SerumPeakSulfamethoxazoleConcentrationsDemonstrateDifinAchievingaTarge - PDF document

1 SerumPeakSulfamethoxazoleConcentrationsD
SerumPeakSulfamethoxazoleConcentrationsDemonstrateDifinAchievingaTargetRange:ARetrospectiveCohortStudyBaoD.Dao,PharmD,JasonN.Barreto,PharmD,RobertC.Wolf,PharmDRossA.Dierkhising,MS,MatthewF.Plevak,BS,PritishK.Tosh,MDDepartmentofPharmacyServices,MayoClinic,Rochester,MinnesotaDivisionofBiomedicalStatisticsandInformatics,DepartmentofHealthSciencesResearch,MayoClinic,Rochester,Minnesota Contentslistsavailableat Addresscorrespondenceto:JasonBarreto,PharmD,DepartmentofPharmacyServices,MayoClinic,200FirstSt,SW,Rochester,MN55905.E-mailaddress:Barreto.Jason@mayo.edu(J.N.Barreto). CurrentTherapeuticResearch76(2014)104109 TMP/SMX.MortalityinTMP/SMX-treatedpatientswassimilartopreviousstudieswithahighrateofTMP/SMX-relatedadverseevents.Additionally,peakSMXconcentrations200demonstratedanassociationwithsevereadverseeffects.Despiteextensiveclinicalexperience,difcultiesremaininachiev-ingtheproposedtherapeuticSMXpeakserumconcentrationof100to150ThelimiteddatasurroundingarelationshipbetweenpeakSMXserumconcentrationsandclinicallymean-ingfuloutcomescallintoquestiontheuseofroutinetherapeuticdrugmonitoringduringhigh-doseTMP/SMXtherapy.TheuseofTMP/SMXtherapyatourinstitutionisfrequentlycoupledwiththerapeuticdrugmonitoringinanefforttoattainatargetedSMXpeakserumconcentration.OurinstitutionaldosingalgorithmhasnotbeenveriedforitsaccuracyofattainmentoftheprespeciedpeakserumSMXconcentrationgoalof100to150g/mL.ThepurposeofourstudyistocomparetheperformanceofaTMP/SMXdosingalgorithminachievingtargetedserumpeakSMXconcentrationsinhospitalizedpatientswhoreceivedther-apeuticdosesofTMP/SMX.MaterialsandMethodsEligiblepatientsThissingle-center,retrospectivecohortstudywasapprovedbytheMayoClinicInstitutionalReviewBoardandconductedatMayoClinicinRochester,Minnesota.ConsecutiveadultpatientswhoreceivedtherapeuticdosesofTMP/SMXbetweenJanuary2003andNovember2011wereevaluated.Patientswereincludediftheywereaged18yearsorolderandunderwentserumpeakSMXmonitoringduringTMP/SMXtherapy.Intravenousororaladmin-istrationwasallowedduetothenearlycompletebioavailabilityoftheoralformulations.PatientswereexcludediftheyreceivedTMP/SMXforinfectionprophylaxis,underwentTMP/SMXdesen-sitization,orhadtheserumSMXplasmaconcentrationmonitoredoutsideoftheirhospitalization.DatacollectionwaslimitedtotheearliestchronologicoccurrenceoftherapeuticTMP/SMXadmin-istrationwithconcurrenttherapeuticdrugmonitoringforthepurposesofmaintainingindependentdata.OnlytherstpeakserumSMXconcentrationwasconsideredduringthisevaluation.LaboratoryassessmentSMXserumconcentrationlevelsweredeterminedbyHPLCbyourinstitutionsClinicToxicologyandDrugMonitoringLaboratory.ThegoalpeakSMXconcentrationrangeof100to150wasdenedperourinstitutionsantimicrobialtherapyguide.SerumSMXconcentrationswereconsideredpeakconcentrationsiftheyweremeasuredbetween1and2hoursafterintravenousadministrationorbetween2and3hoursafteradministrationofanoraldoseattheonsetofsteady-stateconditions.SerumSMXconcentrationswereconsideredmodiedpeakiftheyweremeasuredwithin4hoursafterintravenousadministrationandwithin5hoursoforaladministration.Thepeakvaluesintheedpeakgroupservedassurrogatepeaklevelsintheabsenceofmultilevelsamplingandpharmacokineticestimation.Thepeakandmodiedpeakcohortswerecategorizedinto2dos-inggroupshighdoseorlowdoseaccordingtoourinstitutiondosingalgorithmfortheprespeciedsubgroupanalysis(TableIThehigh-dosegroupreceivedatotaldailydose15mg/kgactualbodyweightoftheTMPcomponent.Thelow-dosegroupreceivedatotaldailydose15mg/kgactualbodyweightoftheTMPcomponent.Thedosingintervalsrangedfromevery6hourstoevery24hours,dependingonthepatientscreatinineclearanceTableIPatientswereassessedfordosageadjustmentsbasedonestimatedcreatinineclearanceusingtheCockcroft-GaultDatacollectionClinicalanddemographicdatawereretrospectivelyabstractedfrommedicalrecordsanddividedinto3categories:demographicdata,infectiousdiseasedata,andTMP/SMXdata.Demographicdataincludedage,sex,bodyweight,serumcreatinine,estimatedcreatinineclearancecalculatedbytheCockcroft-Gaultformula,andabsence/presenceofpreexistingchronickidneydiseaseorimmunocompromisedstatusasdocumentedinelectronicmedicalrecordsbeforethedateofadmission.Additionally,chronickidneydiseasewasveriedthroughasearchforICD-9-CMandICD-10-CMdiagnosiscodesforchronickidneydisease(585andN18,respec-tively).Infectiousdiseasedataincludedsiteofinfectionandinfec-tiousorganism.Lastly,TMP/SMXdataincludedTMP/SMXstartdateandtime;TMP/SMXdose(milligramsperkilogramTMPcompo-nent);andinterval,date,time,andvalueofpeakserumpeakSMXconcentration.TheprimaryoutcomemeasuredwasthefrequencyofserumpeakSMXconcentrationwithinthedenedgoalof100to150g/mL.StatisticalanalysisVaria

2 blesweresummarizedasmedian(rangeorinterq
blesweresummarizedasmedian(rangeorinterquartilerange)orfrequency(%),asappropriate.Baselinecomparisonsbetweenhigh-andlow-dosegroupsweredoneusingtheWil-coxonrank-sumtestforcontinuousvariablesorPearsontestfordiscretevariables.Toadjustforpossiblecovariateimbalancebetweenthehigh-andlow-dosegroups,propensityscoresoftheprobabilityofreceivingahighdosewerecomputedforeachpatientusingamultivariablelogisticregressionmodelthatincludedvariablesforchronickidneydisease,dialysis,immuno-compromisedstatus,intensivecareunitadmission,pulmonarydiagnosis,identiedinfectiousorganism(eg,Stenotrophomonasmaltophilia,Pneumocystisjiroveci,Nocardia,Staphylococcusorpolymicrobial),bodymassindex(BMI),andcreatinineclear-TheassociationbetweendosinggroupandtheoutcomeoftheSMXlevelbeingwithinthetherapeuticrangewasmeasuredusing4differentlogisticregressionmodels:includingonlythedosegroupasapredictor(unadjustedmodel),includingthedosegroupandallthevariablesthatwentintothepropensityscorecomputation(standardcovariateadjustmentmodel),includingthedosegroupandthepropensityscoreasacovariate(propensityscorecovariateadjustmentmodel),andmodelstratiedbypro-pensityscorequintilegroupswithapredictorofdosegroup(propensityscorestratiedmodel).Models2through4adjustforthecovariates,butindifferentways.Model1isprovidedfor TableITrimethoprim/sulfamethoxazoledosingalgorithm.CreatinineclearanceHighdoseLowdose30mL/min20mg/kg/din4divideddoses15mg/kg/din4divideddoses30mL/min10mg/kg/24hin2divideddoses7mg/kg/24hdividedq12hDosebasedontrimethoprimcomponent.PatientsreceivingdialysiswererecommendedtoreceivethedoseindicatedforpatientswithCrCl30ml/minwiththedosescheduledafterdialysisondialysisdays.B.D.Daoetal./CurrentTherapeuticResearch76(2014)104109105 comparisontoassessthelevelofcovariateadjustment.Anoddsratiowith95%CIforbeinginrange,comparingthehigh-andlow-dosegroups,isprovidedforeachmodel.These4modelsaretfor2differentcohorts.TherstcohortconsistedofpatientswithSMXlevelsthatweremeasuredduringthepurepeakperiod.ThesecondcohortincludedpatientswhohadaSMXlevelmeasuredduringthepurepeakperiodorthemodiedpeakperiod.ResultsOnethousandfourhundredsixty-threeindividualserumSMXconcentrationswererecordedfrom686patientsbetweenJanuary2003andNovember2011.Ofthese,atotalof381patientsmetourinclusionandexclusioncriteria(Figure1).Fromthe381patients,76patientswereexcludedbecausetheserumSMXconcentrationwastakenoutsidethemodiedpeakwindow,leaving305patientsforanalysisinthemodiedpeakgroupand119patientsforanalysisinthepeakgroup(Figure1PeakgroupThepeakgroupconsistedof119patientswith82patientsinthelow-dosegroupand37patientsinthehigh-dosegroup.BaselinecharacteristicsofthepeakcohortareshowninTableIITableIII.Themedianagewas65.2years(interquartilerange74.9years)andthemajority(90%)wereimmunocompro-mised.Mostpatientsexperiencedapulmonaryinfection(70%)Stenotrophomonasmaltophilia(32%)andPneumocystiscarinii(36%)asthepredominantcausativeorganisms.Baselinecharacter-isticsweresimilarbetweenpatientswhencomparingthelow-andhigh-dosegroupsexceptforBMIandtypeofinfection.Thelow-dosegroupmemberswerefoundtohaveahighermedianBMIcomparedwithmembersofthehigh-dosegroup(25.3vs23.0,respectively;0.01).Overall,28.6%ofpatientswerefoundtobewithinthether-apeuticrangeontherstpeakSMXconcentration.Fortheremainingpatients,27.7%werebelowthetargetand43.7%wereabovethetarget.ThemedianSMXconcentrationwas144(range471g/mL).MediantimefromthestartofTMP/SMXtherapytotherstlevelwas2days(range32days).Thelow-dosegrouphad32%ofpatientswithinthetherapeuticrange,whereasthehigh-dosegrouphad22%ofpatientswithinthetargetrange(TableIV).Inthepeakcohort,31.5%ofthosereceivingoraldosing(23outof73patients)wereinrangecomparedwith23.9%ofthosereceivingintravenousdosing(11outof46patients)0.37byPearsontest).Thepropensityscoreanalysisrevealednostatisticaldifferencesbetweenthe2dosinggroupsinregardtotherapeuticconcentrationrangeattainment.Compar-isonofthedosinggroupsshowedconsistentresultsacrossallthemultiplepropensityscoremodels(TableVedpeakgroupThemodiedpeakgroupconsistedof305patientswith195categorizedasreceivingalowdoseand110asreceivingahighdose(Figure1).Themedianagewithinthecohortwas63.6years.Comparisonofthebaselinecharacteristicsbetweenthe2dosingarmsshowedstatisticallysignicanthigherfrequenciesofpatientswithdiabetes(0.0014)andpatientsundergoingdialysis0.033)inthelow-dosegroup(TableII).Additionally,thelowdosegrouphadahigherBMIcomparedwiththehigh-dosegroup(0.0355).Thehigh-dosegroupwascharacterizedbymoreimmunocompromisedpatients(0.0005)andmorepatientswithhighercreatinineclearance(0.0010).Theattainmentinthemodiedpeakgrouphad26%ofpatientswithinthetherapeuticrangeontherstpeakSMXconcentra

3 tion.Theremainingpatientswerefoundtobebe
tion.Theremainingpatientswerefoundtobebelowthetarget29%ofthetimeandabovethetarget46%ofthetime.Ahigherproportionofpatientswithinthelow-dosegroupwasinthetherapeuticrange(28%)comparedwiththehigh-dosegroup(22%).ThemodipeakcohorthadamedianpeakSMXconcentrationof144(range471g/mL).MediantimefromthestartofTMP/SMXtherapytotherstlevelinthemodiedpeakcohortwas2days(range32days).Inthemodiedpeakcohort,27.6%ofthosereceivingoraldosing(34outof123patients)wereinrangecomparedwith24.2%ofthose(44outof182patients)receivingintravenousdosing(0.50byPearsontest).Thepropensityscorematchinganalysesdemonstratednodifferenceintherapeu-ticattainmentbetweenthe2dosingarms(TableV).Theresultswereunchangedregardlessofthemethod.TMP/SMXisacommonlyprescribedantimicrobialagentforthetreatmentofmanydifferentinfections.OurinstitutioncommonlypairsTMP/SMXwiththerapeuticdrugmonitoringforseriousinfectionssuchasStenotrophomonasmaltophiliaPneumocystisjiroveci,andNocardiaspp.Theresultsofourstudydemonstratethatourinstitutionsdosingalgorithmwasunsuitabletoattainthesuggestedgoaltherapeuticrangeforthemajorityofpatients(71.4%)inthepeakcohort.Additionally,peakSMXconcentrationsexhibitedhighvariabilitydespiteweight-baseddosingadjustedforrenalfunctionwherebyamajorityoftheresultsinthepeakcohort(44%)wereabovethetarget. Patients with a sulfamethoxazole concentration drawn during TMP/SMX(n = 686) ExcludedInsufficient data (n = 145) Outpatient status (n = 96)TMP/SMX as prophylaxis (n = 48)Age ()Desensitization required (n = 1) Modified peak group(n = 305) High dose modified peak group(n = 110) Low dose modified peak group(n = 195) Peak group(n = 119) Low dose peak group(n = 82) High dose peak group(n = 39) ExcludedOutside peak timeframe (n = 186) Figure1.Consortdiagram.TMP/SMXtrimethoprim/sulfamethoxazole.B.D.Daoetal./CurrentTherapeuticResearch76(2014)104109106 DelaysofobtainingappropriatelytimedserumpeakSMXconcentrationsmaybeunavoidableinclinicalpractice.Therearenumerousclinicalsituations,suchasproceduresorimagingstudies,thatmayimpedethepropertimingoflaboratoryserumdraws.Forthisreason,wefurtherdescribedamodiedpeakcohorttoaccountforvaryingclinicalsituationsandthetimeframeforpeakserumSMXconcentrationwasextendedtowithin4hoursafterintravenousadministrationandwithin5hoursafteroraladministration.Theextensionofthepeaktimewindowwasperformedtobetterrepresentrealclinicalpractice.RegardlessoftheallowedtimeframeofserumpeakSMXconcentrationquanti-cation,the2dosingregimensweevaluateddidnothaveanycantinuenceontherateoftargetrangeattainment.Themodiedpeakcohortwasconsistentinresultsreturningabovethetargetrange(46%).Interestingly,thelow-dosegroupdidshowatrendofhighertendencytoachievethetargetrangebutthiswasnotfoundtobestatisticallysignicantinallofthepropensityscoremodels.Theresultswereconsistentacrosstheunadjustedandadjustedpropen-sityscoremodels,strengtheningtheresultofnosignicantdiffer-encebetweenthehigh-andlow-dosegroupsforattainmentoftherapeuticpeakSMXconcentrations.Despitenoapparentdiffer-enceinattainmentrates,thepurepeakandmodiedpeakcohortshad44%and46%ofpatientswithabove-targetSMXpeakconcen-trations,respectively.Thismayindicatethatthedosingalgorithmisoverlyaggressiveinregardtoobtainingagoal-directedrange. TableIIBaselinedemographiccharacteristics.CharacteristicPeak(n119)Modiedpeak(nTotalLow-dose37)TotalLow-dose195)110)Malegender82(68.9)55(67.1)27(73.0)0.52208(68.2)134(68.7)74(67.3)0.7965.2(53.874.0)64.5(53.874.1)68.2(54.872.8)0.9163.6(49.872.6)64.6(53.574.1)60.7(45.569.4)0.0067White102(85.7)71(86.6)31(83.8)0.6860260(85.2)167(85.6)93(84.5)0.7956Hispanic2(1.7)2(2.4)0(0)4(1.3)4(2.1)0(0)AfricanAmerican1(0.8)1(1.2)0(0)2(0.7)2(1.0)0(0)cIslander0(0)0(0)0(0)2(0.7)0(0)2(1.8)NativeAmerican0(0)0(0)0(0)1(0.3)1(0.5)0(0)Other/notreported14(11.8)8(9.8)6(16.2)36(11.8)21(10.8)15(13.6)Weight(kg)74.0(63.385.8)75.1(65.887.7)71.5(60.479.8)0.05875.4(63.488.1)74.8(64.690.0)73.3(61.184.5)0.087Bodymassindex24.8(21.527.9)25.3(22.029.7)23.0(20.325.1)0.01125.0(21.929.2)25.4(22.730.1)24.6(21.527.9)0.036Creatinineclearance68.4(44.997.6)65.3(37.595.9)78.5(52.0106.8)0.06569.8(46.3103.3)64.1(39.694.1)78.0(53.2110.5)0.001Chronickidneydisease25(21.0)17(20.7)8(21.6)0.9162(20.3)42(21.5)20(18.3)0.48Dialysis17(14.3)15(18.3)2(5.4)0.06342(13.8)33(16.9)9(8.2)0.033Hemodialysis11(9.2)11(13.4)0(0)27(8.9)22(11.3)5(4.5)Continuousvenovenous6(5.0)4(4.9)2(5.4)15(4.9)11(5.6)4(3.6)30(25.2)24(29.3)6(16.2)0.1370(23.0)56(28.7)14(12.7)0.0014107(89.9)71(86.6)36(97.3)0.073267(87.5)161(82.6)106(96.4)0.0005Valuesaregivenasn(%).Valuesaregivenasmedian(interquartilerange).Valuesaregivenasmedian(mL/min). TableIIIMicrobiologycharacteristics.Characteris

4 ticPeak(n119)Modiedpeak(nTotalLow-dose(n
ticPeak(n119)Modiedpeak(nTotalLow-dose(n82)High-dose(n37)TotalLow-dose(n195)High-dose(n110)SiteofinfectionN/AN/ACentralnervoussystem1(0.8)1(1.2)0(0.0)2(0.7)2(1.0)0(0.0)Intra-abdominal6(5.0)5(6.1)1(2.7)11(3.6)10(5.1)1(0.9)Pulmonary83(69.7)55(67.1)28(75.7)194(63.6)120(61.5)74(67.3)Bone5(4.2)4(4.9)1(2.7)9(3.0)8(4.1)1(0.9)Skin,softtissue1(0.8)1(1.2)0(0.0)8(2.6)8(4.1)0(0.0)Urine1(0.8)1(1.2)0(0.0)1(0.3)1(0.5)0(0.0)Bloodstream6(5.0)4(4.9)2(5.4)23(7.5)15(7.7)8(7.3)Empirictherapy15(12.6)10(12.2)5(13.5)54(17.7)29(14.9)25(22.7)Multifocalinfection1(0.8)1(1.2)0(0.0)3(1.0)2(1.0)1(0.9)0.00020.0001Stenotrophomonasmaltophilia40(33.6)32(39.0)8(21.6)104(34.1)88(45.1)16(14.5)Pneumocystis(carinii)jiroveci43(36.1)20(24.4)23(62.2)108(35.4)47(24.1)61(55.5)Empirictherapy15(12.6)10(12.2)5(13.5)53(17.4)28(14.4)25(22.7)21(17.6)20(24.4)1(2.7)40(13.1)32(16.4)8(7.3)N/A,notapplicable.Valuesaregivenasn(%).OtherorganismsincludeStaphylococcusspp:methicillin-sensitiveStaphylococcusaureus(peakn1,modiedpeaknStaphylococcusaureus(peakn1,modiedpeakn,Staphylococcusepidermidis(peakn1,modiedpeakn2)andNocardiaspp(peakn12,modiedpeakn21).Basedonthecombinationofallorganismgroupswithineachcohort.B.D.Daoetal./CurrentTherapeuticResearch76(2014)104109107 OurstudysupportspreviousclinicalandpharmacokineticstudiesthathaveshownhighinterindividualvariabilityofSMXinregardtoplasmaconcentrations.ThepeakSMXconcentra-tionsinourstudyaresimilartoserumlevelsofSMXreportedinotherclinicalstudies.RemarkableinterpatientvariabilitywasshownbyBlaseretalinastudyofhigh-doseTMP/SMXinPCPpneumoniawhereTMP/SMXwasdosedat15to22mg/kg/doftheTMPcomponentandresultedinamedianpeakSMXconcentrationof198g/mLwithmultiplepatientsfoundtohaveconcentrations300g/mL.Manystudieshaveattemptedtoestablisharelation-shipbetweenTMP/SMXdoseandresultantserumconcentrationwithoutsuccess;however,thesestudieswerelimitedbysmallsamplesize.Highvariabilityhasbeenseendespitecon-trolledadministrationandweight-specicdosingwithoutacor-relationtoTMP,SMX,orN-acetyl-SMX.Anotherstudyshowednocorrelationbetweenserumcreatinineandplasmaconcentrations.Asarenallyeliminatedantimicrobialagent,evensubclinicalchangesinglomerularltrationrate(GFR)maysignicantlyaltertheplasmaconcentrationsofTMP/SMX.Unfortunately,clinicallyapplicablebedsidesurrogatesofrenalfunctionincompletelyecttrueGFR.Serumcreatinineinspecicisaffectedbyage,sex,race,andhabitus.Furthermore,TMPitselfaltersserumcreatinineconcentrations(thereforealteringcreatinineclearance)independentofchangingtrueGFR.Drug-inducedinhibitionoftherenaltubularsecretionofcreatinineresultsinanarticialincreaseinserumcreatinineconcentrationsandanunderestimationoftrueGFRbycreatinineclearance.Lastly,recentevidencesuggeststhatcontemporarymethodsofrenalreplacementsubstantiallyremovesTMP/SMX,leadingtobelow-targetSMXconcentrationsandapotentialneedforreviseddosinginthispopulation.thepeakcohort,16.7%werewithinrangewhilereceivinghemo-dialysis,whereas27.3%achievedthetargetrangewhilereceivingcontinuousvenovenoushemoltration.Inthemodiedpeakcohort,20%wereinrangewhilereceivinghemodialysis,whereas22.2%wereinrangewhilereceivingcontinuousvenovenousltration.Unfortunately,thenumbersofpatientsreceivingdialysisweretoofewtoallowanyinferencesaboutbeinginrangewithindialysissubgroups.Allofthesefactorslikelycontributetothechallengesofaccuraterenalfunctioninterpretationinthesepatientsandthesignicantinterindividualvariabilitynotedinourstudy.ChinetalfoundsimilarattainmentratesintheirinvestigationoftheinuenceofmonitoringserumTMP/SMXconcentrationsinpatientswithPCPpneumonia.TMP/SMXwasdosedat20mg/kg/doftheTMPcomponentwithanintendedgoalpeakSMXconcen-trationrangeof150to200g/mL.Doseadjustmentswereperformedintheinterventionarmtoimprovethetherapeuticrangeattainment;however,researchersdemonstratedthatonly28%ofSMXconcentrationsinthedose-adjustmentgroupwerewithinthetherapeuticrangecomparedwith32%withoutadjust-ment.Despitethehigherestablishedtargettherapeuticrange,theresultsweresimilartoourstudysattainmentof26%withinthetherapeuticrange.Thereareanumberoflimitationstoourstudy.Firstisthepotentialforselectionbiasgiventhesingle-center,retrospectivenatureofourstudydesign.Ourpatientpopulationconsistedofamajorityofwhite,malepatients.Theenrollmentofpatientsconsecutivelyduringthestudyperiodandimplementationofthepropensityscorematchingmethodwereourattempttominimizetheeffectsofconfoundingvariableswhencomparingthelow-andhigh-dosegroups.ThepeakSMXconcentrationsfrombothoralandintravenousadministrationwerecombinedforanalysis,whichmayleadtodifcultiesininterpretation.PeakSMXconcentrationswerecombinedfrom2differentroutesofadministrationbecauseoforaladministrationre

5 sultsinalmostcompleteabsorption.Analysis
sultsinalmostcompleteabsorption.Analysisdemonstratedsimilardistributionoflevelsbetweendifferentroutesofadministration.Further,therewasnostatisticaldifferenceintargetconcentrationattainmentwhencomparingtheintravenousversusoralroute(24%and27%,respectively).Third,therapeuticdrugmonitoringofserumpeakSMXlevelsareobtainedatthephysiciansandpharmacistsdiscretionasopposedtofollowingastandardizedalgorithm;however,themediantimeof2daysofadministrationbeforeconcentrationquantiensuredthatSMXlevelsweredrawnatsteadystateconcentra-tions.Thepotentialfordrugaccumulationafterthetimeatwhichsteadystateoccursmayaugmentthealreadyhighpercentageofpatientsintheabove-targetclassicationandmakeouranalysisanoverestimationofpatientswithinthetargetrange.DailyprocessingandreportingofserumpeakSMXconcentrationsbyourinstitutionslaboratoryallowsdoseadjustmentstooccurinatimelyfashionifnecessary;however,routinelaboratorymonitor-ingisnotavailableinallinstitutionssoreal-timelaboratoryassessmentmaybeachallenge.Toourknowledge,thisstudyrepresentsthelargestreportedsampletodateofTMP/SMXmonitoring.ThisstudyaddstotheliteratureontherapeuticdrugmonitoringofSMXcurrentlycen-teredonPneumocystisjirovecipneumoniatreatmentandprovidesarobustsetofpatientsusingtherapeuticdrugmonitoringofpeakSMXconcentrationsforvariousinfectionsrequiringTMP/SMXtherapy.Inaddition,includingamodiedpeakcohortallowsourresultstobeapplicabletoroutineclinicalpractice.Clinicalout-comeswerenotassessedinourstudy,butourresultsestablishafoundationtosupportfurtherassessmentoftheinuenceofSMXconcentrationsontheefcacyandsafetyofthehighdoses TableVLogisticregressionmodelscomparingthehigh-tolow-dosegroupsfortherapeuticCohortOddsratio(95%CI)PeakcohortStatisticalmodelUnadjusted0.594(0.2391.477)Standardcovariateadjustment0.864(0.282Propensityscorecovariateadjustment0.852(0.285Propensityscorestratied0.793(0.2680.68edpeakcohortUnadjusted0.729(0.4201.264)Standardcovariateadjustment0.681(0.3581.293)Propensityscorecovariateadjustment0.650(0.3481.212)0.18Propensityscorestratied0.67(0.3631.263) TableIVTherapeuticattainment.ValueofpeaksulfamethoxazolePeakcohortModiedpeakcohortOverall(n119)Lowdose(n82)Highdose(n37)Overall(n305)Lowdose(n195)Highdose(n110)Belowtarget(100g/mL)33(27.7)32(39.0)1(2.7)91(28.8)85(43.6)6(5.5)Target(100-150g/mL)34(28.6)26(31.7)8(21.6)75(25.6)52(26.7)23(20.9)Abovetarget(150g/mL)52(43.7)24(29.3)28(75.7)139(45.6)58(29.7)81(73.6)Valuesaregivenasn(%).B.D.Daoetal./CurrentTherapeuticResearch76(2014)104109108 ofTMP/SMXtypicallyusedasinfectiontreatment.GiventheheterogeneityoftheindicationsforusingTMP/SMXtreatmentandthelowattainmentratesofgoal-directedtherapeuticSMXconcentrations,furtherprospective,randomizedstudiesareneededtoelucidatetheoptimaldoseofTMP/SMX,furtherdetheidealgoaltherapeuticrangesforNocardiasppandStenotro-phomonasmaltophiliainfections,andinvestigatetheassociationofpeakSMXconcentrationandclinicaloutcomes.PeakSMXconcentrationsdemonstratewidevariability,result-inginlowoverallattainmentofintendedtargetconcentrationranges.Therewasnodifferenceinattainmentbetweenthelow-andhigh-dosecohorts.Therapeuticrangeattainmentrateswerepoorregardlessofadministrationofhigh-orlow-doseTMP/SMX.Higherproportionsofpatientshadanabove-targetSMXpeak,whichmaybeanindicationthatthedosingalgorithmisoverlyaggressiveinregardtoobtainingthetherapeuticgoal.ThewidetherapeuticindexofTMP/SMXcoupledwiththebroadrangeofresultantserumconcentrationsmakestargetedtherapydifandofquestionablenecessity.FurtherinvestigationintotheassociationbetweenpeakSMXconcentrationmonitoringandclinicallymeaningfuloutcomes,includingtreatmentresponseandadverseeffects,shouldbeconductedinlarger,prospectiveclinicaltrialswithamorediversepatientpopulation.AcknowledgmentsThereisnofundingtodisclosenoranyacknowledgments.AuthorContributions:BDDaoparticipatedinconceptandstudydesign,datacollectionanddataanalysis/interpretation,andmanuscriptcreationinvolvingcriticalwritingandrevisingoftheintellectualcontent.JNBarretoparticipatedinconceptandstudydesign,datacollectionanddataanalysis/interpretation,andmanuscriptcreationinvolvingcriticalwritingandrevisingoftheintellectualcontent.RCWolfparticipatedinconceptandstudydesign,dataanalysis/interpretation,andmanuscriptcreationinvolvingcriticalwritingandrevisingoftheintellectualcontent.RADierkhisingparticipatedinstudydesign,dataanalysis/inter-pretation,andmanuscriptcreationinvolvingcriticalwritingandrevisingoftheintellectualcontent.MFPlevakparticipatedinstudydesign,dataanalysis/interpretation,andmanuscriptcreationinvolvingcriticalwritingandrevisingoftheintellectualcontent.PritishK.Toshparticipatedinconceptandstudydesign,dataanalys

6 is/interpretation,andmanuscriptcreationi
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