brazjinfectdis2020;24(4):356–359
w w w . e l s e v ie r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Brief
communication
Comparison
of
intermittent
versus
continuous-infusion
vancomycin
for
treating
severe
patients
in
intensive
care
units
Carolina
Hikari
Yamada
a,
João
Paulo
Telles
b,c,d,
Dayana
dos
Santos
Oliveira
c,
Juliette
Cieslinski
a,d,
Victoria
Stadler
Tasca
Ribeiro
a,d,
Juliano
Gasparetto
a,c,
Felipe
Francisco
Tuon
a,c,d,∗aPontifíciaUniversidadeCatólicadoParaná,FaculdadedeMedicina,Curitiba,Paraná,PR,Brazil bACCamargoCancerCenter,SãoPaulo,SP,Brazil
cHospitalUniversitárioCajuru,Curitiba,Paraná,PR,Brazil
dPontifíciaUniversidadeCatólicadoParaná,FaculdadedeMedicina,LaboratóriodeDoenc¸asInfeccionasEmergentes,Curitiba,PR,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received4March2020 Accepted1July2020
Availableonline5August2020
Keywords:
Pharmacokinetics Vancomycin Infusion
Intensivecareunit
a
b
s
t
r
a
c
t
Purpose:Theaimofthisstudywastocomparepharmacokineticcharacteristicsbetween intermittentinfusionandcontinuousinfusionofvancomycinforcriticallyillpatients admit-tedtointensivecareunits.
Methods:Intermittenttherapywasadministeredfor60minutesandprescribedasaloading doseof30mg/kgandcontinuedwith15mg/kgq12h.Continuousinfusionwasprescribedas aloadingdoseof30mg/kgfollowedby30mg/kgonconstantinfusionpump.Bloodsamples fromvancomycinintermittentinfusiongroupwerecollected1hbeforethirddose,1h,8h and24hafterthirddoseinfusion.Bloodsamplesfromvancomycincontinuousinfusion groupwerecollected1hafterloadingdose,12h,24h,36h,and48haftercontinuousinfusion initiation.
Results:Median serum concentration of continuous infusion group at 24-hour was 23.59g/mL[14.52–28.97],whileofintermittentinfusiongroupat23-hourwas12.30g/mL [7.27–18.12] and on 25-hour was 17.58g/mL [12.5–22.5]. Medians AUC24–48h were
357.2mg.h/Land530.2mg.h/Lforintermittentinfusionandcontinuousinfusiongroups, respectively(p=0.559).
Conclusion:VancomycinCIreachedsteadystateearlier,whichguaranteedtherapeuticlevels fromthefirstdayandmadeitpossibletomanagetherapeuticdrugmonitoringfaster.
©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mailaddress:felipe.tuon@pucpr.br(F.F.Tuon).
Patientsadmittedtointensivecareunit(ICU)areunderrisk for infections by methicillin-resistant Staphylococcus aureus
(MRSA)strains1,2andvancomycincontinuestobean
impor-tant therapeutic option for Gram-positive infections.3 This
glycopolypeptideinhibitsthesecondstageofcell-wall
synthe-https://doi.org/10.1016/j.bjid.2020.07.001
1413-8670/©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
brazj infect dis.2020;24(4):356–359
357
sisofGram-positivebacteria4 andbecauseofitsareaunder
thecurve (AUC)dependentpharmacodynamics,itdoes not require a high peak level to be effective.5 Moreover,
van-comycinusageisgrowingduetoincreasingincidenceofMRSA infectionswhichisrelatedtohighmortalityrate.Therefore, vancomycinstillhasamajorroleinthetreatmentofthese infections.6
Onceit iseliminatedthroughglomerularfiltration, ther-apeutic drug monitoring (TDM) is needed to avoid the well-known vancomycin nephrotoxicity asa resultofdrug accumulationinthepresenceofrenalimpairment.Recently, Infectious Diseases Society of American (IDSA) changed recommendationstovancomycin TDMprotocol.Previously, treatment recommendation was based on trough serum concentrations and aimed between (i) 15–25g/mL for severeinfections causedbytheMRSA, suchasbacteremia, endocarditis, pneumonia,or (ii)10–15g/mL tonon-severe infections.7 Nevertheless, IDSA updated recommendations
whichnolongersupportvancomycintreatmentbasedonly ontroughlevelsandemphasizestheimportanceofBayesian softwareprogramstoindividuallyfitserumlevelsofpatient’s pharmacokineticstoachievearatio≥400betweenAUCand minimuminhibitoryconcentration(MIC).5,8Serumtarget
lev-elsofthedrugmaybeachievedwithcontinuousinfusion(CI) orintermittentinfusion(II).Valuesaboveandbelowthese con-centrationsareconsideredinadequateandneedadjustment. CIreachestargetserumlevelsfasterthanII,withlowerdaily dosesandfeweradversereactions.9Moreover,CIisconvenient
fordosageadjustmentsinceitcanbedonebymodifying infu-sionspeed,andnotbychangingdoseinterval,asitisthecase withII.10However,therearenoreportsintheliterature
show-ingdifference inpatient’soutcomes betweenbothtypesof administration.11,12
Thereareseveralpharmacodynamic(PD)parameterstobe consideredwhen prescribingvancomycin,includingtrough serumbactericidal titers,AUCandMIC.Moise-Broderetal. describedanAUC24h/MICratio>350–400relatedtobetter
clin-icalandbacteriologicaloutcomesonpatientswithpneumonia byStaphylococcusaureus.13 However,thisPDtargetisusually
extrapolatedtoothersiteofinfections,whichmustbeused cautiously.Besidesit,AUC:MIC>400with MRSAMICabove 1.5–2.0g/mLisrarelyachieved.14
Theaimofthisstudy was tocompare pharmacokinetic characteristicsbetweenIIandCIvancomycintherapyfor crit-icallyillpatientsadmittedtointensivecareunits.Thisstudy wasapprovedby theethical committeeatPUCPR(number 75526017.0.0000.0020).Informedauthorizationwasobtained fromallpatients.
Thiswas an observationalprospective study performed from January 2018 to July 2019, comparing pharmacoki-netic/pharmacodynamic parameters and clinical data of patientswithsuspectedordocumentedGram-positive infec-tionsreceivingvancomycin conventionaldose(intermittent infusion)or continuousinfusion. Treatmentregimens were prescribed atthe discretionofthemedical assistantteam. Vancomycinbloodconcentrationswerecollectedasdescribed below.
Inclusion criteria were patients admitted to Inten-sive Care Unit of Hospital Universitario Cajuru (Curitiba, Paraná, Brazil) for whom vancomycin was prescribed for
Fig.1–Serumlevelofvancomycinincriticallyillpatients treatedwithcontinuous(n=11)andintermittent(n=13) infusionofintravenousvancomycin.
presumed or documented Gram-positive infections. Exclu-sion criteria were (i) history of hypersensitivity to van-comycin, (ii) life expectancy≤48h, (iii) renal dysfunction (serum creatinine≥2.5mg/dl or estimated creatinine clear-ance≤40mL/min),(iv)age<18yearsoraninabilitytoobtain informed consent. Demographic data, including age, sex, weight,height,andinfectiousdiagnosis,werecollectedupon enrollmentinthestudy.Serumcreatininewasmeasured,and creatinineclearancewasestimatedoneachdayofthestudy. Patientswerefollowedupuntilendingvancomycintreatment. AcuteKidneyInjuryNetworkclassification(AKIN)wasusedto evaluaterenaltoxicityfrombothCIandIIvancomycingroups. Allpatientsreceivedvancomycin(ABL,Cosmópolis,Brazil) reconstitutedaccordingmanufacture’sguidelines. Intermit-tenttherapywasadministeredfor60minutesandprescribed asaloadingdoseof30mg/kgandcontinuedwith15mg/kg q12h.Continuousinfusionwasprescribedasaloadingdose of30mg/kgfollowedby30mg/kgonconstantinfusionpump. Bloodsamplesfromvancomycinintermittentinfusiongroup were collected 1hbefore thirddose, 1h,8h and24hafter thirddoseinfusion.Bloodsamplesfromvancomycin contin-uous infusion group were collected 1h after loading dose, 12h,24h,36hand48haftercontinuousinfusioninitiation, aspreviouspublishedstudies.15Allsamplesweremeasured
by Siemens Dimension Xpand Plus® HM clinical analyzer (Siemens,Munich,Germany).
Twenty-three patientswereenrolled inthis study,11 on CIgroup(63%male)and 12onIIgroup(76%male).Clinical characteristicsweresimilarbetweenCIandIIgroup(Table1). Mostfrequentsitesofinfectionwerelungs(n=12)andcentral nervoussystem(CNS)(n=4),followedbyskin/softtissue(n=3) andabdominal(n=2).
BloodsamplesfromIIgroupwerecollected23hafterfirst dose(H23)and1(H25),8(H32)and24h(H48)afterthird infu-sion.Medianserumvancomycinconcentrationswere12.30, 17.58,14.56and19.10g/mL,respectively.Bloodsamplesfrom CI group were collected 1h afterloadingdose (H1) and 12 (H12),24(H24),36(H36)and48h(H48)afterCIstarted.Median serum vancomycin concentrations were 23.91, 19.68, 23.59, 21.53and 18.28g/mL,respectively(Table1). IIandCI van-comycinAUC24–48h werecalculated (Table2).Medians[IQR]
AUC24–48h were 357.2mg.h/L [150.1–564.3] and 530.2mg.h/L
358
braz j infect dis.2020;24(4):356–359Table1–Pharmacokineticcharacteristicsofvancomycin therapy. Characteristics Continuous infusion(n=11) Intermittent infusion(n=13) VSLaH1(g/mL) 23.9(9.5–38.6) VSLH12(g/mL) 19.6(14.4–23.7) VSLH24(g/mL) 23.6(14.5–28.9) VSLH36(g/mL) 21.5(12.2–30.0) VSLH23(g/mL) 12.3(7.3–18.1) VSLH25(g/mL) 17.9(12.5–22.5) VSLH32(g/mL) 14.6(7.1–16.0) VSLH48(g/mL) 18.3(10.6–27.1) 19.1(10.3–20.5) AUC24–48h 530.2 357.2 Creatinine clearance 0–24h (mL/min)b 118.45(111.2–119.7) 125.2(121.4–127.5)
Dataarepresentedasmedians(25thto75thpercentiles).
a VSL–vancomycinserumlevel.
b Creatinine clearance calculated according to the CKD-EPI
formula.
Medianserum concentrationofCIgroupat24-hourwas 23.59g/mL[14.52–28.97],while ofII groupat 23-hourwas 12.30g/mL [7.27–18.12] and at 25-hour was 17.58g/mL [12.5–22.5]. Thus,medianserum concentrations ofIIgroup onehouraftervancomycinthirddosewerelowerthanthose ofCIgroupat24-hour,andsteadystatewasreachedfaster onCIgroup.However,therewerenosignificantdifferences onvancomycin serumlevels betweenbothinfusiongroups at48-hours [CI 18.28g/mL (10.6–27.125) vs. II 19.10g/mL (10.25–20.5).
Inthisstudy,pharmacokineticparametersofIIversusCI vancomycintherapyforcriticalillpatientsadmittedto inten-sivecareunitswereassessed.Moreover,serumlevelcurvesof 11CIpatientsand12IIpatientswerecompared.Themedian serumconcentrationsonIIgrouponehouraftervancomycin thirddosewerelowerthanthoseofCIgroupat24-hourand steadystatewasprobablyreachedfasteronCIgroup. How-ever, there were no significant differences on vancomycin serumlevelsbetweenbothinfusiongroupsat48-hours,since
atthistimesteadystatehad alreadybeenreachedonboth groups.
Differencebetweenfirst 24-hourvancomycin concentra-tions(IIvs.CI)isimportantwhenconsideringtreatingsevere ICU patients. Critical patients with renal failure may be sparedfromtoxicityduemorepredictablevancomycinAUC and benefitted from CI premature steady state attainment when compared with II. Nevertheless, patients’ outcomes didnotdifferbetweeninfusionregimens.15–17 Cataldoetal.
2011 compared both infusion regimens and found simi-lar mortality rates (CI vs. II), however, with minor renal impairmentratetoCIgroup.Therehasbeenconcernabout vancomycin nephrotoxicity since its approval and when used concomitantly with other drugs potentially nephro-toxic drugs, such as aminoglycosides, amphotericin, and acyclovir.Additionally, thecombination ofvancomycin and piperacillin-tazobactamcanresultinaugmented nephrotox-icity compared tovancomycin alone.18–20 Toxicitiesduring
vancomycin therapywithconcomitant aminoglycosidesare showninTable2.
Divergence onPktarget concentrationofvancomycin CI ispresentedonliterature.Cristallinietal.consideredvalues from20to30g/mLwhileSinetal.proposed15–25g/mL.8,21
ThetargetconcentrationaccordingourhospitalTDM proto-colwas15–25g/mL.Middle-incomeregionsmaynotafford the new IDSArecommendations ofBayesian software pro-grams to guide vancomycin treatment. However,given the importance to optimizeTDM, CI may be acheaper option once it does not require expensive softwares, but only two measures within24h to establish the AUC in agiven patient.
This study has several limitations. Few patients were includedandpatientswithrenalfailurewereexcluded. How-ever,thereisalackofdataonvancomycinCIadministration anditspharmacokineticparameters,whichareessentialsto realeffectivenessandsparingpatientsfromtoxicities.
VancomycinCIreachedsteadystateearlier,which guaran-teedtherapeuticlevelsfromthefirstdayandmadeitpossible tomanagetherapeuticdrugmonitoringfaster.Thispractice may reduce nephrotoxicityrisk and assure bothtreatment efficacyandsafety.
Table2–Clinicalcharacteristicsofpatientstreatedwithcontinuousandintermittentinfusionofintravenousvancomycin. Clinicalcharacteristics Continuousinfusion(n=11) Intermittentinfusion(n=13)
Age,median[IQR] 49[42.5–64] 49[36–64]
Male,n(%) 7(63%) 10(76%)
Weight,median[IQR] 63[62–66] 62[55.8–67]
APACHEII,median[IQR] 15[14–18.5] 17[10–21]
Lungs,n(%) 45.5(5) 53.8(7)
CentralNervousSystem,n(%) 18.2(2) 15.4(2)
Skinorsofttissue,n(%) 9.05(1) 15.4(2)
Abdominal,n(%) 18.2(2) 0
Catheterrelated,n(%) 9.02(1) 7.7(1)
Others,n(%) 0 7.7(1)
Aminoglycosidesconcomitanttherapy 9%(1) 23%(3)
Acutekidneyinjuryaftervancomycintherapya Stage1–9%(1)Stage2–0%Stage3–0% Stage1–0%Stage2–7.7%Stage3–0%
Death,n(%) 4(36%) 4(31%)
brazj infect dis.2020;24(4):356–359
359
Authorship
AllauthorsmeettheICMJEauthorshipcriteria.
Conflicts
of
interest
FelipeF.TuonisaCNPqresearcher.
Financial
support
None.
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