w w w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Review
article
Mobile
genetic
elements
associated
with
carbapenemase
genes
in
South
American
Enterobacterales
Jorge
Aníbal
Reyes
a,b,∗,
Roberto
Melano
c,d,
Paúl
Andrés
Cárdenas
a,
Gabriel
Trueba
aaUniversidadSanFranciscodeQuito,ColegiodeCienciasBiológicasyAmbientales,InstitutodeMicrobiología,Quito,Ecuador bUniversidadCentraldelEcuador,FacultaddeCienciasQuímicas,Quito,Ecuador
cPublicHealthOntario,Toronto,Canada
dUniversityofToronto,DepartmentofLaboratoryMedicineandPathobiology,Toronto,Canada
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Articlehistory:
Received15November2019 Accepted21March2020 Availableonline21April2020
Keywords:
Mobilegeneticelements Carbapenemase SouthAmerica
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Introduction:CarbapenemresistanceinmembersoforderEnterobacteralesisagrowing pub-lichealthproblemcausinghighmortalityindevelopingandindustrializedcountries.Its emergenceandrapidpropagationworldwidewasduetobothintercontinentalspreadof pandemicstrainsandhorizontaldisseminationviamobilegeneticelements(MGE)suchas plasmidsandtransposons.
Objective:TodescribeMGEcarryingcarbapenemresistancegenesinEnterobacteraleswhich havebeenreportedinSouthAmerica.
Searchstrategyandselectioncriteria:AsearchoftheliteratureinEnglishorSpanish pub-lisheduntil2019inPubMed,GoogleScholar,LILACSandSciELOdatabaseswasperformed forstudiesofMGEinEnterobacteralesreportedinSouthAmericancountries.
Results:Seven South American countries reported MGE related to carbapenemases. Carbapenemase-producingKlebsiellapneumoniaebelongingtoclonalcomplex258werethe most prevalent pathogens reported; others carbapenemase-producing Enterobacterales suchasEscherichiacoli,Serratiamarcescens,andProvidenciarettgerialsohavebeenreported. TheMGEimplicatedinthespreadofthemostprevalentcarbapenemasegenesareTn4401 andnon-Tn4401elementsforblaKPCandISAba125forblaNDM,locatedindifferentplasmid
incompatibilitygroups,i.e.L/M,A/C,FIIandbacterialclones.
Conclusion: Thisreviewindicatesthat,likeinotherpartsoftheworld,themostcommonly reportedcarbapenemasesinEnterobacteralesfromSouthAmericaarebeingdisseminated throughclones,plasmids,andtransposonswhichhavebeenpreviouslyreportedinother partsoftheworld.
©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
∗ Correspondingauthor.
E-mailaddress:jorgereyes83@gmail.com(J.A.Reyes).
https://doi.org/10.1016/j.bjid.2020.03.002
1413-8670/©2020SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Enterobacterales are the most prevalent opportunistic pathogens inhospitalsettings,causing sepsis, pneumonia, soft tissue infections, urinary tract infections, and others. Tomakethisproblemworse,theemergenceofresistanceto -lactams,themostcommonlyusedfamilyofantibiotics,has drasticallyreducedtreatmentoptions forthose infections.1
SinceAlexander Flemingdescribed thepenicillinin1928,a largenumberof-lactamshavebeendevelopedbelongingto fivegroups: penams,penems,cephems,monobactams,and carbapenems,allofwhichpossessa-lactamring.The car-bapenemsgroupistheelectiontotreatinfectionscausedby bacteriaproducingextended-spectrum-lactamases(ESBLs) orAmpCcephalosporinases.2
Inrecentyears,thecarbapenem-resistantEnterobacterales (CRE) have rapidly emerged and disseminated worldwide. Thisresistanceiscausedbyeitherproductionof carbapen-emases or a combination of mechanisms such as the presenceofdifferentESBLs (orAmpC) inaddition toporin loss. The evidence suggests that clonal dissemination of carbapenemase-producingEnterobacterales(CPE)playsa crit-icalroleinhospitaloutbreaksoflife-threateninginfections, whichhaveincreasedmortality,morbidityandhospitalization costs.3 However, mobilegenetic elements (MGEs)including
plasmids, transposable elements (TEs), and integrons are probably the most important factors implicated with the disseminationofcarbapenemasegenesamongdifferent bac-terial species. TE, including insertion sequences (ISs) and transposons (Tns), are discrete DNA structures, located in plasmids or chromosomes, which can move (through the activityofself-encodedtransposases)tonewlocationsinthe genome.TheISsare thesmallestTEsthatcanmove resis-tancegenesaspartofacompositetransposon;agenebounded bytwocopiesofthesame orrelatedISthatcanmoveasa singleunit.4,5Inthisreview,wedescribedifferentMGEs
associ-atedwithcarbapenemasegenesinEnterobacteralesmembers reportedinSouthAmericancountries.
Methodology
AsearchofliteraturepublishedinEnglishorSpanish until August2019was performedusingPubMed, GoogleScholar, LILACSandSciELOdatabases.Inafirst-round,thekeywords ‘mobilegeneticelementsANDcarbapenemaseresistance, car-bapenemaseANDEnterobacteriaceaeorEnterobacteralesAND (Argentina OR Brazil OR Bolivia OR Colombia ORChile OR EcuadorORGuyanaORFrenchGuianaORParaguayORPeru ORSurinameORUruguayORVenezuela)’wereused.Abstracts or conferencereports were not included unlessthe article formwasunavailable.Allselectedarticlesweresubjectedto asecondsearchroundforselectionofspecificstudiesusing molecularanalysiscriteria:(a)descriptionofclonalitybasedin sequencetype(ST)usingmultilocussequencetyping(MLST) orwhole genomesequencing and(b)descriptions ofMGEs associated with carbapenemase genes in Enterobacterales species,includingplasmidincompatibilitygroups(basedon replicon typing or restriction digestion performed with S1
nuclease) and/or description of TE or integrons structures usingDNAsequencing.
Results
Argentina
ThefirstreportofchromosomallyencodedNMC-A carbapen-emasewasinanEnterobactercloacaeisolaterecoveredfroma leukemiapatientin2004.6FouryearslateraKPC-2-producing
K. pneumoniaestrain wasreported.7 Gomezet al. described
the Tn4401a isoform associated with blaKPC-2 harbored in
theinternationalcloneK.pneumoniaeST258.Interestingly,a
blaKPC-2genewasassociatedwithnon-Tn4401elements(NTE)
inthenon-ST258clonesofK.pneumoniae(ST11,ST476, and ST526).InotherEnterobacteriaceaespecies,itwasharboredin transferableplasmidsbelongingtoIncHI2,IncL/MandIncA/C incompatibilitygroups.8Thebla
NDM-1 genewaslocatedina
Tn125compositetransposonharboredinplasmidsof differ-entsizes,reportedinProvidenciarettgeri.9Abla
IMP-8-harboring
plasmid IncA/C1-ST13wasdescribed inE.coli,andthe car-bapenemasegenewasassociatedwithintegronclassIflanked by twoIS26 elements.10 Other metallo--lactamases (MBL),
such as blaVIM-2 and blaVIM-11, were associated with
inte-gronsIn883,In885,In346,In900inE.cloacae,11andbla
VIM-16
associatedwithclassIintegroninSerratiamarcescens.12 Two
geneticallyrelatedK.pneumoniaeisolateswererecoveredfrom the same patient, one isolate harboringblaOXA-163 and the
other blaOXA-247. Interestingly,theirgenetic environmentin
bothgenescomprisedtheinsertionsequenceIS4321upstream andIS4-likeinsertiondownstream.13
Colombia
ThefirstdescriptionofKPC-2-producingK.pneumoniaeisolate inSouthAmericawasreportedinColombiain2005.14Later,
aKPC-3-producingK.pneumoniaewasisolatedfromanIsraeli patient(internationalspread).15Anotherreportshowedthat
the blaKPC-2 wasmoreprevalentthan blaKPC-3 inST258 and
non-ST258K. pneumoniae isolates, and the isoform Tn4401a was moreprevalent than Tn4401b.16 Other reportsshowed
a close relationshipof blaKPC-2 with Tn4401b isoform
(har-boredinIncL/Mplasmids)inisolatesofK.pneumoniaeST14, ST338, and ST339.17 Interestingly,the isoform “b”wasalso
harboredinIncA/CandIncFplasmidsinnon-K.pneumoniae
isolates.18bla
NDM-1wasreportedinEscherichiacoliassociated
withTn125andTn5393,locatedinIncA/Cplasmids.19An
out-breakcausedbyaK.pneumoniaeST1043carryinganIncA/C,
blaNDM-1-plasmidwasalsoreported.20
Brazil
Carbapenem-resistant K. pneumoniae is the most common CPEpathogeninthiscountry.KPC-2-producingK.pneumoniae
belongingto theclonalcomplex (CC)258(including ST258, ST11,andST437)hasbeendescribedinavarietyofMGEs asso-ciations(IncFII,IncN,IncL/M,anduntypableplasmidscarrying Tn4401aorTn4401b),whichweresuccessfullydisseminated amongspeciesofEnterobacterales.21Similarly,anotherstudy
described a KPC-2-producing K. pneumoniae ST11 carrying aTn4401 locatedin a IncWplasmid group.22 Recent work
describedtwoK.pneumoniaeisolatescarryingtheblaKPC-2gene
inNTE IIdlocatedinIncQ1andCol-likeplasmids.23 Inone
study the authors showed an association of blaKPC-2 with
Tn4401band IncNplasmids inCC11K. pneumoniae.24 E.coli,
E.cloacae,Enterobacteraerogenes,Citrobacterfreundiihavealso been reportedcarrying blaKPC-2 gene locatedinTn4401bor
Tn4401disoformsonplasmidsofdifferentsizes.25Anew
car-bapenemase,blaBKC-1,wasreportedinK.pneumoniaeST1781
anditwasclassifiedasanewmemberofmolecularAmbler classAserinecarbapenemasesin2015;itwaslocatedina 10-kbnon-conjugativeIncQplasmidthatincludedamobilization system,ISKpn23.26
ReportsofMBL andtheir MGEswere relatedtoblaNDM-1
and associated with a truncated ISAba125 in Enterobacter hormaechei27 orinsidea ∼10kb, compositetransposon (two
copiesofISAba125)namedTn125inP.rettgeri.28Interestingly,
thisgenehasalsobeenlocatedinthetransposonTn3000in
E.coliandE.hormaechei.29OtherMBLssuchbla
IMP-1geneinK. pneumoniaeandP.rettgerii30,31andbla
IMP-10 inS.marcescens32
werelinkedtoclass1integrons.
TheblaOXA-370reportedinE.hormaecheidifferedfrom
OXA-48onlybyasingleaminoacid substitution.Thisgenewas flankedupstreambyaTn3familytransposasegenetnpA (trun-catedbyanIS5075-likeinsertion)anddownstreamofaTn4 familytnpAgene(truncatedbyanIS15-likeinsertion).33
Ecuador
A blaKPC-2 gene was detected in K. pneumoniae ST258 and
ST25andassociatedwithTn4401a(Reyesetal.,manuscript inpreparation),whereastheblaNDM-1geneharboredinIncA/C
plasmidwasreportedinK.pneumoniaeST147.34Abla
OXA48-like
geneharboredinaTn1999wasreportedinaclinicalisolate
Raoultellaornithinolytica.35
Chile
TheTn4401aisoformharboringblaKPCgenewasreportedinK. pneumoniaeST258,ST101,ST25clonesandanNTEvariant1in
K.pneumoniaeST11,ST1161,andST29.36
Uruguay
ThepresenceofblaKPC-2geneharboredinTn4401awas
iden-tifiedinK.pneumoniaeST258causinganoutbreak.37
Venezuela
TheblaKPC-2locatedinaTn4401bwasreportedinK. pneumo-niaeST11,ST15,ST833,ST1271,ST1857,ST1859and ST1860 clones.38 K. pneumoniae ST833 was also described carrying
blaKPC-2andaclass1integronharboringblaVIM-2.39
Discussion
Althoughsomesuccessfulbacterialclonescandisseminate resistancevertically (e.g. K. pneumoniaebelonging toCC258
carrying Tn4401/blaKPC), carbapenemase genes (as well as
otherantibioticresistancedeterminants)arefrequently trans-mittedhorizontallybetweendifferententerobacterialclones, species,andgenera.40Furthermore,thesegenesalso
dissem-inateamongdifferent plasmidsand chromosomesthrough transpositionorrecombinationevents.41
InSouthAmerica,weobservedthesamepatternsreported worldwide (Table1), which indicates that some clonesare beingtransmittedamongSouthAmericancountries(or else-where),raising the needfortrackingcarbapenemase clone dissemination. There is also evidence of carbapenemase gene mobility between plasmids and clones which poten-tiallyfacilitatestheemergenceofnewepidemicCREclones such as K. pneumoniae ST11 and the hypervirulent clone ST25 (Table 1). This type of mobility is more difficult to track;plasmidscarryingthesegenescouldbeidentified(by replicon typingor plasmid/wholegenome sequencing),but therearrangementsduetorecombinationandtransposition sometimes complicate their traceability.8,42 A clear
exam-ple ofthis evolution is the blaKPC-2 gene in K. pneumoniae
CC258, which has been associated with IncFII derivatives suchaspKpQIL43andotherplasmid incompatibilitygroups
inArgentina,Brazil,Colombia,andEcuador(Table1)which havebeenrecoveredfromK.pneumoniaeCC258,non-CC258, andothermembersoftheEnterobacterales.44,45This
variabil-ityofplasmidscarryingsimilarblaKPCgeneticenvironments
suggests active plasmid rearrangements driven by trans-posons (e.g. Tn4401). The blaKPC-2 dissemination from the
original host (K. pneumoniae) to other species of Enter-obacteralesisconsequenceofthis evolutionaryprocess:an active transposonharboringantimicrobial resistancegenes finding broad (e.g. L/M, N, W) or wide host range plas-mids (e.g. IncF, IncH), like it was found in South America (Table1).46
Anotherapproachtopartiallyassesssomeofthese com-plexitiescouldbeanalyzingthegeneticenvironmentinwhich thesegenesarelocated.AclassicexamplewouldbeTn4401, a Tn3-type, 10-kb mobile transposon frequentlyassociated withblaKPCgenes.ItsstructureconsistsofaTn3transposase
gene(tnpA),aresolvasegene(tnpR)andadditionalinsertion sequences(ISKpn6andISKpn7)delimitedbytwo39-bp imper-fectinvertedrepeats(IRs).47Theisoforms(atoh)areclassified
basedinnucleotidedeletionsupstreamofblaKPCgene
(affect-ingitspromotorregionandtheKPC-expression),lackinggenes orboth:forinstance,isoform“a”hasa99bpdeletion;isoform “b”hasno deletion; isoform“c”, a215bpdeletion; isoform “d”, a68bpdeletion;isoform“e”,a255bpdeletion; isoform “f”,atruncationintnpA,absenceoftnpR,ISKpn7leftpartand Tn4401IRL-1;isoform“g”issimilarto“f”plusa215bp dele-tion(likeisoformc);andisoform“h”hasa188-bpdeletion.48
(Fig.1).Non-Tn4401elementsareothergeneticenvironments oftheblaKPCgene.ThesearecomplexDNAstructures
shar-ing someTn4401elementssuchasISKpn6. Someexamples are shown in Fig. 1.11,49,50 In South America the isoforms
Tn4401a andbwerethe mostcommonlyfoundinregional studies (e.g. inArgentina,Colombia, Brazil, Chile, Ecuador, and Venezuela),but NTEs and theisoforms Tn4401cand d
werealsodescribedinBrazil,respectively,mainlyinnon-K.
pneumoniaeisolates(Table1).Asmentionedbefore,this lat-eraldisseminationbetweengeneraandspecieswouldbemore
Table1–Summaryofmobilegeneticelementsreportedincarbapenemase-producingEnterobacteralesinSouthAmerica.
Country Isolate Replicontyping (incompatibility group) Transposable element Carbapenemase gene Reference
Argentina K.pneumoniaeST258 L/M Tn4401a blaKPC-2 8 C.freundii,E.cloacae
K.pneumoniae
non-258
HI2,L/M,A/C NTE:variantIaand VariantIb blaKPC-2 8 P.rettgeri E.coli B/O Tn125 Class1integron blaNDM-1 blaIMP-8 9,10
E.cloacae Non-typeable Class1integron: In883,In885,In346 andIn900
blaVIM-2andblaVIM-11 11
K.pneumoniae N/D IS4321-IS4 blaOXA-48 13
Colombia K.pneumoniaeST14 ST387,ST388
L/M Tn4401b blaKPC-2 16,17
K.pneumoniaeST258 N/D Tn4401aorTn4401b blaKPC-2
blaKPC-3 16 K.pneumoniaeST147 andST14 N/D Tn4401aorTn4401b blaKPC-2 18 K.pneumoniaeST512 N/D Tn4401b blaKPC-3 17
S.marcescens A/C Tn4401b blaKPC-2 18
E.coli F Tn4401b blaKPC-2 18
E.coli A/C Tn125andTn5393 blaNDM-1 19
K.pneumoniae
ST1043
A/C N/D blaNDM-1 20
Brazil K.pneumoniaeST258, ST11andST48
FII Tn4401a blaKPC-2 21
K.pneumoniaeST327 andST437andE.coli
K.pneumoniae N Q1 Tn4401b NTE blaKPC-2 blaKPC-2 21,23 S.marcescensandC. freundii L/M N/D blaKPC-2 25 E.coli,E.cloacae,E. aerogenes,C.freundii andP.stuartii N/D Tn4401band Tn4401d blaKPC-2 25 K.pneumoniaeST11 andE.coliST502 K.pneumoniae ST1781 W IncQ Tn4401c ISKpn23 blaKPC-2 blaBKC-1 21,26 Enterobacter hormaechei
FII ISAba125and Tn3000 blaNDM-1 27,29 P.rettgeri E.coli N/D IncX3 Tn125 Tn3000 blaNDM-1 blaNDM-1 28,29 K.pneumoniae,P. rettgeri S.marcescens N/D N/D ClassIintegrons ClassIintegrons blaIMP-1 blaIMP-10 30,32 E.hormaechei N/D Tn3truncated-Tn4 truncated blaOXA-370 33 Chile K.pneumoniaeST258, ST101,ST25 N/D Tn4401a blaKPC-2 36 K.pneumoniaeST258, ST101,ST25
N/D NTE:variant1a blaKPC-2 36
Ecuador K.pneumoniaeST147 K.pneumoniaeST248, 25,42 Raoultella ornithinolytica A/C FII N/D N/D Tn4401a Tn1999 blaNDM-1 blaKPC-2 blaOXA-48 34–35
Uruguay K.pneumoniaeST258 N/D Tn4401a blaKPC-2 37
Venezuela K.pneumoniaeST11, ST15,ST833,ST1271, ST1857,ST1859and ST1860
N/D Tn4401b blaKPC-2 38
K.pneumoniaeST833 N/D class1integron blaVIM-2-blaKPC-2 39
Fig.1–TransposableelementsassociatedwithblaKPC,blaOXA-likeandblaNDMcarbapenemasesfoundinthe
Enterobacteralesmembers.
relatedtothetypeofconjugativeplasmidwherethe transpo-son‘landed’.
Currently, more than 70 MBLs (chromosomally- and plasmid-encoded)havebeenreportedandgroupedbasedon DNA sequence similarity.51 NDM is one of the most
suc-cessfully plasmid-disseminated MBL detected in different
membersoftheEnterobacteralesaroundtheworldandtheir frequentassociationwithISAba125suggestsapossible Acine-tobacterspp.origin,abacteriuminwhichthisassociationis verycommon.52Tn125,anISAba125-basedcomposite
trans-poson, was one of the genetic elements described to be involved in blaNDM dissemination, but in Enterobacteriaceae
Tn125ithasbeeninterruptedortruncated,generatinga vari-etyofdifferentgeneticcontextsforblaNDM.53K.pneumoniae, E.coli,andEnterobacterspp.are thepredominantcarriersof
blaNDM, withheterogeneous clonalbackgroundsand
multi-pleacquisitionsofblaNDMgenesacrossbacterialspecies,also,
differentreplicon typesofblaNDM-carrying plasmids inthe Enterobacteriaceae were described,being the most common IncA/C, FIA, FIB, FII and X353 (in our bibliographic review
wefoundlessfrequentdescriptionsofMBL-producing Enter-obacteriaceae).ReportedblaNDM-1 geneswereassociatedwith
ISAba125 composite transposon Tn125 (Table 1). There are no extensive descriptions of bacterial clones and plasmid incompatibilitygroupsrelatedtoblaNDMinSouthAmerica.In
Argentina,therewasonedescriptionofablaNDM-1-harboring,
IncB/O plasmid recovered from P. rettgeri; in Colombiaand Ecuador,blaNDM-1wasdetectedonIncA/CplasmidsfromE.coli
(Colombia) and K. pneumoniae(both countries). More infor-mationhastobedevelopedand analyzedtohaveaclearer pictureofblaNDMspreadinSouthAmerica.Asimilarscenario
wasfoundregardingblaVIM(Argentina-Venezuela)andblaIMP
(Brazil),bothcarbapenemasegenesassociatedtoclass1 inte-grons,alsodescribed inPseudomonasaeruginosa, evidencing thatclassIintegronsareefficientgeneticplatformsto incor-porateMBLsgenesand disseminatedonceatransposonor plasmidisinvolved.54,55
TheOXA-enzymes have higher hydrolysis rates against cloxacillin and oxacillin than other -lactams.In addition, they are poorly inhibited by clavulanic acid, tazobactam, and aztreonam, and some can inactivate carbapenems.56
Wefound few descriptions of MGEsassociated with these carbapenemase genes in South America; in Ecuador, the
blaOXA-48-likegenewasrelatedtoTn1999-like.57However,in
Brazil blaOXA-347, avariant of blaOXA-48, showed association
withtruncatedTn3andTn4transposons.
Conclusions
CurrentevidenceenhancestheimportanceofMGEsfor car-bapenemasegenedissemination.ExceptforArgentina,Brazil, andColombia,thereportsofMGEsarescarceinotherSouth American countries. The blaKPC and blaNDM are the most
prevalentcarbapenemasegenesreportedinEnterobacterales speciesareassociatedwithTn4401/non-Tn4401elementsand ISAba125/Tn125respectivelywhileblaVIMandblaIMP
carbapen-emasegenesarerelatedtoclass1integrons.Thelocationof transposonsorintegronsindifferentplasmidincompatibility groupsandbacterialclonesdenotestheircapacityin trans-ferabilityandmobilization.Itispossiblethatintercontinental disseminationofCREcloneswasfollowedbyhorizontalgene transferofplasmidscarryingcarbapenemresistancegenesto localbacteria.Anycontrolmeasureintendedtotackle antibi-oticresistancegenesdisseminationrequirestheidentification ofthepotentialsourcesofthesegenes,whichnowadaysis car-riedoutbyDNApolymorphisms.Unfortunately,carbapenem resistancegeneshavevery little polymorphisms.Weargue thatthestudyofMGEsassociatedwiththesegenescould pro-videveryvaluableepidemiologicalinformationtodetectthe potentialsources.
Funding
information
ThisstudywasfundedbyInstitutodemicrobiología, Univer-sidadSanFranciscodeQuito.
Conflict
of
interest
Theauthorsdeclarenoconflictsofinterest.
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