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PoweredbyEditorialManager®andProduXionManager®fromAriesSystemsCorporation Vancomycin Toxicityin Neonates:A Review of the Evidence LestnerJM1,Hill LF2,HeathPT2,SharlandM2 Universityof Liverpool, UK St George's, Universityof London, UK CorrespondingAuthor DrJodi Lestner Antimicrobial Pharmacodynamics &Therapeutics (APT)Group Universityof Liverpool 1.12Sherrington Buildings AshtonStreet Liverpool L693GE Tel: +44(0)1517945466 Email: [email protected] ABSTRACT Purposeof review: Vancomycinis afirst-lineagentinthe treatment ofserious Gram-positiveinfections intheneonatal population. The publishedevidenceonvancomycintoxicityin neonates is limited. This reviewsummarises pre-clinical studies andclinical trials describingvancomycintoxicity.Wediscuss proposedpathophysiologyand summariseevidencesupportingdose-response relationships, genetic and environmental determinants, andconsider futureresearchrequiredtofurtherdefine vancomycintoxicity. Recentfindings: Current dosing regimens forvancomycin result insub-therapeuticlevels in alarge proportionofpatients. Higher dailydoses havebeenproposed,whichhave ledto concerns regardingincreasedtoxicity.Nephrotoxicityoccurs in1-9%ofneonates receivingcurrentlyrecommendeddoses. Theincidenceis highest inthose receiving concomitant nephrotoxic drugs. Vancomycin-associatedototoxicityis rareinpatients ofall ages. Exposure-toxicityrelationships inrelationtonephro-andototoxicityhave not beenclearlydefinedinneonates receivingvancomycin. Summary: Current evidencesupports thefavourablesafetyprofile ofvancomycininneonates. Furtherstudies that address safetyconcerns relatingtohigh-doseintermittentdosing regimens areneeded.Suchstudies must includerobust andstandardiseddefinitions of renal andhearingimpairment,andincludefollow-upofsufficient lengthto establish thelong-term implications of experimental findings. KEYWORDS Vancomycin,toxicity, neonates, renalimpairment,hearingloss INTRODUCTION Vancomycinis a glycopeptide bactericidalantibioticthatdisrupts cell wall synthesis inGram-positivebacteria. (1) Impurities from earlyfermentationprocesses were associatedwithsignificant toxicitywhenthedrugwasfirst introducedintheearly thedisparaging thesafetyprofileofvancomycin,and Foodand DrugAdministrationapproval was grantedin1958. Despitethis, use. Inrecentdecades clinical usehas increased,however,owingtothe rising incidenceofinfectionscausedbymethicillin-resistantStaphylococcus aureus and otherresistant Gram-positivepathogens that aresusceptibletovancomycin. (2) Vancomycindosingstrategies varygreatlyandaregenerallybasedonacombination ofpost-menstrual age (PMA),post-natal age(PNA),weight and/or renal function(see table1). Therapeuticdrugmonitoring(TDM)is widelyadvocated.Currentlyclinical guidelines recommendtarget troughconcentrations of 10-15 (3,4) However, recent studies suggest the needfortarget troughlevels >15 ,basedonthe concernthat lowertroughconcentrations maybe selectiveforhetero-resistance.(5-7) In adults, higher dailydoses ofvancomycin (15mg/kg6hourly) have yet toreceive regulatoryapproval but havebeenproposedinrecentconsensus documents published bythe Infectious Diseases SocietyofAmerica, AmericanSocietyof Health-System Pharmacists, andtheSocietyof Infectious Diseases Pharmacists. (8-10) Theuseof highervancomycindoses has raisedconcerns regardingthe potentiallyincreasedrisk oftoxicity.Thesignificanceoftheseconcerns in paediatric populations is unclear. Here wesummarisethe current evidencerelatingtovancomycintoxicityincluding proposedpathophysiology, dose-toxicityrelationships, geneticandenvironmental factors and future researchneeds. Studies pertainingtovancomycin-inducedtoxicity betweenMarch1950 and March2015wereidentifiedfrom PubMed,Embase, CochraneControlledTrial Registry,andMedlinedatabases. Thefollowingsearch NEPHROTOXICITY Quantification of Nephrotoxicity Kidneyfunctionis difficult todefineinthefirst monthof lifewhenrenal physiology andfluidbalanceevolve rapidly.Serum creatinine (SCr)concentrations reflect maternal renal functioninthe first 48hours after birth.(11,12) Inaddition,preterm infants experience ariseinSCrduetotubularreabsorption,makingthis animprecise proxyfor glomerular filtration. (13)Clinical reports alsooftenomit details of the laboratorymethods used toquantifySCr(Jaffé colorimetry, enzymaticquantification, orisotopedilutionmass spectroscopy),whichcan haveaninter-test variabilityofup to25%inneonates. (14, 15)Despitetheselimitationsmost studies definerenal impairment as anincreaseinSCr. (16-19)Definitions forchildren andneonates have beenreportedbasedonseveral classifications systems, all ofwhichwereoriginally developedandvalidatedinadults. (20,21)Modifiedneonatal criteriaexcludeurine output oruseahighercut-off(<1.0mL/kg/h) inorder toaccount forthenon-oliguric renal dysfunctionthat occurs inneonates duetofluidredistributionandimpaired absorptionintheimmaturerenal tubule.(22,23) Pre-Clinical Studies Murinemodels havedemonstratedthatvancomycinhas anaffinityforbiological membranes and accumulatesinrenal tissue.(24,25)Theenergy-dependent transport mechanisms withinthe tubularepithelium render thekidneyhighlysusceptibleto toxin-induced cellularinjury. Vancomycin enhances cellularATP concentrations and stimulateoxygenconsumption,resultinginoxidativephosphorylation. (26-31) However,oxidative stress of sufficientmagnitude tocauseclinicallydetectablerenal impairment has not been demonstratedinanimals, evenatsupra-therapeuticdoses. (32)Histopathologicalchanges andbiochemical evidenceofnephrotoxicityhavebeen observedinanuninfectedmurinemodelinwhichhigh-dosevancomycin was co- administeredwithtobramycin. (25) Clinical Studies ThelinearrelationshipbetweenSCrandvancomycin exposurereflects thedrugs primaryrouteof eliminationthroughrenal excretion.As aresult,adecreaseinrenal functionfrom anycause will increaseserum vancomycinconcentrations, a fact that confounds theestablishment ofexposure-toxicityrelationships. (33)Manystudies that describevancomycin-associatednephrotoxicityareconductedinpatients otherwiseat risk of renal impairment,suchas thoserequiringintensive care and frequentlyincludethose receivingother potentiallynephrotoxic drugs (e.g. NSAIDs, diuretics andaminoglycosideantibiotics).However,irrespectiveof thedifficultyin definingcausal relationships, acutekidneyinjuryfromanycauseis associatedwitha significantlyincreasedrisk of mortality,hospital lengthofstay,andcost,evenafter adjustment forage,gender,chronickidneydisease,andco-morbidities atadmission. (34) Adult Studies Nephrotoxicityinpatients receivingvancomycin hasbeenmoresystematically reportedinadults thanin neonates and children.Thereportedincidenceof nephrotoxicityinadults receivingvancomycinis10-15%.(35) Inarecent meta- analysis, vanHal,et al.reviewedfifteenstudies inwhichvancomycinwas administeredvia intermittent infusiontoadults >18 years ofage.Randomisedtrials andobservationalstudies in whichdataonrenal functionandtroughvancomycin concentrations wereavailablewereincluded.The analysis foundtrough nephrotoxicity(OR,2.67; 95%CI,1.95-3.65),and also suggestedanincremental increaseinnephrotoxicityrisk withvancomycinadministration beyondsevendays. (36)Themajorityof reportedcases wereselfresolving,withprolongedimpairment requiringshort-term dialysis occuringin3%ofcases. Similarly, aretrospectivecohort studyof246adultsreceivingintermittent-dosingofvancomycinfordurations of>48 hours foundtoxicitytobecorrelatedwithexposure(basedondose).Patients comparedwiththosereceiving<4 gdaily(34.6% vs.10.9%; p=0.001).(18) Concomitant aminoglycosideusehas consistentlybeenshowntoincreasetherisk of nephrotoxicityinadults receivingvancomycin. In2007,Fowler, et al reporteda seminal open-label randomisedtrial of daptomycinversus either anti-staphylococcal penicillinorvancomycin plus low-dosegentamicinin236patientswith S.aureus bacteremia.Thehighest proportionofrenal impairment occurredinpatients receiving vancomycinplusgentamicin(20.4%),althoughthis was not significantlyhigherthan withpenicillinplus gentamicin(18.6%). Furthermore,thestudyfoundthatthehighest incidenceof renalimpairmentin patients receivingvancomycinoccurredlaterintreatment,peakingat 14-28days. (37) Paediatric &Neonatal Studies Vancomycinadministration withintermittentdosingandin accordancewith publishedguidancehasbeenshowntoresult insub-therapeutictroughconcentrations inuptohalfoftreatedneonates. (4)Furthermore, antimicrobial point prevalence surveys that describeprescribingpractices havedemonstratedthat significant variationinprescribingof vancomycininneonates exists inclinical practice,witha largeproportionofneonates receivingdailydoses ofvancomycinthat are significantlybelow eventhe most conservativecurrent recommendations. (38)Table 2outlines theclinicalstudiesthat havereportednephrotoxicityassociatedwith vancomycinuse inneonatesandinfants. Themajorityofstudies identified are heterogeneous observational oropportunisticpharmacokinetic studies basedon routineTDM andareinsufficientlypoweredtodetect toxicity. As withadults, casesof renal impairment aremorefrequentlyreportedinneonates andchildrenreceivingconcomitant nephrotoxic drugs. (19,35)Eight often studies describingconcomitant nephrotoxicdrugs alongsidevancomycintherapy demonstratedevidenceof renal impairment,whichwas mildandtransient inall reported cases (seetable 2). Otherreports havenot foundvancomycinto bean independent predictorof nephrotoxicity.Constance,et al,forexample,foundno significant differenceintheproportionofneonates developingnephrotoxicityinthose receivingvancomycinplus gentamicin (12/533,2.2%)versus those receiving gentamicinalone(7/533, 1.3%). Logistic regressiondemonstratedthatwhilepositive bloodculture,lowbirthweight,patentductus arteriosus,concomitant non-steroidal anti-inflammatorydrug(NSAID)use, andillness severitywereall independent risk factors fornephrotoxicity,vancomycininconjunction withgentamicinwas not.(23) Six studiesreport rates ofnephrotoxicityinneonatesreceivingvancomycin alone.A transient riseinSCr,microproteinuria,and elevatedNAGwere reportedinonlythree, twoandonepatient, respectively(seetable2).(51,54,59-61) Exposure-toxicityrelationships havenot beenclearlydefinedfor vancomycinin neonates. Two case reports havedescribedclinical outcomes infourneonates receivingaccidental overdoses ofupto10-foldthemaximumrecommendeddose. (51,59)All fourpatients developedtransient renal impairment,thoughall hadnormal renal functionat6months. It is noteworthythat thesecases all involvedsingleor briefexposures that weremanagedwithimmediatevancomycinwithdrawal,andso thesefindings donot address thepotential risk of cumulativeexposure. Anumberofrecentstudieshavedescribedthe administrationofvancomycinvia continuous infusioninneonates. Continuous infusionhas thetheoreticaladvantage of maintainingconstantplasma concentrations, meaningthat overall drugexposurecan beincreasedwithout ariseinpeakconcentrations. Studiesinvestigatingcontinuous vancomycininfusionsinneonateshave,todate,been basedonstudies defined toxicitydifferentlyandinvolvedsmall patient cohorts that receivedvaried dosing regimens. Aloadingdose of 7-15mg/kgwas givenin threestudies. Collectively,the results ofthesestudiessuggest that continuous infusion mayresult inahigher proportionofpatientsachievingtarget concentrations between15- Reportedrates ofnephrotoxicitydonot differsignificantlyfrom thoseinpatients receivingintermittent dosing,andthereis currentlyno evidencetosuggest theuseof aloadingdoseincreases therisk ofnephrotoxicity. (3,45,47,60) Continuous infusions may,however,beimpractical intheneonatalpopulationwherevenous access iflimited,andmayleadtoperiods without effectiveantibioticcover ifaccess is lost.Therehave, as yet,beennosystematicstudiescomparingthesafetyand efficacyof continuous infusionwithhigh-doseintermittentregimens that specifically OTOTOXICITY Quantification ofOtotoxicityin Neonates Theassessment ofhearingininfants is challenging. Behaviouraltests (e.g. visual reinforcement audiometry) arethe goldstandard, butcannot be performed reliablyin childrenbelow~8months. (67)Themethods currentlyemployedtoquantifyauditory functioninneonates are otoacoustic emissions (OAE)andauditorybrainstem responses (ABR).Serial diagnosticOAEandABR testinghas beenusedtomonitor ototoxicityin childrenreceivingaminoglycosides. (68-71)Thereareno equivalent reports describingserial OAEorABR followingvancomycinuse.DiagnosticOAEor ABR is labour-intensive anddifficulttointerpret inprematureinfants(PMA<34 weeks)dueto immaturityof the cochleaand centralauditorypathways (72-78). Universal newbornhearingscreening(UNHS)uses acombinationofautomatedOAE andABR,andis designedtoidentifyseverepermanent hearingimpairmentinterm neonates. Standardised UNHS programmes arenowbeingimplementedintheUSA
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