J. Pediatr. (Rio J.) vol.92 número5

JPediatr(RioJ).2016;92(5):432---435

www.jped.com.br

EDITORIAL

Empiric

therapy

with

vancomycin

in

the

neonatal

intensive

care

unit:

let’s

‘‘get

smart’’

globally!

夽

,

夽夽

Terapia

empírica

com

vancomicina

na

unidade

de

terapia

intensiva

neonatal:

vamos

‘‘ficar

espertos’’

globalmente!

Pablo

J.

Sánchez

,

Mohannad

Moallem

,

Joseph

B.

Cantey

,

Avante

Milton

,

Ian

C.

Michelow

a_{CenterforPerinatalResearch,DivisionofNeonatology,Columbus,UnitedStates}

b_{TheOhioStateUniversityCollegeofMedicine,NationwideChildren’sHospital,Columbus,UnitedStates} c_{TexasA&MHealthScienceCenterCollegeofMedicine,BaylorScott&White,Temple,UnitedStates} d_{RhodeIslandHospital,Providence,UnitedStates}

e_{AlpertMedicalSchoolofBrownUniversity,Providence,UnitedStates}

Coagulase-negativestaphylococci(CoNS) remain the most common organisms causing late-onset bloodstream infec-tions(BSIs)amongpreterminfantsintheneonatalintensive care unit(NICU).1---4 _{Since the vast majority,if notall, of}

CoNSisolatesareresistanttobeta-lactamagents,including thepenicillinase-resistantpenicillins, vancomycinremains the drug of choice for proven infections. When CoNS emerged in the 1980s as the most frequently detected pathogen among preterm infants in the NICU,5 _many

neonatologists and pediatric infectious disease special-ists,includingoneoftheauthors(PJS),recommendedthe empiricuseofvancomycinalongwithanaminoglycosidefor suspectedlate-onsetsepsis.Thebasisforthisapproach con-formedtothetraditionalinfectiousdiseasesdogmathatone

DOIoforiginalarticle:

http://dx.doi.org/10.1016/j.jped.2016.01.008

夽

Pleasecitethisarticleas:SánchezPJ,MoallemM,CanteyJB, Milton A, Michelow IC. Empiric therapy with vancomycin inthe neonatalintensivecareunit:let’s‘‘getsmart’’globally!JPediatr (RioJ).2016;92:432---5.

夽夽

SeepaperbyRomanellietal.inpages472---8.

∗_{Correspondingauthor.}

E-mail:pablo.sanchez@nationwidechildrens.org(P.J.Sánchez).

shouldcoverthemostcommonorganismsaspartofempiric therapy.

With the emergence of vancomycin resistance among methicillin-resistant Staphylococcus aureus (MRSA)6 _and

Enterococcus faeciumisolates,7 _{and itsknownassociation}

with previous vancomycin use,8 _{it became imperative to}

considerthe publichealth of our NICUsanddecrease the usage of vancomycin. Outbreaks of vancomycin-resistant

Enterococcialongwithreportsofreducedvancomycin sus-ceptibility among methicillin-resistant CoNS in the NICU addedtotheemergentsituation.9---12_{SeveralstudiesinNorth}

AmericaandEuropedemonstratedthatvancomycin reduc-tion could be accomplished safely and without changes in mortality, duration of bacteremia, or complications attributabletolate-onsetsepsis.13---18_Now,dataare

emerg-ingfromLatin Americathatsuchanapproachworksthere aswell!19,20_{InBrazil,Bentlinetal.}20 _{surveyedthe16}

cen-tersoftheBrazilianNeonatalResearchNetworkonpractices relatedtolate-onset sepsis,andthecenter withthe low-estincidenceoflate-onsetsepsisusedempirictherapywith oxacillinandanaminoglycoside.

Neonatologists are among the single largest users of vancomycin, and much of this use is inappropriate.2,21---23

However,mostantibioticusage intheNICU isactuallyfor empirictherapy.24_{Therefore,anystrategytoreduceoverall}

http://dx.doi.org/10.1016/j.jped.2016.06.001

Empirictherapywithvancomycinintheneonatalintensivecareunit 433

vancomycinusagemusttargetinitiationandnotjust discon-tinuationoftherapywhenculturesdonotyieldapathogen susceptible only tovancomycin. Romanelli etal.19 _{are to}

becommendedforpursuingthismuch-neededinvestigation andworthygoal!

As others before them have shown, Romanelli et al.19

havedemonstratedthatonecansafelyreducetheempiric useofvancomycininvery-low-birth-weightinfants(VLBW; birth weight <1500g). In an NICU with a high prevalence of CoNS andlow rate of MRSA disease, the authors com-pared healthcare-associated infections (HAI) among high riskinfants (VLBW, presenceofacentral venouscatheter, use of mechanical ventilation, surgery, and treatment with an antimicrobial agent) during a period (January 2011---December 2012) when vancomycin was used for empiric therapy for possible late-onset sepsis (>48 hours ofage)withasubsequentperiod(January2013---December 2014),whenoxacillinwasthepreferredagent.Theirintent wastocomparethebacteriologyofHAIsthatoccurred dur-ingthetwoperiods,andimportantly,measuresuchsafety outcomesasmortality.Amongthe1229infantsenrolled dur-ingthestudyperiod,367(30%)had538HAIepisodes,and thetotalnumberofHAIswasreducedsignificantlyduringthe oxacillintreatmentperiod.Alsounexpectedly,andpossibly duetoaHawthorneeffect,therewasasignificantreduction inHAIsduetoS.aureus,withallbutoneisolate suscepti-ble tomethicillin (during the empiric oxacillintreatment period). Therewasa concomitantincrease inHAIs dueto CoNSduringtheoxacillinperiod,soitisnotunexpectedthat theduration oftreatment withoxacillindecreased during thesecondperiod(mediantime,11.5tosixdays),while van-comycinuseincreasedfromamedianofeighttoninedays. Unfortunately,theauthorsdidnotprovidethedaysof ther-apyper 1000patientdaysfor oxacillinandvancomycinin ordertodocumenttheiractualusageandtheeffectthatthe changeinguidelinehadonoveralluse,nordidtheyprovide informationonthe actualmanagement ofthese infants ---howmanybloodcultureswereperformed?Thepracticeof obtaining twoblood culturesfromdifferentsites helpsto distinguishpathogensfromcontaminants,sincetheisolation ofCoNSfromjustoneoftwobloodculturesshouldbe con-sideredascontaminationandnotbetreatedwithprolonged vancomycin therapy. Moreover,if a blood culture yielded CoNS,wasa repeatcultureperformed beforechangingto vancomycin?Methicillin-resistantCoNS,isolatedfroma sin-glebloodcultureinaninfantwhoreceivedempiricoxacillin therapy, should be considered a contaminant if a repeat blood culture before switching to vancomycin is sterile. Suchpracticescanleadtoafurtherdecreaseinvancomycin usageinNICUs.Finally,theauthorsdidnotprovide informa-tionon whatwasused for empiriccoverage of suspected Gram-negative infection. It is known that such coverage cansignificantlyimpactthetypesofmicroorganisms respon-sible for neonatal sepsis and their antibiotic resistance patterns.16

The authors also report no change in BSIs due to fungi or Gram-negative organisms.19 _{The latter finding}

is of interest given the increase in Gram-negative BSIs in many NICUs in the United States --- infections that tend to be of higher virulence25 _{and more resistant to}

usualantimicrobialtherapy.Ofnote,previousstudies,one in children26 _{and others in the NICU setting,}27---29 _have

associatedprior vancomycinexposure withlater develop-mentofGram-negativeBSIs.Itmaybethatinthecurrent report19 _{the sample size was insufficient to find such an}

association.

Importantly,asseeninotherstudies,15,17,30_theauthors19

found no change in either mortality or case-fatality rates between the two periods. In addition, there was no significant difference in the number of central-line-associated-BSIs, ventilator-associated pneumonia, or catheter-associated urinary tract infections between the twoperiods.

BSIs due to CoNS in preterm infants are associated withsubstantialshort-termmorbidityaswell aslongterm neurodevelopmentalimpairment.31 _{However,theyarenot}

associated with increased mortality, and in fact, CoNS BSIs have significantly less mortality than that due to otherbacterialpathogens.32_{Moreover,preterminfantswho}

haveCoNSbacteremiahavemortalityratessimilartothat observedamonguninfectedpreterminfants.2_With

improve-ments in blood culture techniques that provide culture resultsapproximatelyevery 10min, theneonatologist can treat neonates empirically with oxacillin/nafcillin safely untiltheinfant’s blood culture yieldsGram-positivecocci suggestiveofstaphylococcalspecies,atwhichtimeachange tovancomycintherapy is prudent. Over80% ofblood cul-tures containing CoNS isolates are positive after 24h of incubationand virtuallyall after36---48h.Moreover, since themajorityofrule-outsepsisepisodesareculture-negative and antibiotics are not continued beyond 48h, the use of a non-vancomycin empiric regimen means that many infants are never exposed to this agent --- an important goal in this era of widespread antimicrobial resistance! Increasedroutineuseoftechnologiessuchasmatrix-assisted laserdesorption/ionization time-of-flight (MALDI-TOF)and polymerase chain reaction (PCR) for determination of themecA genewhich confers methicillinresistancecould assist in the early identification of these organisms and their resistance patterns, further obviating the need for empiricvancomycintherapy.However,amajorcaveat for a vancomycin reduction guideline must be knowledge of MRSA colonization of infants in the NICU in communi-tieswithahigh prevalence of MRSAcolonization/disease. MRSA-colonizedinfants shouldreceiveempiricvancomycin therapy,asthemorbidityandmortalityduetoMRSAcanbe substantial.33

Inconclusion,Romanellietal.19_{shouldbeapplaudedfor}

their support of antimicrobial stewardship in their NICU. Theirefforts, aswell as thoseof others that supportthe recommendationsoftheBrazilian NationalHealth Surveil-lance Agency,34 _{should encourage other Latin American}

NICUstochangetheirprescribinghabits,thusminimizingthe emergenceofantimicrobialresistance.Nonetheless, appro-priate empiric antibiotic therapy is only the beginning ---the nextfrontier must be duration of antimicrobial ther-apy,knowingthatprolongedantibiotictherapyinhigh-risk preterm infants is associated with changes in the micro-biome, resulting in necrotizing enterocolitis, late-onset sepsis, bronchopulmonary dysplasia, invasive candidiasis, andevendeath.WithrespecttoCoNS,durationoftherapy asshortasthreetofivedaysmaybesufficient.35,36 _Inthe

meantime,prudentvancomycinuse1_{must remainaglobal}

434 SánchezPJetal.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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