumeC,XuerebF,SauxM-C,BouvetL,ChassardD,AllaouchicheB.Alveolarconcentrationsofpiperacillin/tazobactamadministeredincontinuousinfusiontopatientswithventilator-associatedpneumonia.CritCareMed2008,36:1500-1506.
37. FeltonTW,McCalmanK,MalagonI,IsalskaB,WhalleyS,GoodwinJ,BentleyAM,HopeWW.Pulmonarypenetrationofpiperacillinandtazobactamincriticallyillpatients.ClinPharmacolTher2014,96:438-448.
•• Outstandingresearchmanuscriptusingbronchoalveolarlavageandpharmacokinetic-pharmacodynamicmodellingtodetermineintrapulmonarypenetrationofpiperacillinandtazobactamincriticallyillpatients
38. LodiseTP,SorgelF,MelnickD,MasonB,KinzigM,DrusanoGL.Penetrationofmeropenemintoepithelialliningfluidofpatientswithventilator-associatedpneumonia.AntimicrobAgentsChemother2011,55:1606-1610.
39. FrippiatF,MusuambaFT,SeidelL,AlbertA,DenoozR,CharlierC,VanBambekeF,WallemacqP,DescyJ,LambermontB,LayiosN,DamasD,MoutschenM.Modelledtargetattainmentaftermeropeneminfusioninpatientswithseverenosocomialpneumonia:thePROMESSEstudy.JAntimicrobChemother2015,70:207-216.
• Illustratesthevariabilityinmeropenemconcentrationsinseriouslyillpatientswithnosocomialpneumoniaandtheimpactoftwodifferentmodesofdrugadministrationontargetattainmentrates
40. BoselliE,BreilhD,SauxM-C,GordienJ-B,AllaouchicheB.Pharmacokineticsandlungconcentrationsofertapeneminpatientswithventilator-associatedpneumonia.IntensiveCareMed2006,32:2059-2062.
16
41. BurkhardtO,Majcher-PeszynskaJ,BornerK,MundkowskiR,DrewelowB,DerendorfH,WelteT.Penetrationofertapenemintodifferentpulmonarycomparatmentsofpatientsundergoinglungsurgery.JClinPharmacol2005,45:659-665.
42. BoselliE,BreilhD,DufloF,SauxM-C,DebonR,ChassardD,AllaouchicheB.Steady-stateplasmaandintrapulmonaryconcentrationsofcefepimeadministeredincontinuousinfusionincriticallyillpatientswithseverenosocomialpneumonia.CritCareMed2003,31:2102-2106.
43. BoselliE,BreilhD,RimmeleT,PoupelinJ-C,SauxM-C,ChassardD,AllaouchicheB.Plasmaandlungconcentrationsofceftazidimeadministeredincontinuousinfusiontocriticallyillpatientswithseverenosocomialpneumonia.IntensiveCareMed2004,30:989-991.
44. BoselliE,BreilhD,RimmeleT,DjabaroutiS,SauxM-C,ChassardD,AllaouchicheB.Pharmacokineticsandintrapulmonarydiffusionoflevofloxacinincriticallyillpatientswithcommunity-acquiredpneumonia.CritCareMed2005,33:104-109.
45. LamerC,DeBecoV,SolerP,CalvatS,FagonJ-Y,DombretM-C,FarinottiR,ChastreJ,GilbertC.Analysisofvancomycinentryintopulmonaryliningfluidbybronchoalveolarlavageincriticallyillpatients.AntimicrobAgentsChemother1993,37:281-286.
46. BoselliE,BreilhD,RimmeleT,DjabaroutiS,ToutainJ,ChassardD,SauxM-C,AllaouchicheB.Pharmacokineticsandintrapulmonaryconcentrationsoflinezolidadministeredtocriticallyillpatientswithventilator-associatedpneumonia.CritCareMed2005,33:1529-1533.
47. BoselliE,BreilhD,Caillault-SergentA,DjabaroutiS,GuillaumeC,XuerebF,BouvetL,RimmeleT,SauxM-C,AllaouchicheB.Alveolardiffusionandpharmacokineticsoflinezolidadministeredincontinuousinfusiontocriticallyillpatientswithventilator-associatedpneumonia.JAntimicrobChemother2012,67:1207-1210.
48. DePascaleG,FortunaS,TumbarelloM,CutuliSL,VallecocciaM,SpanuT,BelloG,MontiniL,PennisiMA,NavarraP,AntonelliM.Linezolidplasmaandintrapulmonaryconcentrationsincriticallyillobesepatientswithventilator-associatedpneumonia:intermittentvscontinuousadministration.IntensiveCareMed2015,41:103-110.
49. FeltonTW,HopeWW,RobertsJA.Howsevereisantibioticpharmacokineticvariabilityincriticallyillpatientsandwhatcanbedoneaboutit?DiagnMicrobiolInfectDis2014,79:41-447.
50. Asin-PrietoE,Rodriguez-GasconA,IslaA.Applicationsofthepharmacokinetic/pharmacodynamics(PK/PD)analysisofantimicrobialagents.JInfectChemother2015,21:319-329.
51. TangdenT,RamowMartinV,FeltonTW,NielsenEI,MarchandS,BruggemannRJ,BulittaJB,BassettiM,TheuretzbacherU,TsujiBT,WarehamDW,FribergLE,DeWaeleJJ,TamVH,RobertsJA.TheroleofinfectionmodelsandPK/PDmodellingforoptimizingcareofcriticallyillpatientswithsevereinfections.IntensiveCareMed2017,43:1021-1032.
52. MimozO,Dahyot-FizelierC.Mini-broncho-alveolarlavage:asimpleandpromisingmethodforassessmentofantibioticconcentrationinepithelialliningfluid.IntensiveCareMed2007,33:1495-1497.
53. HerknerH,MullerMR,KreischitzN,MayerBX,FrossardM,JoukhadarC,KleinN,LacknerE,andMullerM.Close-chestmicrodialysistomeasureantibioticpenetrationintohumanlungtissue.IntensiveCareMed2007,33:1519-1523.
54. LindenmannJ,KuglerSA,MatziV,PorubskyC,MaierA,DittrichP,GraningerW,Smolle-JuttnerFM,JoukhadarC.Highextracellularlevelsofcefpiromeinunaffectedandinfectedlungtissuesofpatients.JAntimicrobChemother2011,66:160-164.
55. TomaselliF,DittrichP,MaierA,WoltscheM,MatziV,PinterJ,NuhsbaumerS,PinterH,SmolleJ,Smolle-JuttnerFM.Penetrationofpiperacillinandtazobactamintopneumonichumanlungtissuemeasuredbyinvivomicrodialysis.BrJClinPharmacol2003,55:620-624.
17
56. TomaselliF,MaierA,MatziV,Smolle-JuttnerFM,DittrichP.Penetrationofmeropenemintopneumonichumanlungtissueasmeasuredbyinvivomicrodialysis.AntimicrobAgentsChemother2004,48:2228-2232.
57. HutschalaD,SkhirtladzeK,ZuckermannA,WisserW,JakschP,Mayer-HelmBX,BurgmannH,WolnerE,MullerM,TschernkoEM.Invivomeasurementoflevofloxacinpenetrationintolungtissueaftercardiacsurgery.AntimicrobAgentsChemother2005,49:5107-5111.
58. HutschalaD,KinstnerC,SkhirtladzeK,Mayer-HelmB-X,ZeitlilngerM,WisserW,MullerM,TschernkoE.Theimpactofperioperativeatelectasisonantibioticpenetrationintolungtissue:aninvivomicrodialysisstudy.IntensiveCareMed2008,34:1827-1834.
59. ZeitlingerMA,TraunmullerF,AbrahimA,MullerMR,ErdoganZ,MullerM,JoukhadarC.Apilotstudytestingwhetherconcentrationsoflevofloxacinininterstitialspacefluidofsofttissuesmayserveasasurrogateforpredictingitspharmacokineticsinlung.IntJAntimicrobAgents2007,29:44-50.
60. MatziV,LindenmannJ,PorubskyC,KuglerSA,MaierA,DitrichP,Smolle-JuttnerFM,JoukhadarC.Extracellularconcentrationsoffosfomycininlungtissuesofsepticpatients.JAntimicrobChemother2010,65:995-998.
61. PrideauxB,ElNaggarMS,ZimmermanM,WidemanJM,LiX,DartoisV.MassspectrometryimagingoflevofloxacindistributioninTB-infectedpulmonarylesionsbyMALDI-MSIandcontinuousliquidmicrojunctionsurfacesampling.IntJMassSpectrom.2015;377:699-708.
62. ZhaoY,PrideauxB,NagasakiY,LeeMH,ChenPY,BlancL,HoH,ClancyCJ,NguyenMH,Dartois,PerlinDS.UnravellingDrugPenetrationofEchinocandinAntifungalsattheSiteofInfectioninanIntra-AbdominalAbscessModel.AntimicrobAgentsChemother.2017.Doi:10.1128/AAC.01009-17.[Epubaheadofprint]
63. ZhangZ,GogartyKR,FereidoonD,TongePJ.PharmacokineticandPharmacodynamicsRelationships.In:ImagingInfections.EditedbyJainS.Springer,Cham;2017:195-207.
64. Arroyo-CurrásN,SomersonJ,VieiraPA,PloenseKL,KippenTE,PlaxcoKW.Real-timemeasurementofsmallmoleculesdirectlyinawake,ambulatoryanimals.ProcNatlAcadSciU.S.A.2017;114(4):645-650
65. RawsonTM,SharmaS,GeorgiouP,HolmesA,CassA,O’HareD.Towardsaminimallyinvasivedeviceforbeta-lactammonitoringinhumans.Electrochemistrycommunications.2017;88:1-5
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.