Antimicrobial resistance in Enterobacteriaceae in Brazil: focus on β-lactams and polymyxins

h tt p : / / w w w . b j m i c r o b i o l . c o m . b r /

Medical

Microbiology

Antimicrobial

resistance

in

Enterobacteriaceae

in

Brazil:

focus

on

␤-lactams

and

polymyxins

Jorge

Luiz

Mello

Sampaio

_,

_Ana

_Cristina

_Gales

a_{UniversidadedeSãoPaulo,FaculdadedeCiênciasFarmacêuticas,DepartamentodeAnálisesClínicaseToxicológicas,SãoPaulo,}

SP,Brazil

b_{FleuryMedicinaeSaúde,Sec¸ãodeMicrobiologia,SãoPaulo,SP,Brazil}

c_{UniversidadeFederaldeSãoPaulo,EscolaPaulistadeMedicina,DepartamentodeMedicinaInterna,SãoPaulo,Brazil}

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Articlehistory:

Received7October2016 Accepted7October2016 Availableonline25October2016 AssociateEditor:MarinaBaquerizo

Keywords:

ESBL KPC NDM

Extendedspectrum␤-lactamases NewDelhimetallo-␤-lactamase Klebsiellapneumoniae carbapenemase PolymyxinB Colistin Antimicrobialresistance Carbapenemases Brazil Enterobacteriaceae

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Duringthelast30yearstherehasbeenadisseminationofplasmid-mediated␤-lactamases

inEnterobacteriaceaeinBrazil.Extendedspectrum␤-lactamases(ESBL)arewidely

dissem-inated inthehospitalsettingandaredetectedina lowerfrequencyinthecommunity setting.CefotaximasesarethemostfrequentlydetectedESBLtypeandKlebsiellapneumoniae

isthepredominantspeciesamongESBLproducers.Klebsiellapneumoniae carbapenemase-producingEnterobacteriaceaebecamewidelydisseminatedinBrazilduringthelastdecade andKPCproductioniscurrentlythemostfrequentresistancemechanism(96.2%)in car-bapenem resistant K. pneumoniae.To dateKPC-2is the onlyvariant reportedin Brazil. PolymyxinBresistanceinKPC-2-producingK. pneumoniaehascometoanalarmingrate of27.1%in2015inSãoPaulo,thelargestcityinBrazil.NewDelhimetallo-␤-lactamasewas detectedinBrazilin2013,hasbeenreportedindifferentBrazilianstatesbutarenotwidely disseminated.AntimicrobialresistanceinEnterobacteriaceaeinBrazilisaveryserious prob-lemthatneedsurgentactionswhichincludesbothmorestrictadherencetoinfectioncontrol measuresandmorejudicioususeofantimicrobials.

©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/

licenses/by-nc-nd/4.0/).

ThefirstreportsonantimicrobialresistanceinGram-negative rods from Brazil, available at PubMed, were restricted to community-acquiredinfections.Thesereportswereon sul-fadiazineresistanceinEscherichiacoli,ShigellaandSalmonella

anddatedfrom1968.1,2 _{In1971chloramphenicol resistance}

wasreportedinSalmonellaTyphidetectedinvarious Brazil-ianstates3 _{andShigella resistant tomultipleantimicrobials}

∗ _{Correspondingauthors.}

E-mails:sampaio@usp.br(J.L.Sampaio),ana.gales@gmail.com(A.C.Gales).

were reported from RiodeJaneiro.4 _{Atthat time,␤-lactam}

resistancewasonlyreportedforampicillin.

The

rise

of

extended-spectrum

␤-lactamases

Thirdgeneration cephalosporinsbecameavailablefor clini-caluseinBrazilinearly1980s.Inourmedicalpractice,we

http://dx.doi.org/10.1016/j.bjm.2016.10.002

1517-8382/©2016SociedadeBrasileiradeMicrobiologia.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

haveobservedresistancetothird-generationcephalosporins amongEnterobacteriaceae since 1985, but the first report of thisfindinginBrazilianhospitalswaspublishedonlyin1994, describinga52%cefepimeresistancerateamong ceftazidime-resistantEnterobacteriaceae.5_{Thiswasthefirstpublishedclue}

onthepresenceofextendedspectrum␤-lactamases(ESBLs) inBrazil.In1997,the firstconfirmationofESBLproduction

inEnterobacteriaceaefromBrazilcameout.Theauthors

doc-umentedthepresenceofESBLsin72K.pneumoniaeclinical isolates,fromprivateandpublictertiaryhospitalslocatedin RiodeJaneiroandSãoPaulo,byclavulanicacidinhibition.Of note,theyalsoreportedalowsusceptibilityratesforamikacin (41.4%)andgentamicin(29.6%)butallisolateswerestill sus-ceptible toimipenem.6 _{A subsequent work,also published}

in1997,including982consecutiveisolatesfrom18hospitals, fromfourdifferentstatesandsevendifferentcities,wasthe firstpublicationthatcouldbeusedtoestimatetheESBLrate amongEnterobacteriaceae.Assumingthat resistancetothird generationcephalosporinswasonlyduetoESBLproduction,

16%and5%ofK.pneumoniaeandE.coli,respectively,wouldbe

classifiedasESBLproducersatthattime.7

The first molecular studies on ESBLs from Brazil came outin2000,evidencingthepredominanceofblaCTX-Mgenes and describing the CTX-M-8 enzymein strains other than

K. pneumoniae from Rio de Janeiro.8 _{The same group of}

researchersdescribedtheBES-1andtheCTX-M-16enzymesin strainsfromthesamecity.9,10_{Subsequentsurveillancestudies}

evidencedagrowingESBLproductionratesamong

Enterobacte-riaceaecollectedfrominpatients.In2000,theESBLproduction

rateinK.pneumoniaecollectedfromintensivecareunitswas

59.2%,whiletheseratesinEnterobacterspp.andE.coliwere 19.5%and14.6%,respectively.11_{Themostrecentstudyonthe}

diversityofESBLtypesinEnterobacteriaceaeisolatedfromBrazil refersto1827isolates collectedduring theperiod between August2003andMarch2008inthecity ofCuritiba,Paraná. CTX-M-2wasthemostfrequentlydetectedESBLinall

Entero-bacteriaceaespecies,exceptinEnterobacteraerogenes,inwhicha

CTX-M-59-producingclonewaspredominant.12_Recent

stud-ieshavereportedthatESBL-producingEnterobacteriaceaeare nowdetectedinasignificantrateinoutpatientspresenting cystitis.InapublicinstitutionlocatedinBrasilia,theESBL pro-ductionrateinE.colicollectedfromJuly2013toApril2014was 7.1%.13_{WhenwereviewedallpublicationfromBrazilabout}

ESBLs,CTX-M-2wasthemostfrequentlydetectedenzymeand wasalsodetectedinthelargestnumberofdifferent

Enterobac-teriaceaespecies(Table1).

Plasmid-mediated

AmpCs

FOX-5-like andCMY-2-like werethe first plasmid-mediated AmpCs(pAmpC)reportedinBrazilianisolates.Bothenzymes were detected inE. coli.42,43 _{TheFOX-5-like encodinggene}

was detected during the DNA sequencing of a 41-kb con-jugative plasmid that harbored a qnrA gene and a class 1 integronwiththeaadBandcatB3genecassettes.43_The

CMY-2-like enzyme was detected in four carbapenem-resistant

E.coli strains,which alsopossessed alterationin theouter membrane proteins, isolated from a single patient.42 _Dias

and colleagues studied the prevalence of pAmpC among

Table1–Extendedspectrum␤-lactamasesdetectedin

EnterobacteriaceaeinBrazil.

Enzyme Species

BES-1 Serratiamarcescens9

CTX-M-1 K.pneumoniae14

CTX-M-2 Enterobacteraerogenes12,15_{;Enterobactercloacae}12,16_; Escherichiacoli12,16–22_{;Klebsiellapneumoniae}14,16,21,23–29_; K.oxytoca21_{;Morganellamorganii}16,21_;Proteus mirabilis8,17,21_{;Providenciastuartii}16,21,30_;Salmonella typhimurium31_{;S.marcescens}17

CTX-M-3 E.coli22

CTX-M-8 Citrobacteramalonaticus8_{;Enterobactercloacae}8_;E. aerogenes8_;E.coli12,16,22_{;K.pneumoniae}14

CTX-M-9 Citrobacterfreundii16_;E.cloacae10,12_;E.coli10,12,16,20_;K. pneumoniae16

CTX-M-14 E.coli18,32

CTX-M-15 E.aerogenes12_;E.cloacae12,33_;E.coli18,22,32,34_;K. pneumoniae27,33,35

CTX-M-16 E.coli10_;E.cloacae10 CTX-M-28 K.pneumoniae24_;K.oxytoca21

CTX-M-59 E.aerogenes15_;E.cloacae15_;E.coli20,21,27_;K. pneumoniae21,23,27 CTX-M-74 E.cloacae16 CTX-M-75 P.stuartii16 CTX-M-131 P.stuartii36 GES-1 K.pneumoniae37 GES-7 K.pneumoniae38 PER-2 E.cloacae12,15 SHV-2 K.pneumoniae;E.coli22 SHV-4 K.pneumoniae39

SHV-5 E.cloacae16_;E.coli16,19,21_{;K.pneumoniae}16

SHV-12 E.aerogenes12,15_;E.cloacae12,15_{;K.pneumoniae}21,25,35 SHV-27 K.pneumoniae21,40 SHV-28 K.pneumoniae21,41 SHV-31 K.pneumoniae35 SHV-38 K.pneumoniae35 SHV-40 K.pneumoniae38 SHV-45 K.pneumoniae21 SHV-55 K.pneumoniae21 SHV-108 K.pneumoniae41 SHV-122 K.pneumoniae41 TEM-15 K.pneumoniae21 TEM-115 K.pneumoniae21 TEM-116 K.pneumoniae38 TEM-135 E.cloacae12

Enterobacteriaceae isolated from a teaching hospital in Rio

de Janeiro. In that study pAmpC encodinggenes were not detectedand the multidrugresistancephenotypeobserved in five E. coli strain was attributed to hyperexpression of chromosomallyencodedAmpC.44_{Veryfewstudiesdescribed}

the frequency of pAmpCs in Enterobacteriaceae in Brazil, althoughpAmpCs areofepidemiologicalimportance,since carbapenem resistancecan occur instrainswith concomi-tantpermeabilityalterationsandpAmpCexpression.Astudy conducted in a public tertiary hospital from São Paulo included41E.coli,fiveKlebsiellaoxytoca,65Klebsiella

pneumo-niae,18P.mirabilis,andfourSalmonellaspp.detectedduring

the periodfrom January and July 2006 and found a 0.75% plasmid-mediatedAmpCproductionrateandasingleisolate producing aCMY-2-likeenzymewasidentified.45 _Themost

recentstudyonpAmpCsinBrazilevaluatedthefrequencyof plasmid-mediatedAmpCsinE. coliisolated fromurine cul-tures from bothoutpatientsand inpatients. Thefrequency

Table2–KPC-producingspeciesdetectedinBrazil.

Species Location(City,State) MLST

C.freundii AL59_{;DuquedeCaxias,RJ}60_;GO59_;RJ59 _– E.aerogenes CE59_;DF59_;PE59

E.cloacae CE59_;DF59_;GO59_;MG59_{;PortoAlegre,RS}60,61_;Riode Janeiro59,62

–

E.gergoviae Recife,PE63 _–

E.hormaechei RiodeJaneiro64 _–

E.coli BA59_;DF59_;MG59_;Recife,PE59,65_{;RiodeJaneiro,RJ}59,66 _ST259_;ST3959_;ST4359_;ST30559_;ST47959_;ST50265_; ST62959_;ST63059_;ST63159_;ST63259

K.pneumoniae AL67_;AM67_{;Brasília,DF}67_{;CampoGrande,MS}68,69_; CE67_;ES67,70_{;Florianópolis,SC}67,71_;Franca,SP60_; GO67,70_{;JoãoPessoa,PB}72_;Lageado,RS73_;MA67_; MG67,70_;PE67,70_;PI67_{;PortoAlegre,RS}61,73,74_;Recife, PE28,56,65,67,75_{;RibeirãoPreto,SP}26,60_{;RiodeJaneiro,} RJ14,60,67,76_{;SãoPaulo,SP}27,77–80 ST1126,60,67,70,80_;ST1367_;ST1667,70_;ST1767_;ST1967_; ST2567,70_;ST5567_;ST7070_;ST10170_;ST13867_;ST25860_; ST32367_;ST34067,75_;ST42370_;ST43760,67,72,80_;ST44270_; ST44370_;ST75667_;ST75767_;ST75867_;ST75967_; ST76067_;ST83767_;ST83867_;ST83967_;ST84067_; ST84167_;ST84267_;ST85567 K.oxytoca Recife,PE81_;RJ59_;MG59 _–

K.georgiana PortoAlegre,PA82 _–

M.morganii MG59 _–

P.agglomerans RJ59 _–

P.mirabilis Recife,PE83 _–

P.stuartii Recife,PE84_;MG59 _–

S.marcescens DuquedeCaxias,RJ60_{;PortoAlegre,RS}61_;Recife, PE59,85_;Dourados,MS52

–

ThefollowingabbreviationscorrespondtoBrazilanStates:AL,Alagoas;AM,Amazonas;BA,Bahia;DF,DistritoFederal;ES,EspíritoSanto;GO, Goiás;MA,Maranhão;MG,MinasGerais;MS,MatoGrossodoSul;PB,Paraíba;PE,Pernambuco;RJ,RiodeJaneiro;RS,RioGrandedoSul;SC, SantaCatarina;SP,SãoPaulo.

of plasmid-mediated AmpC was 0.46% in outpatients and 1.8%ininpatients.Thefullnucleotidesequenceswere deter-minedandblaCMY-2wasthemostfrequentlydetectedgene, butblaCMY-4wasalsodetected.46

The

rise

of

carbapenemases

in

Brazil

Imipenemhasbeen availableforclinicaluseinBrazilsince the end of the 80s. In 1989 a surveillance study, carried outwith1231isolates,mainlyfrominpatientsfromfive dif-ferent medicalcenters from São Paulo, Riode Janeiro and Salvador,reporteda1%imipenemresistancerateforE.coli,

whilethisratewas6%forEnterobactersp.butresistant iso-lates were also found among K. pneumoniae.47 _{In 1998, a}

cefpiromesusceptibilitystudyalsoreportedimipenem resis-tance inEnterobacteriaceae. Using commercial microdilution plates,349Enterobacteriaceaefromtertiaryhospitalsfromfour differentstateswereevaluated.48 _{Imipenem resistancerate}

amongEnterobacterspeciesvariedfrom2to8%,whilethisrate amongK.pneumoniaewas7%,butunfortunately,nofurther studieswerepublishedonthosestrains.In2005,almost20 yearsaftertheintroductionofcarbapenemsinclinicalusein Brazil,thefirstreportofanEnterobacteriaceaeproducinga car-bapenemasecameout.TheworkofLincopanetal.described thepresenceofIMP-1inaK.pneumoniaestraindetectedina patientfromauniversityhospitalfromSãoPaulo,locatedat theSoutheastofBrazil.49_{ThesameIMP-1-producingK.}

pneu-moniaestrainwasdetectedinsixdistincthospitalsofthecity

ofSãoPaulobetweentheyears2003and2005.50_Inoneofthese

hospitals,it wasresponsible forcausing anoutbreak inan intensivecareunit.51_{IMP-1wasalsodetectedinaP.rettgeri}

isolatethatwasco-producerofCTX-M-like,and SHV-like.50

Theco-production ofIMP-10and KPC-2was detectedinS.

marcescenscausinganoutbreakinatertiary,teachinghospital

inDourados,MS.52

GES-5,anenzymeoftheGESfamilywithspectrumtoward carbapenems,wasinitiallydetectedinBrazilinaK.pneumoniae

isolatedfromarectalsurveillanceswabofanelderlypatient admittedtoaprivatehospitalinSãoPaulo,in2008.Thisisolate alsoshoweddeletionsonompK35andompK36genes.53_GES-5

wasalsodetectedinthreegeneticallyrelatedKluyvera

inter-mediathatwereisolatedfromonesinkandtwodistincttaps

ofanintensivecareunitofatertiary-carehospitalinPorto Alegre,inMay2013,duringanenvironmentalsurveillancefor NDM-1-producingisolates.54_{Althoughonlyreportedin2014,}

GES-5wasalsorecoveredfromthebloodofanadultpatient admittedtoauniversityhospitalinPortoAlegre,in2011.The patienthadacutemyeloidleukemiaandhadrecentexposure tomultipleantibiotics.55

Thefirst reportonthe detectionofKlebsiellapneumoniae

carbapenemase(KPC)inBrazilwaspublishedin2009,56 _and

describedthedetectionofKPC-2in2006,tenyearsafterthe firstdetectionofKPC-2inworld,in1996,inNorthCarolina, intheUnitedStatesofAmerica.57,58_{Theworkdescribedthe}

detectionofKPC-2inK.pneumoniaeinfourpatientsfromthe cityofRecife,locatedattheNortheastofBrazil.Earlier dissem-inationofKPC-2productionwaslaterreportedinSãoPaulo. Subsequently,KPC-2wasdescribedinmanyEnterobacteriaceae

speciesandlocationsalloverBrazil(Table2).Todatethisis the onlyvariantreported fromBrazil,although23 variants

(

http://www.ncbi.nlm.nih.gov/pathogens/beta-lactamase-data-resources/)havebeendescribedworldwide.

KPC-2-producingEnterobacteriaceaearenowdisseminated alloverBrazilbutK.pneumoniaeisthemostfrequentspecies. Among this species, ST11 and ST437, which belong to the

clonalcomplex258,arethemostfrequentlydetectedclonal groups(Table2).Arecentpublicationanalyzed3085K. pneumo-niaeisolatescultivatedfrompatientsfrom10privatehospitals fromthegreatSãoPaulourbanarea,duringtheperiodfrom January2011 to December 2015. Most ofthe isolates were recoveredfrombloodcultures.Theworkshowedanamazing increaseinthecarbapenemresistancerate,from6.8%in2011 to35.5%in2015;ofnote,KPC-2wasdetectedin96.2%ofthe carbapenem-resistantisolates,andtherewereboth interhos-pitalandintrahospitalclonaldissemination.80

NewDelhimetallo-␤-lactamase(NDM)wasfirstlydetected inBrazilin2013,inProvidenciarettgeri,from apatientfrom PortoAlegre,acitylocatedattheSouthofBrazil.86_This

detec-tionoccurredfouryearsaftertheinitialdetectioninaST14

K. pneumoniaestrain causing urinary tract infection and in

anE.colistrainfromfecesfromaSwedishpatientofIndian origin.87_{ComparedtowhathappenedwithKPC,whichwas}

detectedinBrazil10yearsaftertheinitialdescription, NDM-1-producingstrainsweredetectedmuchearlier,whichindicates agreatpotentialformoreefficientdisseminationinBrazil.

ThisP.rettgeristrainwaslatershowntohaveheterogeneous

carbapenem resistance, which could make its detection a challengingtask.88 _{Subsequently,expressionofNDM-1was}

reportedinE.hormaecheifromthesamecitywherethefirst casehadbeendetected.89_{E.cloacaecomplexstrainsand}

Mor-ganellamorganiiexpressingNDM-1werealsoreportedbyother

researchgroupfromPortoAlegre.90_{Inthesameyearof2013,}

thefirstcomplete nucleotidesequences ofblaNDM-1-bearing plasmids from Brazil were described, in E. coli and E.

hor-maecheicultured fromthe samerectal swabfromapatient

fromRiodeJaneirowhohadneverbeenexposedto carbapen-ems.TheblaNDM-1genewasfoundtobelocatedonaIncFIIk

inE.hormaecheiandonaIncX3plasmidinaST2E.coli,but

bothplasmidscontainedanewstructuredesignatedTn3000, thatcouldpossiblymediatethetranspositionoftheblaNDM-1 gene.91_{Subsequently,coproductionofNDM-1andKPC-2was}

describedinP.rettgeriandE.cloacaefromRiodeJaneiro.62,64

Morerecently,anewclassAcarbapenemase,designated BrazilianKlebsiellacarbapenemase(BKC-1)wasdescribed in Brazil.92_{TodateithasonlybeenfoundinK.pneumoniaeina}

lowfrequency,possibleduetothefactthattheblaBKC-1geneis locatedinasmalltransferable,non-conjugativeplasmid.92,93

Polymyxin

resistance

in

carbapenem-resistant

K.

pneumoniae:

a

nightmare

Thefirstreportonpolymyxin-resistanceinBrazilian

Entero-bacteriaceae came out in 2006.94 _{At that time, with a low}

colistinandpolymyxinBclinicaluse,thepolymyxinB resis-tance rate was 0.5% in E. coli, 1.8% in K. pneumoniae and 16.7% in Enterobacter spp. In a subsequent publication the samegroupevidenceda3.0%resistancerateamongK.

pneu-moniae in Latin America.95 _{In 2013, Pereira et al. reported}

a 15% polymyxin resistance rate amongKPC-producing K.

pneumoniaefrom diverseBrazilianstates.67 _Polymyxin

resis-tanceinE.cloacaeandK.pneumoniaestrainswasalsoreported fromPorto Alegre,south ofBrazil.61,96 _{Todate,interruption}

ofmgrBgenebyinsertionsequencesormissensemutations isthemostfrequentmechanismofpolymyxinresistancein

K.pneumoniaeinBrazil.93,97_{Themostrecentevidenceofthe}

amazingpolymyxinresistanceprobleminBrazilcamefroma reportfromSãoPaulo,thelargestcityinLatinAmerica.The authorsdescribeda35.5%carbapenemresistanceratedueto KPC-2production,amongK.pneumoniaecausinginfectionsin 2015,andalsofoundanincreaseinpolymyxinBresistance amongKPC-producingK.pneumoniae,from0%in2011to27.1% in2015.80 _{Thisincreasecoincidedwiththeincreaseduseof}

polymyxinsasempirictherapytotreatsevereinfectiouswhen Gramnegativesarepossibleetiologicagentsinintensivecare units. Moreconcerningwasfindinginterhospitaland intra-hospitalclonaldisseminationandthefactthatmostisolates includedinthestudyweredetectedfrombloodcultures.This isatherapeuticnightmare,sinceintravenousfosfomycinand ceftazidime-avibactamarestillnotavailableinBrazil.

Recently,the mcr-1(mobile colistinresistance) genewas detectedinaclinicalstrainofE.coliST101fromtheNortheast ofBrazil.98_{Theauthors foundthegene locatedon aIncX4}

plasmid,andconsequentlytheselectivepressurerepresented bytheoveruseofpolymyxinscouldhavecontributedtothe disseminationofthisresistancemechanism.

Insummary,antimicrobialresistanceinEnterobacteriaceae

inBrazilisaveryseriousproblemthatneedsurgentactions which includes more strict adherence to infection control measures, more judicioususe of antimicrobials inhuman and animal husbandriesand fast approvalofold and new antimicrobialslikefosfomycinandceftazidime-avibactamfor clinicaluseinBrazil,inordertodecreasethepolymyxin con-sume.Ifthesemeasuresarenotappliedtogether,therelease ofceftazidime-avibactamwillbeapartialmeasurethatwill beprobablyfollowedbydisseminationofNDM-1producersin Brazil.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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