JPediatr(RioJ).2015;91(5):410---412
www.jped.com.br
EDITORIAL
The
global
threat
of
antimicrobial
resistance
-
The
need
for
standardized
surveillance
tools
to
define
burden
and
develop
interventions
夽
,
夽夽
A
ameac
¸a
global
da
resistência
antimicrobiana
-
A
necessidade
de
instrumentos
de
vigilância
padronizados
para
definir
carga
e
desenvolver
intervenc
¸ões
Mike
Sharland
a,∗,
Praveen
Saroey
a,
Eitan
Naaman
Berezin
baPaediatricInfectiousDiseasesResearchGroup,StGeorge’sUniversityofLondon,London,UnitedKingdom bFaculdadedeCiênciasMédicasdaSantaCasadeSãoPaulo,SãoPaulo,SP,Brazil
Anti-microbial resistance (AMR) is one the biggest issues the medical community is currently facing, as evidenced by the increasing prevalence of pan-resistant strains. In additionto treatment options, AMR alsohas major finan-cial and economical implications. It has been estimated thatupto50%of antimicrobialuseis inappropriate;each yearapproximately2millionpeopleintheUSareinfected witharesistantorganism.1Upto23,000yearlydeathsare reportedlycauseddirectlybysuchinfections.1Thesituation isfurther complicated in low-incomecountriesby lack of effectivesurveillancesystems,laboratorydiagnostics,and accesstoappropriateantimicrobialsinthefaceoffinancial limitations.
The emergence of MDRGram-negative bacterial (GNB) resistance is particularly of concern, especially in inten-sive care units (ICUs) and immunocompromised patients,
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2014.11.009
夽 Pleasecitethisarticleas:SharlandM,SaroeyP,BerezinEN.The
globalthreatofantimicrobialresistance-Theneedfor
standard-izedsurveillancetoolstodefineburdenanddevelopinterventions.
JPediatr(RioJ).2015;91:410---2.
夽夽
SeepaperbydeOliveiraCostaetal.inpages435---41.
∗Correspondingauthor.
E-mails:[email protected],[email protected]
(M.Sharland).
as there are often limited treatment options avail-able andsecond-line treatmentsusuallyhave unfavorable pharmacokinetic and pharmacodynamics profiles, which has been linked to adverse outcomes.2 Intensive care units have a disproportionatelyhigh incidence of nosoco-mial infections relative to the number of patients, and this incidence continues to rapidly rise.3,4 For example, in ICUs in the United States, the prevalence of MDR pathogens suchasvancomycin-resistantEnterococci (VRE) and carbapenem-resistant Acinetobacter baumannii has risento33.3%and30%,respectively.5Mostofthese infec-tions arecatheter-relatedblood streaminfections(CRBSI) and ventilator-associatedpneumonia (VAP).6,7 Inaddition, medicalequipmentisalsoariskfactorforhorizontal trans-mission of nosocomial organisms.8 The high incidence of resistance may be due to the high burden of antimicro-bial use in this population, causing selective pressure. TheEuropeanpointprevalencesurveyofantimicrobialuse conducted by the AntibioticResistance and Prescribing in European Children (ARPEC) group reporteda significantly higher prevalence of antibiotic use in intensive care and hematology---oncologywards.9
In Brazil and Latin America, the frequency of Gram-negativebacilliinhospital-acquiredbloodstreaminfections surpassesthoseofGram-positive,withasignificant propor-tionofmulti-resistantinfections.
In a multicenter study evaluating nosocomial blood-stream infections (NBSIs) in Brazil, Pereira et al. found
http://dx.doi.org/10.1016/j.jped.2015.06.001
Thegrowingthreatofantimicrobialresistancetochildhealthandtheneedtostandardizesurveillancemethods 411
342clinicallysignificantepisodesinpediatricpatients(≤16 years). 96% of BSIs were monomicrobial. Gram-negative organismscaused49.0%oftheseNBSIs,Gram-positive orga-nisms caused 42.6%, and fungi caused 8.4%. The most commonpathogenswerecoagulase-negativestaphylococci (CoNS) (21.3%), Klebsiella spp. (15.7%), Staphylococcus
aureus (10.6%),and Acinetobacterspp. (9.2%). The crude
mortalitywas21.6%(74 of342). 45%of NBSIsoccurredin apediatricor neonatalICU. Themostfrequentunderlying conditionsweremalignancy,in 95patients(27.8%).Inthis study,theprevalenceofantibiotic-resistantGram-negative bacteriawasveryhigh,especiallyPseudomonasaeruginosa
andA.baumannii.Carbapenem-resistance ratesashighas
40%forAcinetobacterspp.and23%forP.aeruginosawere
observed,amongthehighestdescribedintheliteraturefor thepediatricpopulation.10
In2007,Arnonietal.reportedtheGram-negativeprofile ofinfectionsinapediatriccenterin Brazilandfound that 47.8%weremultidrug-resistant,54.2%wereKlebsiellaspp. Extendedspectrum-lactamaseproducersand36.4%were imipenem-resistant P.aeruginosa. The mortality rate was 36.9%in thestudiedcases,and wassignificantlyhigherin thegroupofpatientswithmultidrugresistantinfections.11
ThisretrospectivestudybyCostaetal.12provides valu-ablepediatricdataonAMRrates inthisvulnerablecohort withhematological malignanciesin an intensive care set-ting, which has not previously been reported.It found a high burden of GNB infection in this cohort, with MDR-GNBaccountingfor justunderhalfof thecases.Themost common MDR-GNB pathogens were A. baumannii (17%),
Stenotrophomonas maltophilia (15%), Enterobacter spp.
(15%),andK.pneumonia(15%).Thefrequencyofresistance amongstthesepathogens rangedfrom18.5%upto50%.P.
aeruginosa was the most commonly found non MDR-GNB
pathogen(41%).InbothMDR-GNBandnonMDR-GNBgroups, bacteria wereisolated most frequently fromthe tracheal aspirate,followed byblood andurine cultures. Solid CNS tumorswerethemostfrequentunderlyingconditioninboth thesegroups.
Thestudy’smostsignificantfindingwastheassociationof MDR-GNBinfectionwithhospital-acquiredinfections(HAIs) and hematological disease (p=0.015, p=0.021, respec-tively).Other significant findingswere the notably higher rateof MDR-GNB infectionin patientswho received inap-propriateinitialantibiotictherapyordelayedtreatment.
The overallprevalencerateof46.5%of MDR-GNB orga-nismsinthestudyissimilartothatfoundinaretrospective observationalstudyfromatertiaryhospitalinRome(39%).13 Although the patient groups in these studies were not entirely similar,theywere comparablein that 86.3% sub-jectshadanunderlyingcondition.However,thefrequencies
ofMDR,suchasEscherichiacoli,Klebsiellapneumoniaeand
A.baumannii (50%,46.6%, and36.4%,respectively), were
significantlylower thanresource-limitedintensive care or sepsiscohorts.LeDoareetal.observedthat66.8%ofall iso-lateswereGNBinresourcepoorsettings;K.pneumoniaewas the predominant pathogen, accounting for approximately half ofthe isolatesand demonstratingthehighest overall resistance(50---84.4%tothirdgenerationcephalosporins).14 Similarly, Cai et al. reported Gram-negative organisms as responsible for 65.5% cases of VAP in PICU patients from Wuhan, China. MDR A. baumannii was responsible
for more than 50% of these infections; over 70% strains were carbapenem- and cephalosporin-resistant.15 A small prospectiveThaistudy inPICUpatientsalsodemonstrated thatapproximatelyhalfofHAIswereduetoMDR-GNB orga-nisms, in particular A. baumannii and Pseudomonas spp., allof which werecarbapenem-resistant.16 This studyalso foundstayofmorethansevendaysinPICUtobean indepen-dentriskfactorforMDR-HAI.16Severalpreviousstudieshave alsodemonstratedtheassociationbetweenpriorantibiotic useandinfectionwithdrug-resistantorganisms,especially Gram-negativebacteria.17,18Anassociationbetween emer-genceofresistantorganismsanduseofparticularantibiotic agentsmorecommonlyhasalsobeenfoundinlongitudinal time-seriesanalyses.19
Berezin etal. reviewed GNB in PICU andneonatal ICU (NICU)set-upsinLatinAmerica,20however,onlysixofthe12 includedstudiesreportedsusceptibilitydata,suggestingthe generalpaucity ofsurveillance datafromtheregion.One studyreported64%ofK.pneumoniaeisolateswereresistant tothird-generation cephalosporins,butall K.pneumoniae
and80%ofP.aeruginosaweresusceptibletocarbapenems,
whichdifferedfromthefindingsofCostaetal.12Ingeneral, thereviewfoundahigherrateofHAIinchildrenadmittedto PICUinLatin AmericawhencomparedtosimilarEuropean andNorthAmericansettings.Therewasa widevariability in frequency of GNB, depending on the region, although the commonest organismswere similar(i.e., K.
pneumo-niae,E.coli,andP.aeruginosa),withonlysporadiccasesof
AcinetobacterbutwithahighlevelofMDR.
Giventhenationalandregionalvariationsofresistance patterns,asindicatedbypreviousstudies,aswellas likeli-hoodofadmissionstosuchcentersoccurringfromdifferent partsofthecountry,largerprevalencestudiesarerequired toenhanceunderstandingofresistancepatterns.Longterm outcomeinthesepatients,takingintoaccounttheprognosis of underlying malignancies,would alsoadd to the under-standingoftheimplicationsofinfectionwithMDR-GNB.
The WHO six-point package, issued to combat AMR at theWorldHealthDay2011,emphasizedneed forfinancial commitment,strengtheningsurveillance,accesstoquality medicines, stewardship, infection control, and promoting researchintonewwaysofcombatinginfectiousdiseases.21 TheGARPECprojectisonesuchinitiativethataimsto pro-motecollaborativeresearchandcollectionandsharingdata betweenparticipantsataregionalandgloballevelinorder toaccumulate an evidence base for developing appropri-atestewardship programs based onantibiotic prescribing patternsandresistancesurveillancedata.International col-laborationon standardised surveillace efforts linked with evidencebasedinterventionswillbekeyinovercomingthis impendingthreattointernationalchildhealth.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
References
412 SharlandMetal.
2.GleasonTG,CrabtreeTD,PelletierSJ,RaymondDP,Karchmer TB,PruettTL,etal.Predictionofpoorerprognosisbyinfection withantibiotic-resistantGram-positivecoccithanbyinfection withantibiotic-sensitivestrains.ArchSurg.1999;134:1033---40.
3.FridkinSK,WelbelSF,WeinsteinRA.Magnitudeandprevention ofnosocomialinfectionsintheintensivecareunit.InfectDis ClinNorthAm.1997;11:479---96.
4.Raymond J, Aujard Y. Nosocomial infections in pediatric patients:aEuropean,multicenterprospectivestudy.European StudyGroup.InfectControlHospEpidemiol.2000;21:260---3.
5.Hidron AI,Edwards JR, Patel J, Horan TC, Sievert DM, Pol-lock DA, et al. NHSN annualupdate: antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Health-care Safety Network at the Centers for Disease Control and Prevention, 2006---2007. Infect Control Hosp Epidemiol. 2008;29:996---1011.
6.MarschallJ,MermelLA,FakihM,HadawayL,KallenA,O’Grady NP,etal.Strategiestopreventcentralline-associated blood-streaminfectionsinacutecarehospitals:2014update.Infect ControlHospEpidemiol.2014;35:753---71.
7.CoffinSE,KlompasM,ClassenD,AriasKM,PodgornyK,Anderson DJ, et al. Strategies to prevent ventilator-associated pneu-moniainacutecarehospitals.InfectControlHospEpidemiol. 2008;29:S31---40.
8.KayeKS,MarchaimD,SmialowiczC,BentleyL.Suction regula-tors:apotentialvectorforhospital-acquiredpathogens.Infect ControlHospEpidemiol.2010;31:772---4.
9.VersportenA,SharlandM,BielickiJ,DrapierN,Vankerckhoven V,Goossens H, etal. Theantibiotic resistance and prescrib-ing in European children project: a neonatal and pediatric antimicrobialweb-basedpointprevalencesurveyin73hospitals worldwide.PediatrInfectDisJ.2013;32:e242---53.
10.PereiraCA,MarraAR,CamargoLF,Pignatari AC,SukiennikT, BeharPR,etal.Nosocomialbloodstreaminfectionsin Brazil-ianpediatricpatients:microbiology,epidemiology,andclinical features.PLOSONE.2013;8:e68144.
11.ArnoniMV,BerezinEN,MartinoMD.Riskfactorsfornosocomial bloodstream infection caused by multidrug resistant gram-negativebacilliinpediatrics.BrazJInfectDis.2007;11:267---71.
12.deOliveiraCostaP,AttasEH,SilvaAR.Infectionwith multidrug-resistant gram-negative bacteria in a pediatric oncology
intensivecareunit:riskfactorsandoutcomes.JPediatr (Rio J).2015;91:435---41.
13.FolgoriL,LivadiottiS,CarlettiM,BielickiJ,PontrelliG,Ciofi Degli Atti ML, et al. Epidemiology and clinical outcomes of multidrug-resistant,Gram-negativebloodstreaminfectionsina Europeantertiarypediatrichospitalduringa12-monthperiod. PediatrInfectDisJ.2014;33:929---32.
14.LeDoareK,BielickiJ,HeathPT,SharlandM.Systematicreview ofantibiotic resistance ratesamong Gram-negative bacteria inchildrenwithsepsisinresource-limitedcountries.JPediatr InfectDis.2015;4:11---20.
15.Cai XF, Sun JM, Bao LS, Li WB. Distribution and antibiotic resistance of pathogens isolated from ventilator-associated pneumoniapatientsinpediatric intensivecare unit.WorldJ EmergMed.2011;2:117---21.
16.Sritippayawan S, Sri-Singh K, Prapphal N, Samransamruajkit R, Deerojanawong J. Multidrug-resistant hospital-associated infectionsinapediatricintensivecareunit:across-sectional survey in a Thai university hospital. Int J Infect Dis. 2009;13:506---12.
17.Marchaim D, Chopra T, Bhargava A, Bogan C, Dhar S, Hayakawa K, et al. Recent exposure to antimicrobials and carbapenem-resistant Enterobacteriaceae: the role of antimicrobial stewardship. Infect Control Hosp Epidemiol. 2012;33:817---30.
18.Trouillet JL, Vuagnat A, Combes A, Kassis N, Chastre J, GibertC.Pseudomonasaeruginosaventilator-associated pneu-monia: comparison of episodes due to piperacillin-resistant versus piperacillin-susceptible organisms. Clin Infect Dis. 2002;34:1047---54.
19.Carmeli Y, Lidji SK, Shabtai E, Navon-Venezia S, Schwaber MJ. The effects of group 1 versus group 2 carbapenems onimipenem-resistantPseudomonasaeruginosa:anecological study.DiagnMicrobiolInfectDis.2011;70:367---72.
20.BerezinEN,SolórzanoF,LatinAmericaWorkingGroupon Bac-terial Resistance. Gram-negative infections in pediatric and neonatalintensive care unitsof LatinAmerica. JInfect Dev Ctries.2014;8:942---53.
