HealthAdvisory:CarbapenemaseresistantEnterobacteriaceae(CRE)Associatedwith NewDelhiMetallobetalactamase1(NDM1),KingCounty

ThisreportwaspreparedbymembersoftheAntimicrobialStewardshipConsortiumofSeattle*(AMSCOS)in collaborationwithPublicHealthSeattle&KingCounty. Actionrequested Hospitalsshouldestablishaprotocol,inconjunctionwithCLSIguidelines,todetectnonsusceptibilityand carbapenemaseproductioninEnterobacteriaceae,particularlyKlebsiellaspp.andEscherichiacoli,and immediatelyalertepidemiologyandinfectioncontrolstaffmembersiftheseareidentified(MMWR, 2009). AllpatientscolonizedorinfectedwithcarbapenemaseproducingEnterobacteriaceaeshouldbeplaced oncontactprecautions. AllcarbapenemaseproducingisolatesshouldbereportedtoPublicHealthat2062964774(Public Healthcanalsoprovideassistancewithresistancetestingandinfectioncontrolmeasures). Background InJuly2011,apatientwastransferredtoaSeattleareamedicalcenterfromahospitalinCalcutta,India followingsurgeryforseveretrauma.HewashospitalizedinIndiaforapproximately10daysbeforetransfer. Duringthathospitalization,aninfectionofanopenwoundrequiredbroadspectrumantimicrobialsand additionalsurgicaldebridement.UponarrivalinSeattle,woundculturesgrewEnterococcusspp.,Pseudomonas aeruginosa,AeromonashydrophilaandKlebsiellapneumoniae.TheKlebsiellaandPseudomonasisolateswere notedtobemultiplydrugresistant: Klebsiellapneumoniae:resistanttoaztreonam,cefepime,ceftazidime,ceftriaxone,ciprofloxacin, ertapenem,gentamicin,piperacillintazobactam,tobramycinandtrimethoprimsulfamethoxazole,but susceptibletomeropenem(MIC1mcg/ml),imipenem(MIC0.5mcg/ml)andamikacin. Pseudomonasaeruginosa:resistanttoamikacin,ceftazidime,gentamicin,imipenem,levofloxacin, meropenem,piperacillintazobactam,andtobramycin,andintermediatetocefepime(MIC16mcg/ml).The colistinMICwas2mcg/ml. AsecondP.aeruginosastrainwasalsoobtained,whichwassusceptibletoalldrugstested.Perhospitalpolicy, thepatientwasplacedoncontactprecautions,continuedhispreviouslyinitiatedmeropenemtreatment,and followedclosely.Thewoundhealed,butasinustractdevelopedthatwasculturedandgrewthreemultiply drugresistantisolates: Klebsiellapneumoniae:resistanttoalldrugstestedexceptamikacin.ThecolistinMICwas4mcg/ml. Escherichiacoli:resistanttoalltesteddrugsexceptimipenem(I,MIC2mcg/ml).ThecolistinMICwas2 mcg/ml. Pseudomonasaeruginosa:resistanttoalldrugstested.ThecolistinMICwas4mcg/ml.

Afterexcisionofthesinustract,thepatientwastreatedwithIVcolistintwicedaily.Hiscoursewascomplicated by acute kidney injury attributed to colistin. The wound healed completely and the patients renal function recovered. Approximately4monthslater,thepatientnotedanareaoffluctuanceadjacent tothesinustractincision. This was drained in the operating room where purulent material was found several centimeters beneath the skin surface.CulturesfromthismaterialgrewK.pneumoniae,P.aeruginosaandMorganellamorganii. Klebsiellapneumoniae:susceptibletoamikacin,imipenemandmeropenem. Pseudomonasaeruginosa:susceptibletoalldrugstested. Morganella morganii: susceptible to ertapenem and meropenem, with intermediate susceptibility to imipenem (MIC 2 mcg/ml): resistant to aztreonam, ceftazidime, ceftriaxone, ciprofloxacin, gentamicin, levofloxacinandtobramycin. Thepatient wastreated withIV meropenem,IVcolistinandIV tigecycline plusoralrifampin.Asaresult ofside effects, antibiotics were narrowed to IV colistin, IV meropenem and oral rifampin. The surgical site healed completelyandthepatientcompleted4weeksofcombinationtherapywithnorecurrenceoftheinfection. Isolates from each of the three time points were sent to the CDC in Atlanta and Dr. Scott Weissmans lab at Seattle Childrens Hospital. Both labs found evidence of the New Delhi metallobetalactamase1 (NDM1 or blaNDM1), a novel carbapenamase (Yong et al., 2009), in K. pneumoniae, E. coli, and M. morganii. Based on the history and timing of the cultures, the infection most likely occurred in India, either at the time of the trauma orwhileinthehospital. Discussion ThisisthefirstcaseofCREassociatedwithNDM1reportedinWashingtonState.In2010,apatientwith carbapenemresistantK.pneumoniaeduetoVIM(Veronaintegronencodedmetallobetalactamase carbapenemase),whopresumablyacquiredtheinfectionwhilehospitalizedinGreece,wasreportedfrom EasternWashington.NDM1wasoriginallydescribedin2009inapatientwithmultidrugresistantKlebsiella pneumoniaeinfectionreturningtoSwedenafterhospitalizationinIndia(Yongetal.,2009).Subsequently,a 2010reportdocumentedapatternoftraveltoorhospitalizationinIndiaandPakistanasariskfactorfor colonizationorinfectionwithK.pneumoniaeandE.coli(Kumarasamyetal.,2010). ContaminationofbothhealthcareandpublicenvironmentswithbacteriaharboringNDM1hasbeenreported since2009inIndia,andthesubsequentisolationofNDM1carryingisolateshasbeenreportedinpatients frommanyothercountries(Seemaetal.,2011;Walshetal.,2011).TheblaNDM1geneproducesa carbapenamasecapableofhydrolyzingallbetalactamsexceptaztreonam,andiscarriedonmobileplasmids thatoftencarrygenescodingresistancetomultipleclassesofantibiotics(Poireletal.,2011).Infectionscaused byhighlyresistantcarbapenemaseproducingbacteriaarehardertotreatandoftenrequiremoretoxic therapies.Thepatientdescribedherehadacutekidneyinjury,neutropenia,nausea,vomitingandweightloss asaresultofantibiotictreatment. PatientstravelingtoorreturningfromIndiaareathigherriskofacquisitionorinfectionwithorganisms containingthisresistancemechanism(Chanetal.,2011).However,giventheglobalspreadofNDM1, acquisitionispossibleinmanypartsoftheworld.Themostcommonmechanismofcarbapenemresistance amongEnterobacteriaceaeintheUnitedStatesremainstheproductionoftheKPCenzyme,orKlebsiella pneumoniaecarbapenemase(MMWR,2010);suchstrainsaremoreprevalentincertainhospitalsinthe EasternUSandremainuncommonlocally.

AlthoughNDM1doesnotconferresistancetoaztreonam,80%ofNDM1carryingstrainsareresistantto aztreonamduetothepresenceofadditionalbetalactamases(Nordmannetal.,2011).Inthepresentcase, theinvitrosusceptibilitytocarbapenemsmeasuredbybrothmicrodilutionwasvariableinisolatesthatwere verifiedbymoleculartestingtocarryNDM1.AlthoughmostbacteriacarryingNDM1arephenotypically resistanttocarbapenems,somehaveMICsinthesusceptiblerange.TheModifiedHodgeTestusedtodetect KPCcarbapenemasesisunreliableforthedetectionofmetallobetalactamaseslikeNDM1(Girlichetal., 2012),andtheMBLetestmayalsogiveequivocalresults(Mochonetal.,2011).Thus,thedetectionofNDM1 canposeachallengefortheclinicallaboratory.IfNDM1isdetected,anisolateshouldbeconsideredresistant toallbetalactams,includingbetalactam/inhibitorcombinations. *FormoreinformationabouttheAntimicrobialStewardshipConsortiumofSeattle,pleasecontactDr.John Pauk,MedicalDirector,InfectionControlandAntimicrobialStewardship,SwedishMedicalCenter (john.pauk@Polyclinic.com) References Chan,H.L.,L.M.Poon,S.G.Chan&J.W.Teo(2011)Theperilsofmedicaltourism:NDM1positiveEscherichia colicausingfebrileneutropeniainamedicaltourist.SingaporeMedJ,52,299302. Girlich,D.,L.Poirel,&P.Nordmann(2012)ValueofthemodifiedHodgetestfordetectionofemerging carbapenemasesinEnterobactericeae.JClinMicrobiol,50,4779. Kumarasamy,K.K.,M.A.Toleman,T.R.Walsh,J.Bagaria,etal(2010)Emergenceofanewantibioticresistance mechanisminIndia,Pakistan,andtheUK:amolecular,biological,andepidemiologicalstudy.Lancet InfectDis,10,597602. MMWR.Update:DetectionofaVeronaintegronencodedmetallobetalactamase(VIM)carbapenemasein KlebsiellapneumoniaeUnitedStates,2010.September24,2010 MMWR.GuidanceforControlofInfectionswithCarbapenemResistantorCarbapenemaseProducing EnterobacteriaceaeinAcuteCareFacilities.March20,2009.Availableat: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5810a4.htm Mochon,A.B,O.B.Garner,J.A.Hindler,P.Krogstad,K.W.Ward,M.A.Lewinski,J.K.Rasheed,K.F.Anderson, B.M.Limbago&R.MHumphries(2011)NewDelhimetallolactamase(NDM1_producingKlebsiella pneumoniae:casereportandlaboratorydetectionstrategies.JClinMicrobiol,49,166770. Nordmann,P.,L.Poirel,T.R.Walsh&D.M.Livermore(2011)TheemergingNDMcarbapenemases.Trends Microbiol,19,58895. Poirel,L.,A.Ros,A.Carricajo,P.Berthelot,B.Pozzetto,S.Bernabeu&P.Nordmann(2011)Extremelydrug resistantCitrobacterfreundiiisolateproducingNDM1andothercarbapenemasesidentifiedina patientreturningfromIndia.AntimicrobAgentsChemother,55,4478. Seema,K.,M.RanjanSen,S.Upadhyay&A.Bhattacharjee(2011)DisseminationoftheNewDelhimetallo lactamase1(NDM1)amongEnterobacteriaceaeinatertiaryreferralhospitalinnorthIndia.J AntimicrobChemother,66,16467. Walsh,T.R.,J.Weeks,D.M.Livermore&M.A.Toleman(2011)DisseminationofNDM1positivebacteriain theNewDelhienvironmentanditsimplicationsforhumanhealth:anenvironmentalpointprevalence study.LancetInfectDis,11,35562. Yong,D.,M.A.Toleman,C.G.Giske,H.S.Cho,K.Sundman,K.Lee&T.R.Walsh(2009)Characterizationofa newmetallobetalactamasegene,bla(NDM1),andanovelerythromycinesterasegenecarriedona uniquegeneticstructureinKlebsiellapneumoniaesequencetype14fromIndia.AntimicrobAgents Chemother,53,504654.