highapche

ORIGINALPAPERInitialdosingregimenofvancomycintoachieveearlytherapeuticplasmaconcentrationincriticallyillpatientswithMRSAinfectionbasedonAPACHEIIscoreMasaharuImauraHarukoYokoyamaYujiKohataRiichiroKanaiTomokiKohyamaWataruIdemitsuYuichiMakiTakashiIgarashiHiroyukiTakahashiHiroshiKannoYasuhikoYamadaReceived:8August2014/Accepted:2December2014/Publishedonline:12December2014SpringerInternationalPublishingSwitzerland2014AbstractItisessentialtoassuretheefcacyofantimi-crobialsattheinitialphaseoftherapy.
However,increasingthevolumeofdistribution(Vd)ofhydrophilicantimicro-bialsincriticallyillpatientsleadstoreducedantimicrobialconcentrationinplasmaandtissue,whichmayadverselyaffecttheefcacyofthattherapy.
TheaimofthepresentstudywastoestablishatheoreticalmethodologyforsettinganappropriatelevelforinitialvancomycintherapyinindividualpatientsbasedonAcutePhysiologyandChronicHealthEvaluation(APACHE)IIscore.
WeobtaineddatafrompatientswhoreceivedintravenousvancomycinforasuspectedordenitivelydiagnosedGram-positivebacterialinfectionwithin72hafteradmissiontotheintensivecareunit.
TheVdandeliminationhalf-life(t1/2)ofvancomycinvalueswerecalculatedusingtheBayesianmethod,andweinvestigatedtherelationshipbetweenthemandAPACHEIIscore.
ThereweresignicantcorrelationsbetweenAPACHEIIscoresandVd/actualbodyweight(ABW),aswellast1/2(r=0.
58,p\0.
05andr=0.
74,p\0.
01,respectively).
OurresultssuggestedthattheVdandt1/2ofvancomycincouldbeestimatedusingthefollowingregressionequationsusingAPACHEIIscore.
Vd/ABW0:018APACHEIIscore0:63t1=20:70APACHEIIscore4:58WefoundthatAPACHEIIscorewasausefulindexforpredictingtheVdandt1/2ofvancomycin,andusedthattoestablishaninitialvancomycindosingregimencomprisedofinitialdoseandadministrationintervalforindividualpatients.
KeywordsVancomycintherapyInitialdoseDosageintervalAPACHEIIscoreVolumeofdistribution1IntroductionWhentreatingcriticallyillpatients,itisimportantthattheefcacyofadministereddrugsisobtainedasrapidlyaspossible.
Notably,approximately50%ofintensivecareunit(ICU)patientshavebeenshowntobeaffectedbycatheter-associatedbloodstream,ventilator-associatedpneumonia,andsurgicalsiteinfectionsaswellasothers,withsubsequentincreasedmortality(Vincentetal.
2009).
Therefore,itisessentialforantimicrobialsgivenattheinitialphaseoftherapytobeefcacious.
However,path-ophysiologicchangessuchascapillaryleakage,hypoal-buminemia,andpleuraleffusion,aswellasotherfactorscanoccurincriticallyillpatients,leadingtochangesintheM.
ImauraH.
YokoyamaY.
Yamada(&)DepartmentofClinicalEvaluationofDrugEfcacy,SchoolofPharmacy,TokyoUniversityofPharmacyandLifeSciences,1432-1Horinouchi,Hachioji,Tokyo192-0392,Japane-mail:yamada@ps.
toyaku.
ac.
jpM.
ImauraY.
KohataT.
IgarashiH.
KannoDepartmentofPharmacy,SaiseikaiYokohamashiTobuHospital,3-6-1Shimosueyoshi,Tsurumi-ku,Yokohama,Kanagawa230-8765,JapanR.
KanaiT.
KohyamaDepartmentofAnesthesiology,KyorinUniversityScoolofMedicine,6-20-2Shinkawa,Mitaka-shi,Tokyo181-8611,JapanW.
IdemitsuDepartmentofAnesthesiology,TohoUniversityOmoriMedicalCenter,6-11-1Omorinishi,Ota-ku,Tokyo143-8541,JapanY.
MakiH.
TakahashiDepartmentofIntensiveCare,SaiseikaiYokohamashiTobuHospital,3-6-1Shimosueyoshi,Tsurumi-ku,Yokohama,Kanagawa230-8765,JapanEurJDrugMetabPharmacokinet(2016)41:211–218DOI10.
1007/s13318-014-0246-1pharmacokineticsofadministeredantimicrobials.
Previousreportshaveshownthatthevolumeofdistribution(Vd)ofhydrophilicantimicrobialstendedtoincrease(RobertsandLipman2006;Petrosilloetal.
2010;Vargheseetal.
2011),whileantimicrobialconcentrationsinplasmaandtissuedidnotreachaneffectivelevelincriticallyillpatientswithaninfection(Joukhadaretal.
2001;Tacconeetal.
2010a,b).
Moreover,thestartingdosesforwater-solubleantimicro-bialshavebeenfoundtobeinsufcient,whichadverselyaffectstheprognosisofthesepatients(Kollefetal.
1999;Ibrahimetal.
2000;Kumaretal.
2006).
Therefore,itisimportantthatanappropriateinitialdoseforantimicrobialtherapybesetforcriticallyillpatientssufferingfrominfection.
Vancomycinhydrochloride,classiedasaglycopeptideandwater-solubleantibiotic,isrecommendedasrst-linetherapyforamethicillin-resistantStaphylococcusaureus(MRSA)infection.
Theonlyestablishedcriterionforset-tingtheinitialdoseincriticallyillpatientsisbasedonactualbodyweight(ABW)(Liuetal.
2011).
However,itisthoughtthattheVdofvancomycinvariesamongindivid-ualsbecauseofbodyuidretentionandotherconditions.
WeconsideredthatamoreappropriateinitialdosecouldbeestablishedbyestimatingtheVdofvancomycinforindi-vidualpatients.
Inthepresentstudy,weutilizedtheAcutePhysiologyandChronicHealthEvaluation(APACHE)IIscoringsystem(Knausetal.
1985),aclassicationmethodusedtodeterminediseaseseverityintheICUforpredictionofVd.
APACHEIIscoresaredeterminedfromphysiologicalvariablesincludingbodytemperature,bloodpressure,heartrate,respiratoryrate,andwhitebloodcellcount,aswellasinformationaboutprevioushealthstatusandotherdataobtainedatadmissionsuchasage,organdysfunction,andimmunodeciency.
Wespeculatedthattheobtainedscorereectsbodyuidretentioninducedbysystemicinam-matoryresponsesyndrome(SIRS)andorgandysfunction,andattemptedtopredictVdandtheeliminationhalf-life(t1/2)ofvancomycinusingAPACHEIIscores.
Inthisstudy,weattemptedtoestablishatheoreticalmethodologybywhichtheinitialdoseandadministrationintervalofvancomycincouldbeestablishedbasedonAPACHEIIscoreforprovidinganadequateantimicrobialeffectfromtherstadministration.
2Materialsandmethods2.
1PatientdataThisstudywasconductedinaretrospectivemanner.
WeobtaineddatafrompatientsadmittedtotheICUofSais-eikaiYokohamashiTobuHospitalfromApril2010toSeptember2012.
Allreceivedvancomycinhydrochlorideintravenouslyfor1–2h,within72hafteradmissiontotheICU.
Thebloodsamplingformeasuringplasmaconcen-trationwasperformedatleastoncewithin1–2haftertheendoftherstintravenousinfusion.
Moreover,thebloodsamplesweretakenmorethantwicebetweentherstandsecondadministrationofthedrug(Rodvoldetal.
1988;Pateletal.
2011;Matsumotoetal.
2013).
Exclusioncriteriawereundertheageof20years,severerenalimpairmentwithanestimatedglomerularltrationrate(eGFR)lessthan30mL/min/1.
73m2,andreceivinghemodialysis.
2.
2CalculationofAPACHEIIscoreTheAPACHEIIseverityofdiseaseclassicationsystemisshowninTable1indetail.
TheAPACHEIIscorewasconsistedofthreedomains(theAcutePhysiologyScore,theAgeScoreandtheChronicHealthScore)(Knausetal.
1985).
Thescorerangedfrom0to71andhighscorewasconsideredtoindicatehigherriskofdeath.
TheAcutePhysiologyScorepointwascalculatedfrom12routinephysiologicalmeasurementswithintherst24hafteradmissiontotheICU.
TheAgeScorepointwasdeterminedbyage.
TheChronicHealthScorepointwasdeterminedbytheprevioushealthstatussuchasahistoryofsevereorgansysteminsufciency.
Inthepresentstudy,allscoreswerecalculatedretrospectivelybasedondatainthepatientrecords.
2.
3CalculationofVdandt1/2ofvancomycinThepharmacokineticparametersVdandt1/2forvanco-mycinwerecalculatedusingtheBayesianmethodwiththeVCM-TDME_editionVer.
3.
00softwarepackage(Shionogi&Co.
,Ltd.
Japan).
Patientdata(age,gender,ABW,andScrorcreatinineclearance),vancomycindosinghistory(administrationtimeanddate,dosage,anddriptime),andvancomycinconcentrationhistory(samplingtimeanddate,andplasmaconcentrationofvancomycin)wereextractedfrommedicalrecordsforthiscalculation.
Then,thevancomycindosinghistory,andconcentrationhistorybetweentherstandsecondadministrationwereacquiredtoestablishamethodologyforsettingtheinitialdosageofvancomycinhydrochloride.
Furthermore,theratiobetweenVdandABWwasrepresentedasVd/ABW.
Theplasmaconcentrationofvancomycinwasmeasuredusingaparticle-enhancedturbidimetricinhibitionimmu-noassay(DimensionXpand-PlusHM,SiemensHealthcareDiagnostics,Inc.
,Tokyo,Japan)inthehospitallaboratory.
Then,thepharmacistsprovidedanoptimalindividualvancomycindosageregimenbasedonthedataofeachpatienttothephysicians.
212EurJDrugMetabPharmacokinet(2016)41:211–2182.
4Relationshipbetweeninitialdoseandpeakplasmaconcentration(Cpeak)ofvancomycinPresently,theinitialdoseofvancomycinforcriticallyillpatientswithanMRSAinfectioniscalculatedbasedonlyonABW(Liuetal.
2011).
Toexaminetheadequacyofthatmethod,weinvestigatedtherelationshipbetweentheinitialdoseandCpeakvalueofvancomycinat2haftertheendoftherstintravenousinfusioninpatientsinwhomCpeakvaluewasmeasured.
2.
5RelationshipofAPACHEIIscorewithVdandt1/2ofvancomycinWecalculatedtherelationshipofAPACHEIIscorewithVdandt1/2ofvancomycinforeachpatient.
BasedonthoseTable1TheAPACHEIIseverityofdiseaseclassicationsystem(Knausetal.
1985)AcutePhysiologyScorepoints(sumofthe12individualvariablepoints)PhysiologicvariableHighabnormalrangeLowabnormalrange4321012341Rectaltemperature(°C)C4139–40.
938.
5–38.
936–38.
434–35.
932–33.
930–31.
9B29.
92Meanarterialpressure(mmHg)C160130–159110–12970–10950–69B493Heartrate(ventricularresponse)C180140–179110–13970–10955–6940–54B394Respiratoryrate(non-ventilatedorventilated)C5035–4925–3412–2410–116–9B55Oxygenation:A-aDO2orPaO2(a)FiO2C0.
5recordA-aDO2C500350–499200–349\200(b)FiO2\0.
5recordonlyA-aDO2PO2[70PO261–70PO255–60PO2\556ArterialpHC7.
77.
6–7.
697.
5–7.
597.
33–7.
497.
25–7.
327.
15–7.
24\7.
157Serumsodium(mMol/L)C180160–179155–159150–154130–149120–129111–119B1108Serumpotassium(mMol/L)C76–6.
95.
5–5.
93.
5–5.
43–3.
42.
5–2.
9\2.
59Serumcreatinine(mg/100mL)(doublepointscoreforacuterenalfailure)C3.
52–3.
41.
5–1.
90.
6–1.
4\0.
610Hematocrit(%)C6050–59.
946–49.
930–45.
920–29.
9\2011Whitebloodcount(total/mm3)(in1,000s)C4020–39.
915–19.
93–14.
91–2.
9\112Glasgowcomascore(GCS)Score=15minusactualGCSSerumHCO3(venousmMol/L)[notpreferred,useifnoABGs]C5241–51.
932–40.
922–31.
918–21.
915–17.
9\15AgeScorepoints02356Age(years)B4445–5455–6465–74C75ChronicHealthScorepoints2points:forelectivepostoperativepatientwithahistoryofsevereorgansysteminsufciencyorimmunocompromiseda5points:fornonoperativepatientoremergencypostoperativepatientwithahistoryofsevereorgansysteminsufciencyorimmunocompromisedaAPACHEIIscore=AcutePhysiologyScorepointsAgeScorepointsChronicHealthScorepointsaAhistoryofsevereorgansysteminsufciencyorimmunocompromisedstatemusthavebeenevidentpriortothishospitaladmissionandconformtothefollowingcriteria:LiverBiopsyprovencirrhosisanddocumentedportalhypertension;episodesofpastupperGIbleedingattributedtoportalhypertension;orpriorepisodesofhepaticfailure/encephalopathy/comaCardiovascularNewYorkHeartAssociationClassIVRespiratoryChronicrestrictive,obstructive,orvasculardiseaseresultinginsevereexerciserestriction,i.
e.
,unabletoclimbstairsorperformhouseholdduties;ordocumentedchronichypoxia,hypercapnia,secondarypolycythemia,severepulmonaryhypertension(C40mmHg),orrespiratorydependencyRenalReceivingchronicdialysisImmunocompromisedThepatienthasreceivedtherapythatsuppressesresistancetoinfection,e.
g.
,immune-suppression,chemotherapy,radiation,long-termorrecenthigh-dosesteroids,orhasadiseasethatissufcientlyadvancedtosuppressresistancetoinfection,e.
g.
,leukemia,lymphoma,AIDSEurJDrugMetabPharmacokinet(2016)41:211–218213results,weexaminedthebestpredictionmethodforesti-matingtheVdandt1/2ofvancomycinbasedonAPACHEIIscore.
2.
6RelationshipbetweenpredictedandobservedplasmaconcentrationofvancomycinThepredictionmethodusedforestimatingtheVdandt1/2ofvancomycinbasedonAPACHEIIscoreasnotedabovewasvalidated.
Thosevalueswerecalculatedusingaregressionequationfordatafromeachpatient,andthentheplasmaconcentrationofvancomycinatthoursaftertheendofintravenousinfusionofvancomycinhydrochloridewaspredictedusingthevalues.
Thepredictedvalue(Ct),plasmaconcentrationat0haftertheendoftheinfusion(C0),andeliminationrateconstant(ke)wereobtainedusingthefollowingformulas.
CtC0eket;C0Dose/Vdke0:693=t1=2Finally,weinvestigatedtherelationshipbetweenpredictedandobservedplasmaconcentration.
2.
7EthicalapprovalThepresentstudyprotocolwasapprovedbytheinstitu-tionalreviewboardofSaiseikaiYokohamashiTobuHos-pital.
Patientswerenotiedofthisretrospectivestudywithpostersdisplayedinthehospital.
3Results3.
1PatientsTwenty-eightpatientsreceivedintravenousvancomycinwithin72hofadmittancetotheICU,ofwhom13wereexcludedbasedontheexclusioncriteria.
Consequently,15patientswereenrolled(12males,3females;71±8yearsold;ABW64±12kg)andtheirdataareshowninTable2.
Forallpatients,Scrwas1.
1±0.
4mg/dLandeGFRwas53.
0±22.
3mL/min/1.
73m2,whilethetimingoftherstadministrationofvancomycinafteradmissiontotheICUwas29.
3±19.
0h.
3.
2RelationshipbetweeninitialdoseandCpeakofvancomycinTherelationshipbetweentheinitialdoseofvancomycinbasedonABWandCpeakvalueisshowninFig.
1.
Cpeakwasmeasuredin14ofthe15patients.
TheinitialdosesandvaluesforCpeakwere26.
1±1.
8mg/kg(range23.
1–29.
2mg/kg)and24.
4±3.
7mg/L(range17.
1–29.
9mg/L),respectively.
TherewasnocorrelationbetweeninitialvancomycindosebasedonABWandCpeakvalue.
3.
3RelationshipofAPACHEIIscorewithVdandt1/2ofvancomycinTheAPACHEIIscores,andvaluesforVd/ABWandt1/2were22±6pts,1.
03±0.
20L/kg,and20.
1±6.
1h,respectively(Table3).
TherelationshipbetweenAPACHEIIscoreandVd/ABWisshowninFig.
2,whilethatbetweenAPACHEIIscoreandt1/2isshowninFig.
3.
TherewasasignicantcorrelationbetweenAPACHEIIscoreandVd/ABW(r=0.
58,p\0.
05),andbetweenAPACHEIIscoreandt1/2(r=0.
74,p\0.
01).
Further-more,theVdandt1/2ofvancomycincouldbeestimatedusingtheregressionEqs.
(1)and(2),respectively.
Vd/ABW0:018APACHEIIscore0:631t1=20:70APACHEIIscore4:5823.
4RelationshipbetweenpredictedandobservedplasmaconcentrationofvancomycinTherelationshipbetweenpredictedandobservedplasmaconcentrationofvancomycinatthoursaftertheendofinfusionisshowninFig.
4,withasignicantcorrelationfound(r=0.
71,p\0.
01).
Consequently,weconcludedthatourresultsestablishedatheoreticalmethodologyforsettingbothappropriateinitialdosageanddosageintervalforvancomycintherapybasedonAPACHEIIscore(Fig.
5).
4DiscussionItisessentialtoestablishtheeffectsofantimicrobialdrugsfromthetimeofinitialtherapyincriticallyillpatientswithaninfection.
However,sincethedegreeofbodyuidretentionsuchasedema,pleuraleffusion,andperitonealeffusionvarygreatlyinthosepatients,theVdofhydro-philicantimicrobialsalsovaries,makingitdifculttosetanappropriateinitialdose.
Inthepresentstudy,weattemptedtoestablishatheoreticalmethodologytoestablishaninitialdosageanddosageintervaltoprovideanadequateantimicrobialeffectwiththeinitialadminis-trationofvancomycinhydrochloride,awater-solubleantibiotic.
TherewasnocorrelationbetweeninitialdosebasedonABWandtheCpeakvalueofvancomycin,indicatingthatitisdifculttosettheinitialdosageinindividualpatients214EurJDrugMetabPharmacokinet(2016)41:211–218basedonABW,becausetheVdofvancomycinvariesgreatly.
Therefore,weconsideredthatitisnecessarytopredictVdandt1/2priortoadministrationforestablishinganappropriatetherapeuticstrategy.
Inthepresentstudy,wefocusedontheAPACHEIIscoringsystem(Knausetal.
1985),asystemfordiseaseseverityclassicationofpatientsintheICU,andinves-tigatedtherelationshipsofAPACHEIIscorewithVd/ABWandt1/2ofvancomycin,whichshowedsignicantcorrelations(r=0.
58,p\0.
05andr=0.
74,p\0.
01,respectively).
Furthermore,ourresultsshowedthattheVdandt1/2ofvancomycincanbepredictedpriortoadmin-istrationusingthefollowingregressionEqs.
(1)and(2).
However,therewerefewadultpatients(\65years)inthepresentstudy.
WhentheAPACHEIIscoreis0inapatientattheageof44oryoungerwithlowseverity,theestimatedvaluesofVd/ABWandt1/2usingthoseequa-tionsindicate0.
63L/kgand4.
58h,respectively.
Thesevalueswerewithin0.
39–0.
92L/kgand2.
9–9.
1hwhichTable2PatientcharacteristicsABWactualbodyweight,WBCwhitebloodcellcount,CRPserumlevelofC-reactiveprotein,Albserumalbumin,Scrserumcreatinine,eGFRestimatedglomerularltrationrate,ICUintensivecareunitaMean±SDCharacteristicn(Total15)UnderlyingdiseaseSepsis9Pneumonia5Cholecystitis1Gendermale:female12:3Age(years)71±8aABW(kg)64±12aWBC(9103/lL)13.
3±9.
6aCRP(mg/dL)17.
5±10.
3aAlb(g/dL)1.
9±0.
3aScr(mg/dL)1.
1±0.
4aeGFR(mL/min/1.
73m2)53.
0±22.
3aTimingofrstadministrationofvancomycinafteradmissiontoICU(h)29.
3±19.
0a010203040202530Peakconcentration(mg/L)Initialdose(mg/kg)Fig.
1Relationshipbetweeninitialdoseandpeakplasmaconcen-trationofvancomycinTable3APACHEIIscores,volumeofdistribution,andeliminationhalf-lifeofvancomycininthepresentpatientsPatientno.
APACHEIIscore(pt)Vd/ABW(L/kg)t1/2(h)1160.
8117.
32311.
5822.
83220.
9527.
84230.
8213.
25151.
0518.
36301.
1531.
27150.
9115.
88271.
1025.
69190.
9012.
510171.
1711.
011291.
1725.
012331.
1826.
813200.
7617.
614121.
0014.
415220.
8822.
4Mean±SD22±61.
03±0.
2020.
1±6.
1APACHEIIAcutePhysiologyandChronicHealthEvaluationII,Vdvolumeofdistribution,ABWactualbodyweight,t1/2eliminationhalf-lifeEurJDrugMetabPharmacokinet(2016)41:211–218215werereportedinhealthysubjects,respectively(Matzkeetal.
1986).
Consequently,weconcludedthatthismeth-odologywaseffectiveandsuitableforallagesexceptchildren.
Incriticallyillpatientswithaninfection,thevariablefactorsrelatedtotheVdofhydrophilicantimicrobialsarecapillaryleakageduetoSIRScausedbyinammatorycytokinesandbodyuidretentionduetoorgandysfunctionsuchasheart,hepatic,orrenalfailure(RobertsandLipman2006;Petrosilloetal.
2010;Vargheseetal.
2011).
APACHEIIscoresarecalculatedfromtheAcutePhysi-ologyScoreincludingvaluesforbodytemperature,heartrate,respiratoryrate,andwhitebloodcellcount,whicharerequiredfordiagnosisofSIRS(Boneetal.
1992),aswellastheAgeScoreandtheChronicHealthScoreincludinginformationaboutorgandysfunction.
Therefore,APACHEIIscoremayreectthedegreeofcapillaryleakage,bodyuidretention,andtotalbodyclearanceofdrugsduetovariousclinicalconditions.
Wefoundsignicantcorrela-tionsbetweenAPACHEIIscoreandtheVdandt1/2ofvancomycin.
Asforrelatedfactors,patientswithhigherAPACHEIIscoreshadhigherbloodlevelsofinamma-torycytokinessuchastumornecrosisfactorandinterleu-kin-6(Damasetal.
1997),whichcauseanincreaseincapillarypermeabilityanduidshiftfromtheintravascularcompartmenttointerstitialspace(LeeandSlutsky2010),resultinginleakageofvancomycin.
Moreover,patientswithhigherAPACHEIIscoreshaveapotentialfordecreasedglomerularltrationrateduetorenalimpair-ment,thusincreasingbodyuidretentionfromedemaandvascularpermeability.
Therefore,weconcludedthatanincreaseinVdandprolongationoft1/2easilyoccurfol-lowingvancomycinadministration.
Pathophysiologicchangesduetovariousclinicalcon-ditionsleadtoalterationsintheVdofhydrophilicanti-microbialsincriticallyillpatients,makingitdifculttosetanappropriateinitialdose.
Inthepresentstudy,wefoundthattheVdandt1/2ofvancomycincouldbeestimatedbasedonAPACHEIIscore,andestablishedatheoreticalmethodologyforvancomycintherapyregardinginitialdoseandadministrationintervalinindividualpatients(Fig.
5).
y=0.
018x+0.
63r=0.
58p<0.
050.
01.
02.
03.
0010203040506070Vd/ABW(L/kg)APACHEIIscore(pt)Fig.
2RelationshipbetweenAPACHEIIscoreandVd/ABW.
APACHEIIAcutePhysiologyandChronicHealthEvaluationII,Vdvolumeofdistribution,ABWactualbodyweighty=0.
70x+4.
58r=0.
74p<0.
01010203040506070010203040506070t1/2(hr)APACHEIIscore(pt)Fig.
3RelationshipbetweenAPACHEIIscoreandt1/2.
APACHEIIAcutePhysiologyandChronicHealthEvaluationII,t1/2eliminationhalf-lifer=0.
71p<0.
01010203040010203040Observedconcentration(mg/L)Predictedconcentration(mg/L)Fig.
4Relationshipbetweenpredictedandobservedplasmaconcen-trationsofvancomycin216EurJDrugMetabPharmacokinet(2016)41:211–218Inthefuture,toconrmwhetherthismethodologyissuitable,thestudyshouldbeperformedatallages.
ConictofinterestNoneoftheauthorshasanyconictofinteresttodisclosure.
ReferencesBoneRC,BalkRA,CerraFB,DellingerRP,FeinAM,KnausWA,ScheinRM,SibbaldWJ(1992)Denitionsforsepsisandorganfailureandguidelinesfortheuseofinnovativetherapiesinsepsis.
TheACCP/SCCMConsensusConferenceCommittee.
AmericanCollegeofChestPhysicians/SocietyofCriticalCareMedicine.
Chest101:1644–1655.
doi:10.
1378/chest.
101.
6.
1644DamasP,CanivetJL,deGrooteD,VrindtsY,AlbertA,FranchimontP,LamyM(1997)Sepsisandserumcytokineconcentrations.
CritCareMed25:405–412.
doi:10.
1097/00003246-199703000-00006IbrahimEH,ShermanG,WardS,FraserVJ,KollefMH(2000)TheinuenceofinadequateantimicrobialtreatmentofbloodstreaminfectionsonpatientoutcomesintheICUsetting.
Chest118:146–155.
doi:10.
1378/chest.
118.
1.
146JoukhadarC,FrossardM,MayerBX,BrunnerM,KleinN,SiostrzonekP,EichlerHG,Mu¨llerM(2001)Impairedtargetsitepenetrationofbeta-lactamsmayaccountfortherapeuticfailureinpatientswithsepticshock.
CritCareMed29:385–391.
doi:10.
1097/00003246-200102000-00030KnausWA,DraperEA,WagnerDP,ZimmermanJE(1985)APACHEII:aseverityofdiseaseclassicationsystem.
CritCareMed13:818–829.
doi:10.
1097/00003246-198510000-00009KollefMH,ShermanG,WardS,FraserVJ(1999)Inadequateantimicrobialtreatmentofinfections:ariskfactorforhospitalmortalityamongcriticallyillpatients.
Chest115:462–474.
doi:10.
1378/chest.
115.
2.
462KumarA,RobertsD,WoodKE,LightB,ParrilloJE,SharmaS,SuppesR,FeinsteinD,ZanottiS,TaibergL,GurkaD,KumarA,CheangM(2006)Durationofhypotensionbeforeinitiationofeffectiveantimicrobialtherapyisthecriticaldeterminantofsurvivalinhumansepticshock.
CritCareMed34:1589–1596.
doi:10.
1097/01.
CCM.
0000217961.
75225.
E9LeeWL,SlutskyAS(2010)Sepsisandendothelialpermeability.
NEnglJMed363:689–691.
doi:10.
1056/NEJMcibr1007320LiuC,BayerA,CosgroveSE,DaumRS,FridkinSK,GorwitzRJ,KaplanSL,KarchmerAW,LevineDP,MurrayBE,RybakMJ,TalanDA,ChambersHF,InfectiousDiseasesSocietyofAcutePhysiologyScore:Meanarterialpressure,Bodytemperature,Heartrate,Respiratoryrate,Oxygensaturation,Hematocrit,Whitebloodcellcount,ArterialpH,Serumsodium,Serumpotassium,Serumcreatinine,GlasgowComaScoreAgeScore:AgeChronicHealthScore:Healthstatus(chronicorganinsufficiency,immunocompromised)APACHEIIscoresVd/ABW=0.
018*APACHEIIscores+0.
63t1/2=0.
70*APACHEIIscores+4.
58Vd/ABWt1/2Initialdose(mg)=Vd/ABW(L/kg)*ABW(kg)*Cpeak(mg/L)Theseconddosingwast1/2hoursafterthefirstadministration.
PatientdataFig.
5Predictedmethodforinitialvancomycindosingregimen.
APACHEIIAcutePhysiologyandChronicHealthEvaluationII,Vdvolumeofdistribution,ABWactualbodyweight,t1/2eliminationhalf-life,CpeakpeakplasmaconcentrationofvancomycinEurJDrugMetabPharmacokinet(2016)41:211–218217America(2011)ClinicalpracticeguidelinesbytheInfectiousDiseasesSocietyofAmericaforthetreatmentofmethicillin-resistantStaphylococcusaureusinfectionsinadultsandchildren.
ClinInfectDis52:e18–e55.
doi:10.
1093/cid/ciq146MatsumotoK,TakesueY,OhmagariN,MochizukiT,MikamoH,SekiM,TakakuraS,TokimatsuI,TakahashiY,KasaharaK,OkadaK,IgarashiM,KobayashiM,HamadaY,KimuraM,NishiY,TanigawaraY,KimuraT(2013)Practiceguidelinesfortherapeuticdrugmonitoringofvancomycin:aconsensusreviewoftheJapaneseSocietyofChemotherapyandtheJapaneseSocietyofTherapeuticDrugMonitoring.
JInfectChemother19:365–380.
doi:10.
1007/s10156-013-0599-4MatzkeGR,ZhanelGG,GuayDR(1986)Clinicalpharmacokineticsofvancomycin.
ClinPharmacokinet11:257–282.
doi:10.
2165/00003088-198611040-00001PatelN,PaiMP,RodvoldKA,LomaestroB,DrusanoGL,LodiseTP(2011)Vancomycin:wecan'tgettherefromhere.
ClinInfectDis52:969–974.
doi:10.
1093/cid/cir078PetrosilloN,DrapeauCM,AgraotisM,FalagasME(2010)Somecurrentissuesinthepharmacokinetics/pharmacodynamicsofantimicrobialsinintensivecare.
MinervaAnestesiol76:509–524RobertsJA,LipmanJ(2006)Antibacterialdosinginintensivecare:pharmacokinetics,degreeofdiseaseandpharmacodynamicsofsepsis.
ClinPharmacokinet45:755–773.
doi:10.
2165/00003088-200645080-00001RodvoldKA,BlumRA,FischerJH,ZokufaHZ,RotschaferJC,CrossleyKB,RiffLJ(1988)Vancomycinpharmacokineticsinpatientswithvariousdegreesofrenalfunction.
AntimicrobAgentsChemother32:848–852TacconeFS,LaterrePF,DugernierT,SpapenH,DelattreI,WitteboleX,DeBackerD,LayeuxB,WallemacqP,VincentJL,JacobsF(2010a)Insufcientb-lactamconcentrationsintheearlyphaseofseveresepsisandsepticshock.
CritCare14:R126.
doi:10.
1186/cc9091TacconeFS,LaterrePF,SpapenH,DugernierT,DelattreI,LayeuxB,DeBackerD,WitteboleX,WallemacqP,VincentJL,JacobsF(2010b)Revisitingtheloadingdoseofamikacinforpatientswithseveresepsisandsepticshock.
CritCare14:R53.
doi:10.
1186/cc8945VargheseJM,RobertsJA,LipmanJ(2011)Antimicrobialpharma-cokineticandpharmacodynamicissuesinthecriticallyillwithseveresepsisandsepticshock.
CritCareClin27:19–34.
doi:10.
1016/j.
ccc.
2010.
09.
006VincentJL,RelloJ,MarshallJ,SilvaE,AnzuetoA,MartinCD,MorenoR,LipmanJ,GomersallC,SakrY,ReinhartK,EPICIIGroupofInvestigators(2009)Internationalstudyoftheprev-alenceandoutcomesofinfectioninintensivecareunits.
JAMA302:2323–2329.
doi:10.
1001/jama.
2009.
1754218EurJDrugMetabPharmacokinet(2016)41:211–218