Serum levels of vancomycin: is there a prediction using doses in mg/kg/day or m2/day for neonates?

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

Serum

levels

of

vancomycin:

is

there

a

prediction

using

doses

in

mg/kg/day

or

m

2

/day

for

neonates?

Roberta

Maia

de

Castro

Romanelli

,

Lêni

Márcia

Anchieta

,

Juliana

Chaves

Abreu

Fernandes

_,

_Mariana

_Antunes

_Faria

_Lima

_,

Taís

Marina

de

Souza

_,

_Viviane

_Rosado

_,

_Wanessa

_Trindade

_Clemente

,

Paulo

Augusto

Moreira

Camargos

a_{UniversidadeFederaldeMinasGerais(UFMG),FaculdadedeMedicina,DepartamentodePediatria,BeloHorizonte,MG,Brazil} b_{UniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,ComitédeControledeInfec¸ões,BeloHorizonte,MG,Brazil} c_{UniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,UnidadeNeonataldeCuidadosProgressivos,BeloHorizonte,} MG,Brazil

d_{UniversidadeFederaldeMinasGerais(UFMG),HospitaldasClínicas,BeloHorizonte,MG,Brazil}

a

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t

i

c

l

e

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n

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o

Articlehistory:

Received29November2015 Accepted29June2016

Availableonline12August2016

Keywords:

Vancomycin

Drugdosagecalculations Pharmacokinetics Infant

Newborn Sepsis

a

b

s

t

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t

Coagulase-negativeStaphylococcushasbeenidentifiedasthemainnosocomialagentof neonatallate-onsetsepsis.However,basedonthepharmacokineticsanderraticdistribution ofvancomycin,recommendedempiricaldoseisnotideal,duetotheinappropriateserum levelsthathavebeenmeasuredinneonates.Theaimofthisstudywastoevaluateserum levelsofvancomycinusedinnewbornsandcomparethepredictionofadequateserumlevels basedondosescalculatedaccordingtomg/kg/dayandm2_{/day.Thisisanobservational}

reprospectivecohortatareferralneonatalunit,from2011to2013.Newbornstreatedwith vancomycinforthefirstepisodeoflate-onsetsepsiswereincluded.Totaldoseinmg/kg/day, dose/m2_{/day,age,weight,bodysurfaceandgestationalagewereidentifiedasindependent}

variables.Forpredictiveanalysisofadequateserumlevels,multiplelinearregressionswere performed.TheReceiverOperatingCharacteristiccurveforproperserumvancomycinlevels wasalsoobtained.Atotalof98patientsreceived169serumdosagesofthedrug,41(24.3%)of thedoseshadserumlevelsthatweredefinedasappropriate.Dosesprescribedinmg/kg/day anddose/m2_{/daypredictedserumlevelsinonly9%and4%ofcases,respectively.Statistical}

significancewasobservedwithhigherdoseswhentheserumlevelswereconsideredas appropriate(p<0.001).Adoseof27mg/kg/dayhadasensitivityof82.9%toachievecorrect serumlevelsofvancomycin.Althoughvancomycinhaserraticserumlevelsandempirical dosescannotproperlypredictthetargetlevels,highestdosesinmg/kg/daywereassociated withadequateserumlevels.

©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).

∗ _{Correspondingauthor.}

E-mailaddress:rmcromanelli@unifenas.br(R.M.Romanelli).

http://dx.doi.org/10.1016/j.bjid.2016.06.008

1413-8670/©2016SociedadeBrasileiradeInfectologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Theintroductionofnewtechnologiesinneonatalunitshas caused high nosocomial infection rates with subsequent complicationsamongnewborns.Coagulase-negative Staphy-lococcushas been identifiedasthe mainnosocomialagent, affectingmorethan 50%ofallcasesoflate-onset neonatal sepsis.1–3

Vancomycin is widely used for confirmed or suspected neonatalsepsisasaround90%ofcoagulasenegative Staphylo-coccistrainsareoxacillinandpenicillin-resistant.4,5_However,

toxicity,pharmacokineticvariabilityandempiricaldosesused fornewbornsareimportanttopicsrelatedtovancomycinuse inthispopulation.6–11 _{Measurementofareaunderthecurve}

toachieveminimuminhibitoryconcentration(MIC)against

Staphylococciisanimportantparametertotherapeuticswith thisdrug.6,7

The usual empirical dose for the neonatal population rangesfrom 10 to15mg/kg/dose,administered onetofour doses a day.1,3,5,8 _{However, studies in pediatric population}

havereportedontheneedforhigherdosesofvancomycin,up to60mg/kg/day,inordertoachievethedesiredserumlevel.6,7

Aminimumrecommended throughserum level ofatleast 5–10mcg/mLisrequiredforeffectivetherapyandfewerside effects,includingnephrotoxicity.8–10_{Higherconcentration}

tar-getsrangingfrom 15to20mcg/mLarerecommended even forchildrenwithmoresevereinfectionssuchasosteomyelitis andmeningitis.6,11

However,empiricaldoseofvancomycinisnotideal accord-ingtoinappropriateserumlevelsofthedrugthathavebeen reported in neonates in several studies.5,9,10,12,13 _Although

therehave been previous descriptions ofdose calculations based on nomograms and adjustments according to drug clearanceandthepatient’srenalfunction,5,14–17_nostudyhas

analyzeddosesthatwere prescribedaccordingtobody sur-face (m2_{/day) and the resulting serum vancomycin levels.}

Wehypothesizedthathigherserumlevelscouldbeachieved basedondosescalculatedaccordingtobodysurface.

The present study was conducted in order to evaluate serum levels of vancomycin that were used to treat late-onset sepsis in newborns and compare the prediction of adequateserumlevelsbasedondosescalculatedaccording tomg/kg/dayandm2_/day.

Material

and

methods

Design

Thisisanobservationalretrospectivecohort,reallifestudy, heldattheNeonatalProgressiveCareUnit(NPCU)ofthe Hos-pitaldas Clinicas,FederalUniversity ofMinas Gerais,from January2011toJune2013.

Inclusioncriteria

NewbornswhowereadmittedtotheNPCU,diagnosedwith HealthcareAssociatedInfections(HAI),andtreatedwith van-comycinforthefirstepisodeoflate-onsetsepsis(definedas

sepsisafter48hofage),wereincludedinthisstudyiftheyhad vancomycinleveltestedasrecommended.

Datacollection

Information was collected through prospective and active surveillanceofinfantsatriskbytrainedprofessionalsofthe HospitalInfectionControlCommission(HICC).Standardized informationabout gestationalage atdelivery,birthweight, gender,dataandcriteriafordiagnosisandtreatmentof blood-streaminfectionareroutinelyregistered.

Clinicalorlaboratory-confirmedbloodstreaminfection fol-lowed the criteria of the Agência Nacional de Vigilância (ANVISA)basedonNationalHealthcareSafetyNetworkofthe Centers for DiseasesControl and Prevention recommenda-tions.

a) Clinical Bloodstream Infection – at leastone of clinical signs(thermalinstability,apnea,bradycardia,food intoler-ance,worseningrespiratorydistress,glucoseintolerance, hemodynamic instability, and hypoactivity or lethargy) ANDalloffollowingcriteria:hemogramwiththreealtered parametersorincreasedC-Reactiveprotein;notperformed or negative blood culture; no evidence of infection at anothersite;antimicrobialtherapyinitiatedorsustained bytheattendingphysician.

b) Laboratory-confirmedbloodstreaminfection–atleastone ofclinical signs(thermal instability,apnea, bradycardia, foodintolerance,worsening respiratorydistress,glucose intolerance,hemodynamicinstabilityandhypoactivityor lethargy)notrelatedtoaninfectionatanothersiteANDat leastoneofthefollowing:

- commonskincontaminantculturedfromtwoormore bloodculturesdrawnonseparateoccasions;

- commonskin contaminant(e.g.,diphtheroids, Bacillus

sp.,Propionibacterium sp., coagulase-negative staphylo-cocci,or micrococci)cultured from atleastone blood culturefromapatientwithanintravascularline,andthe physicianinstitutesappropriateantimicrobialtherapy. Information were collected daily and systematically includedintheHICCinternalprogramforfurtheranalysis.

Mainoutcome

Vancomycin levels were alwayscollected before next dose, corresponding to through levels. Adequate serum levels of vancomycin were considered as those between 10 and 20mg/dL.Accordingtorecentstudies and consideringthat neonatalsepsisisasevereevent,levelsbelow10mg/dLwere consideredasdecreasedandinappropriatewhilethoseabove 20mg/dLweredefinedasincreasedandinappropriate.6,9,10

Statisticalanalysis

StatisticalanalysiswasperformedwiththeStatisticalPackage forSocialSciences(SPSSInc.,USA),version19.0.

Total doseinmg/kg/day, dose/m2_{/day,age,weight, body}

surfaceandgestationalageatdeliverywereindependent vari-ables in the predictive model ofadequate serum levels in

simplelinearregression.Statisticalsignificancewas consid-eredwhenp<0.05.Multiplelinearregressionwasperformed withallvariableswithp<0.05inunivariatelinearregression. Total daily doses of vancomycin was considered as proposed by previous published studies6,7,10,11,13,17 _because

neonataldosescanvaryaccordingtobirthweightand post-gestationalage.

Doseswerecomparedamonggroupsaccordingto appropri-ate(group1)andinappropriate(group2)serumlevels,using the Mann–Whitney (when variables presented non-normal distribution)ort-test(whenvariablespresentednormal dis-tribution).

TheReceiverOperatingCharacteristiccurve(ROCcurve)for properserumvancomycinlevelswasalsoobtained.

Ethicsconsiderations

ThestudywasapprovedbytheInstitutionalEthicsCommittee.

Results

Atotalof98patientswereincludedinanalysisandthemean gestationalagewas 33.52weeks(SD=4.41)and 63patients (64.3%)werepremature.Forty-eight(49%)weremaleandthe averageageatthestartofvancomycintreatmentwas18.4days (SD=16.5).

First measurement of vancomycin levels of 95 patients showedthat28(28.6%)ofthemadequatevalues,57(58.2%)had diminishedlevels(below10mg/dL)and10(10.2%)presented higherlevels(above20mg/dL).Threepatientshadtheirfirst vancomycindosemodifiedwithoutserumlevelsofthedrug.

Duringtreatment,therewereatotalof169serum measure-mentsofthedrug,withanaverageof1.72dosesperpatient. Therewere64dosemodificationsbasedontheserumlevels. Thus,theaveragenumber ofmodificationsperpatientwas 0.72(SD=0.89)withamedianof1,andvaryingfrom 1to5 times.

Amongthe169measurements,41(24.3%),112(66.3%),and 16 (9.5%) had serum levels thatwere definedas adequate, diminished,andabovethetargetvalue,respectively.

Thesimplelinearregressionmodelshowedthatdoses pre-scribed inmg/kg/day predicted serum levels inonly 9%of cases,but higherdoses presented asignificant association withhighserumvancomycinlevels(p<0.001).Dosesthatwere prescribedindose/m2_{/dayshowedsimilarresults,with}

ade-quateserumpredictioninonly4%ofcases.However,ahigher statistical association was observed between higher doses andhigherserumvancomycinlevels(p=0.014).Weight, ges-tationalage,andbodysurfacedidnotpredictadequatelythe serumlevelsinmultipleregressionanalysis(Table1).

Thediagramofdosedispersioninmg/kg/day(Fig.1)and doseinm2_{/day(Fig.2)revealedthatalthoughtherewasno}

properpredictionwithany ofthe dosesforthe calculation basis,dosesthat werecalculated inm2_{/day showedhigher}

homogeneityingraphicaldistribution.

Duringmultiplelinearregressionanalysisforthe predic-tionoftheserumlevels,onlytheprescribeddoseinmg/kg/day presentedwithstatisticallysignificantassociations(p<0.001).

Table1–Simplelinearregressionforpredictionof

adequateserumvancomycinlevels,referralNeonatal

UnitforProgressiveCare,HospitaldasClínicas/UFMG,

BeloHorizonte,Brazil,from2011to2013.

Predictivevariable R2 _{F p}

Doseinmg/kg/day 0.092 16.85 <0.001

Doseinm2_{/day 0.036 6.21 0.014}

Weight(grams) 0.051 8.99 0.003

Gestationalage(weeks) 0.039 6.78 0.01

Bodysurface(m2_{) 0.360 6.21 0.004} Postnatalage 0.002 0.41 0.525 40.00 30.00 20.00 10.00 0.00 20 40 Dose mg/kg/day V a ncom ycin ser ic le vel 60 80

Fig.1–Scatterplotdiagramofpredictioncorrelationfor adequateserumlevelsofvancomycinconsideringthetotal doseinmg/kg/day,referralNeonatalUnitforProgressive Care,HospitaldasClínicas/UFMG,BeloHorizonte,Brazil, from2011to2013. 40.00 30.00 20.00 10.00 0.00 0.00 100.00 200.00 300.00 Dose m2/day V a ncom ycin ser ic le vel 400.00 500.00 600.00

Fig.2–Scatterplotdiagramofpredictioncorrelationfor adequateserumlevelsofvancomycinconsideringthetotal dose/m2_{/day,referralNeonatalUnitforProgressiveCare,}

HospitaldasClínicas/UFMG,BeloHorizonte,Brazil,from 2011to2013.

1.0 0.8 0.6 Sensitivity Specificity 0.4 0.2 0.0 0.0 0.2 0.4 0.6 0.8 1.0

Fig.3–ReceiverOperatingCharacteristiccurve(ROCcurve) todoseinmg/kg/dayandadequateserumvancomycin, referralNeonatalUnitforProgressiveCare,Hospitaldas Clínicas/UFMG,BeloHorizonte,Brazil,from2011to2013.

Statistical differences were observed when dose in mg/kg day was compared among groups (Mann–Whitney with p<0.001) (Group 1 median=36; Group 2 median=27mg/kg/day).However,differencesbetweengroups werenotobservedwhencomparedtodose/m2_{/day(p=0.213)}

(Group1median=195.6;Group2median=194mg/m2_/day).

After excluding 16 patients with increased serum lev-els(outliers),wecomparedpatientswithlowandadequate serumlevels.Mann–Whitneyalsoshowedstatistically signif-icantdifferenceswhencomparedtototaldoseinmg/kg/day amonggroupswithadequateanddecreased(p<0.001)(Group 1median=36;Group2median=20mg/kg/day).

Statistically significant differences between the serum levelvaluesinterm(mean10.91mg/dL,SD6.88)andpreterm infants(average8.05mg/dL;DP7,46)were observed.Higher serum levels were achieved in the first group (t-test=2.52;

p=0.013).

When comparingthe valueofthe serum level achieved accordingtodaysoflife,therewerenoobserveddifferences inserumlevelsbetweennewbornsat≤7days(median9.14, SD=7.22)or>7daysoflife(mean9.16,SD=7.33;t-test=0.12 andp=0.99.1).

InFig.3,theROCcurvefordoseinmg/kg/daycorrelatedto adequateserumlevels.AnAUCof0.706wasconsideredasthe minimumforasatisfactory(95%CI0.617–0.795)result.Adose of27mg/kg/dayhadasensitivityof82.9%toachievecorrect serumlevelsofvancomycin.

Discussion

Vancomycindoses inmg/kg/day werenothighlypredictive ofadequateserumlevelsbuthigherdosesweresignificantly associatedwithadequatevancomycinserumlevels.Other ret-rospectivestudiesintheneonatalandpediatricpopulation alsoshowedpoorperformanceofempiricaltreatmentswith vancomycin,withadequatetargetlevelsof25–34%, consider-ingtroughlevelsfrom10to20mg/L.9,10,18_{Eveninstudiesthat}

consideredbaselineserumlevelsfrom5to15mg/L,suitable dosagesrangedfrom31to66%.4,12,13,18

Inthisstudy,adoseof27mg/kg/daycouldbetheminimum recommendeddosefornewborns.Althoughempirical recom-mended dosesvary from 10to15mg/kg, intervalsbetween dosesoftenvaryfromq48toq6h,achievingalowpercentage ofvancomycintargetlevels.4,10,12,18,19

Themainreasonsformonitoringthedoseofvancomycin byserumconcentrationsareformaintainingtherapeutic lev-elsandpreventingototoxicityandnephrotoxicity.8,20

Consideringthat vancomycinhasan erraticdistribution and renal elimination,the duration of actioniscrucialfor achievingandmaintainingserumlevelswhichindicatedthe needforlongerdosingintervals.Hoogetal.13_comparedthe

useof30mg/kg/dayat12-hand8-hintervals,andapercentage oftheappropriateconcentrationof95%wasachievedwhen shorterintervalswereused.Inthemodeldescribedby Dersch-Millsetal.10_{doseadjustmentsof10mg/kgevery6hourswere}

necessaryinordertoreachadequateserumlevelsin72%of cases.

Evenclinicaltrialsofcontinuousdoseinfusionindicated theneedof30mg/kg/daytoachieve75–90%ofsuitableserum levels.17,21 _Zhaoetal.15 _{preformedaprospectivestudywith}

continuous infusion ofvancomycin with doses simulation ranging from 15 to 35mg/kg/day and the authors reported 70.7%ofserumlevelsbetween15and25mg/L.

Inthepresentstudy,evenhigherdoseswereobservedin thegroupthatreachedtheappropriatelevelwithamedianof 36mg/kg/dayandamedianofonedosemodification.

In a retrospective study among pediatric patients with normalrenalfunctions,Gloveretal.22_{observedtheneedto}

modify doses at least once on average (ranging from 1to 4 times)in order toachieve adequate serum levels, which requiredupto60mg/kg/dayofvancomycin.

Dosesthatwereadministeredinm2_/daywerenot

inves-tigated inaprevious study.Althoughpredictingthe serum level wasevenlower than thatachievedbymg/kg/day, the scatterplotdiagramrevealedagreaterhomogeneityof mea-surements. Possibly larger doses are needed in mg/m2 _in

order toachieve adequate serum levels. The high percent-agesofbodywaterandextracellularspaceinnewbornslead tolowerplasmadrugsconcentrationsthatdiffuseintothese compartments.23,24_{Thus,inchildrenagedlessthantwoyears,}

hydrophilicdrugswithlowvolumeofdistributionshouldbe normalized bybody surface,25 _{and similarlyconsideredfor}

vancomycin.

Itisnoteworthythat full-termbabieshad higher serum medianlevels(10.91mg/dL)comparedtopretermnewborns but the difference was not significant when adjusting for days of postnatal life. It is known that vancomycin phar-macokinetics is affected by the immaturity of the renal functionofpreterminfantsanddrughalf-lifeandclearance are evenhigher inpreterm newbornsdue tothe high per-centageofbody water,especiallyduringthe first postnatal week.26,27

Some authors suggest dose adjustment through nomo-grams andformulae.28_{Studies investigatingthesemethods}

intheneonatalpopulationshouldconsiderthematurationof renalfunctionandvancomycinclearancefordosecalculation andadjustmentfordrugmaintenance.4,14–17,29

Dosesof up to60mg/kg/day ofvancomycin are recom-mendedforchildrenunderoneyearofagebasedonastudy thatreachedAUC/MIC>400,whichisconsideredappropriate forthetreatmentofStaphylococcusaureus.7_{Stockmannetal.}30

havealsoconsideredtargetconcentrationsofAUC/MIC>400in neonatesandobservedthelinearcorrelationbetweengreater AUCandhigherserumlevels.

Despitebeingastudywithprospectiveandactive surveil-lance,thereweredifficultiesrelatedtoinformationcollection duetonon-standardizedproceduresrelatedtoantibiotics pre-scriptionbytheclinicalstaff.Vancomycinserumlevelswere notalwaysperformedasdemandedanddosemodifications wereobservedevenwithoutmonitoring,limitingthenumber ofdrugevaluations.

Inconclusion, vancomycin haserraticserum levels and empiricaldoses calculated inmg/kg/day or m2_{/day cannot}

properly predict the target levels. Doses based in m2_/day

showedhigherhomogeneity.Besides,higherdosesbasedin mg/kg/daywereassociatedwithadequateserumlevels,even afteradjustingforgestationalage,weight,andbodysurface. Consideringthe influenceofthesevariables ondrug distri-bution,thisindicatesnecessityforhigherdoses,asatleast 30mg/kg/day,inordertoachievethetargetandtherapeutic levels.

Funding

Institutional Program for Scientific Scholarships – Federal UniversityofMinasGerais(UFMG)/Foundation forResearch SupportofMinasGeraisState(FAPEMIG)andResearch Pro-rectoryofResearch–FederalUniversityofMinasGerais.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest

Acknowledgment

TheauthorsthankPaulo HenriqueOrlandiMourão, forhis technicalassistanceintheHICCinternaldatabase.

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