First report of NDM-1-producing Klebsiella pneumoniae imported from Africa to Italy: Evidence of the need for continuous surveillance

Short

Communication

First

report

of

NDM-1-producing

Klebsiella

pneumoniae

imported

from

Africa

to

Italy:

Evidence

of

the

need

for

continuous

surveillance

Luigi

Principe

a

_,

_Carola

_Mauri

a

_,

_Viola

_Conte

b

_,

_Beatrice

_Pini

a

_,

_Tommaso

_Giani

b

_,

Gian

Maria

Rossolini

b,c,d,e

_,

_Francesco

_Luzzaro

a,

_*

a_{ClinicalMicrobiologyandVirologyUnit,A.ManzoniHospital,Viadell’Eremo9/11,23900Lecco,Italy} b_{DepartmentofMedicalBiotechnologies,UniversityofSiena,Siena,Italy}

c_{DepartmentofExperimentalandClinicalMedicine,UniversityofFlorence,Florence,Italy} d_{ClinicalMicrobiologyandVirologyUnit,FlorenceCareggiUniversityHospital,Florence,Italy} e_{DonCarloGnocchiFoundation,Florence,Italy}

ARTICLE INFO Articlehistory:

Received1September2016 Accepted17October2016 Availableonline5December2016 Keywords: Carbapenemase Klebsiellapneumoniae Metallo-b-lactamase Geographicregions Globalepidemiology ABSTRACT

Objectives:NDM-producingEnterobacteriaceaeareconsideredemergentontheAfricancontinentand

havebeenincreasinglyreportedinrecentyears.Incontrast,strainsproducingNDM-typeenzymeshave

beenrarelyreportedinItaly,usuallyassociatedwithsporadiccasesorsmalloutbreaks.Herewereport

twocasesofinfectioncausedbyNDM-1-producingKlebsiellapneumoniae(NDM-KP)intwounrelated

patientsreturnedfromtraveltoEgypt.

Case reports:Thetwopatientshadbeenpreviouslyhospitalised forashortperiodintwodifferent

Egyptian hospitals.InourinstitutioninItaly,NDM-KPisolatesweredetected fromsurgicalwound

drainage(patient#1)andrespiratorysecretionsandbloodcultures(patient#2).Rectalswabsofboth

patientswerepersistentlypositiveforNDM-KP.Inbothcases,NDM-1-producingisolatesexhibiteda

multidrug-resistantphenotype,beingsusceptibleonlytotigecyclineandcolistin.Analysisbymultilocus

sequencetyping(MLST)revealedthatthetwoK.pneumoniaeisolateswerenotclonallyrelated,belonging

todifferentsequencetypes(STs),namelyST15frompatient#1andST11frompatient#2.

Conclusions:Tothebestofourknowledge,thisisthefirstreportofNDM-producingisolatesimported

fromAfricatoItaly,withnoobviouslinktotheIndiansubcontinent.OurexperienceconfirmsthatEgypt

isanemergentsourceofNDM-producingEnterobacteriaceae,thusrepresentingacauseofconcernfor

Mediterraneancountries.Owingtoitsgeographicalposition,Italyisafirst-lineEuropeancheckpoint

withrespecttoAfricancountriesandplaysapivotalroleinlimitingthedisseminationofhigh-riskclones,

especiallyconsideringthelateststrongmigrationflows.

©2016PublishedbyElsevierLtdonbehalfofInternationalSocietyforChemotherapyofInfectionand

Cancer.

1.Introduction

Carbapenem-resistantEnterobacteriaceae(CRE)havebecomea worldwide health issue and pose a major threat due to the narrowing range of therapeutic options [1]. In most cases, resistance is due to carbapenemase production and affects Klebsiellapneumoniaestrains. NewDelhi metallo-

b

-lactamase-1 (NDM-1)wasfirst describedin2008in aK.pneumoniaeisolate fromaSwedishpatientwhohadpreviouslybeenhospitalisedin NewDelhi,India[2].ItisaclassBcarbapenemasethatisableto

conferresistancetoalmostall

b

-lactams,exceptthemonobactam aztreonam.Ofnote,owingtotheco-presenceofotherresistance mechanisms,NDM-producingisolatesareusuallyalsoresistantto aminoglycosides, fluoroquinolones and sulphonamides, leaving fewornotherapeuticoptions[1].Followingthefirstdescription, NDM-typeenzymeshavebeendetectedindifferentstrainsfromall continents,andseveralvariantshavebeenidentified(NDM-1to -14) [1,3]. The Indian subcontinent, the Balkan region and the MiddleEastareconsideredtobethemainendemicareasfor NDM-producers [4]. Focusing on the African continent, the first identification of NDM-1 occurred in 2007 in a K. pneumoniae strainobtainedfromtheurinarytractofapatienthospitalisedin Kenya[5].NDM-producingEnterobacteriaceaehavebeen subse-quently reported from several African nations and have been

* Correspondingauthor.Fax:+390341489601. E-mailaddress:f.luzzaro@asst-lecco.it(F.Luzzaro).

http://dx.doi.org/10.1016/j.jgar.2016.10.004

2213-7165/©2016PublishedbyElsevierLtdonbehalfofInternationalSocietyforChemotherapyofInfectionandCancer.

ContentslistsavailableatScienceDirect

Journal

of

Global

Antimicrobial

Resistance

increasinglydescribedinrecentyears[6].InEurope,asignificant spread,althoughmorelimitedthantheIndiansubcontinent,was alsoobserved in theUK, which hasclose ties withIndia and Pakistan[7].In Italy,thefirstdetectionofNDM-1 occurredin 2009,intwopatientshospitalisedinModena(northernItaly)and colonisedattheintestinallevelbyaNDM-1-producing Escher-ichiacoli.Analysisofhospitalrecordsrevealedanepidemiological linkbetweenthesetwocasesandathirdpatientwithahistoryof hospitaladmissioninIndia(in2008).Thelatterpatienthadfaecal carriageofcarbapenem-resistantE.coliduringastayinthesame unitinthesameperiod[8].Twoyearslater,in2011,NDM-1was detectedinK.pneumoniaeandE.coliisolatesobtainedfromsix patientshospitalisedinfourhealthcarefacilitiesintheBologna area(northernItaly,closetoModena),withonepatienthavinga historyofhospitalisationinNewDelhi,India[9].Morerecently,in 2012,theNDM-4variantwasdetectedinE.colifromtwopatients hospitalisedin award ofa largetertiaryhealthcare facilityin Genoa(northernItaly).Alsointhiscase,oneofthepatientshad been previously hospitalised in India [10]. This kind of epidemiologyhighlightsthepivotalroleoftheIndian subconti-nentintheworldwidedisseminationofNDM-producingisolates. In particular, patients repatriated after hospitalisation abroad may be a risk for introducing multidrug-resistant micro-organismsintohospitalsintheirhomecountries.

Here we report two cases of infection caused by NDM-1-producingK.pneumoniaeintwopatientsreturnedfromtravelto Egypt,wheretheyhadalsobeenhospitalised.Tothebestofour knowledge,thisisthefirstreportofinfectionscausedby NDM-1-producingisolatesimportedfromAfricatoItaly.

2.Casereports 2.1.Case#1

On3April2014,a2-year-oldItalianchildofAfricanorigin wasinvolvedinatrafficaccidentduringaholidayinEgyptand washospitalisedinanintensivecareunit(ICU)atahospitalin Cairo.Radiologicalexaminationevidencedabdominalcrushing, pelvicfracture, hepatic laceration andspleen contusion. The childunderwentabdominalsurgerybylaparotomywithpartial hepatectomy and the placement of subhepatic drainage. No data on the antibiotic regimen during this hospitalisation periodareavailable.On8April2014,hereturnedtoItalywith thefamilyandon11April2014wasadmittedtoourinstitution (A.ManzoniHospital,Lecco,Italy)withanextendedabdominal haematoma,diffuse bruisesanda surgicalabdominal wound withlossofperitonealfluidasaconsequenceofthedrainage. Onadmission,hehadfeverandabdominalpain.Thedrainage fluidand a rectal swab forscreening of CRE were taken for laboratoryanalysis.Empiricalantimicrobial therapybasedon ampicillin (500mg four times daily) plus netilmicin [50mg once daily (o.d.)] was administered. Topical gentamicin was applied to the surgical wound. Cultures both from the rectalswaband the drainage fluid revealed the presence of a carbapenem-resistantK.pneumoniaeisolate.On16April2014,the childwastransferredtothePaediatricSurgeryUnitofanother hospitalforsurgicalexamination,butnosurgicaloperationwas conducted.He wasdischargedon29April2014,but2dayslater the childwas re-admittedtoourhospital forabdominal painand vomitingsyndrome,likelyrelatedtohissurgicalcondition.During hospitalisationhe underwent radiological and microbiological examination.Cultureswerenegativeforcommonfaecal patho-gens(Salmonella,Shigella andCampylobacter), whilsttherectal swabwasagainpositiveforcarbapenem-resistantK.pneumoniae.

Thechildwasdischargedon6May2014ingoodcondition. Table

1 Clinical information of the tw o cases. Pat ient Ag e (y ears) Se x Previo us hospitalisation A dmission to Italian hospital Diagnosis at admission NDM- pro ducing strain (ST ) NDM variant Sour ce of collection Other bacte rial stra ins collect ed Antimicr obial tr eatment in Ital y Outcome Dat e of admission City , country Antimicr obial tre atment Pat ient _#1 2 M ale 3 April 20 14 Cair o, Egyp t N A 11 April 20 14 Pol ytr auma due to tr af fi c accident Klebsiella pneumoniae (ST 15) NDM- 1 Abdominal dr ainag e fl uid, st ool – AMC, AMP ,GEN, NET ,TZP Discharged in good conditions after 26 da ys Pat ient _#2 63 Male 17 Oct ober 20 14 Hurghada, Egyp t FLU ,MTZ, MEM, VAN 20 Oct ober 20 14 Pneumonia K. pneumoniae (ST 11) NDM- 1 R espir at ory secr etions, blood, urine, sto ol Acinet obacter baumannii , Stenotr ophomonas malt ophilia COL, CR O, IMI, LEV, LIN, MEM, RIF ,SXT Discharged in good conditions after 61 da ys ST ,seq uence type; N A, no ta vailable; AMC, amo xicillin/cla vulanic acid; AMP ,ampicillin; GEN, gentamicin; NET ,netilmicin; TZP ,piper acillin/ta zobactam; FLU ,fl uconazole; MTZ, metr onidazole; MEM, mero penem; VAN, vancom ycin; COL, colistin; CR O, ceftriax one; IMI, imipenem; LEV, lev ofl oxacin; LIN, linezolid; RIF ,rifampicin; SXT ,trimethoprim/sulfametho xazole.

2.2.Case#2

On17October2014,a63-year-oldItaliancitizendevelopedan acuterespiratorysyndromeduringacruiseontheRedSeaandwas hospitalised at the Red Sea Hospital (Hurghada, Egypt). On admission he was soporose, with fever (41!_{C), dyspnoea and}

respiratoryfailure.Anempiricalantibiotictreatmentwasinitiated usingmeropenem[1gthreetimesdaily(t.i.d.)],vancomycin[1g twicedaily(b.i.d.)],metronidazole(500mgt.i.d.)andfluconazole (400mg o.d.). Cultures of respiratory secretions revealed the presence of Streptococcus pneumoniae. Because of this severe clinical condition, the patient was intubated for mechanical ventilation.On 20 October2014,thepatientwas transferredto theICUofourinstitutioninaverycriticalcondition,withfever, septicshock,respiratoryfailure,ischaemiccardiopathyandatrial fibrillation. Intubation for mechanical ventilation as well as a centralvenouscatheter(CVC)werepresentatadmission.Hisurine waspositiveforpneumococcalurinaryantigen,andtherapywas started with ceftriaxone (1g b.i.d.), meropenem (1g t.i.d.) and levofloxacin (500mg b.i.d.). Cultures of purulent respiratory secretions(carried outonthefirst dayof hospitalisation) were positive for carbapenem-resistant K. pneumoniae, carbapenem-resistant Acinetobacter baumannii and Stenotrophomonas malto-philia. In addition, the CVC (previously placed in Egypt) was positivefor carbapenem-resistantA.baumannii. Based onthese findings,colistin(2MUt.i.d.)andtrimethoprim/sulfamethoxazole (20mg/kg o.d.)were added totherapy. On 12 November2014, blood cultures resulted positive for carbapenem-resistant K. pneumoniae. Screening rectal swabs were positive for carbape-nem-resistantK.pneumoniaeandA.baumanniiduringtheentire hospitalisationperiod.On3December2014,hewastransferredto themedicalward.Urinecultureswerepositivefor carbapenem-resistant K. pneumoniae on 5 and 15 December 2014, but no antibiotictherapywasadministered.Thepatientwasdischargedin goodconditionon19December2014.

Clinicalinformationaboutthetwocasereportsissummarised inTable1.

Inbothcases,bacterialidentificationwasperformedby matrix-assistedlaserdesorption/ionisationtime-of-flightmass spectrom-etry (MALDI-TOF/MS) (VITEK1 _{MS; bioMérieux, Marcy-l’Étoile,} France).Antimicrobialsusceptibilitytestingagainstthe carbape-nem-resistantK.pneumoniaewasperformedbytheClinicaland LaboratoryStandards Institute(CLSI)broth microdilution refer-encemethodusinglyophilisedcustomplates(Sensititre; Thermo-FisherScientific,Basingstoke,UK)andtheresultswereinterpreted accordingtoEuropeanCommitteeonAntimicrobialSusceptibility

Testing(EUCAST)criteria[11].Carbapenem-resistantK.pneumoniae isolatesweresusceptibleonlytotigecyclineandcolistin(Table2). Thepresenceofametallo-

b

-lactamase(MBL)wasphenotypically evaluatedonthebasisofsynergisticactivitybetweenmeropenem anddipicolinicacidusingboththedoublediskapproximationtest (RoscoDiagnosticaA/S,Taastrup,Denmark)and acommercially availablecombinationmethod(KPC+MBLConfirmIDKit;Rosco DiagnosticaA/S).

The blaNDM gene of both isolates was first detected by the GeneXpert1 _{System using the Xpert Carba-R test (Cepheid,} Sunnyvale,CA).ConventionalPCRandsequencingforconfirmation wereperformedaspreviouslydescribed[8,12]andrevealedthe blaNDM-1 allelicvariant. Multilocussequencetyping(MLST)was carriedoutaccordingtoprotocolsandconditionsasdescribedon the K. pneumoniae MLST website (http://bigsdb.web.pasteur.fr/ klebsiella/klebsiella.html).MLSTanalysisrevealedthatthetwoK. pneumoniaeisolateswerenotclonallyrelated,belongingtotwo differentSTs,namelyST15inpatient#1andST11inpatient#2. Carbapenem-resistantA.baumanniifrompatient#2wasnegative fortheblaNDMgene.

3.Discussionandconclusions

Theglobalspread ofNDM-type carbapenemasesisa serious threat in the field of carbapenem resistance because of rapid dissemination and association with multidrug resistance that greatlylimits therapeuticoptions.To date,thereservoir ofthis carbapenemase was mostly related to theIndian subcontinent, whichisinhabitedbythesecondlargestpopulationintheworld and whereNDM-1-producersarereportedalsofor community-acquiredinfections[4].Thesizeofthatreservoirmayexplainthe rapidityof theworldwidedisseminationofNDM-producers[4]. Accordingtothiscontext,allpreviouslydescribedNDM-producing Enterobacteriaceaeisolatedin Italywereepidemiologically con-nectedtoahistoryofhospitalisationontheIndiansubcontinent

[8–10].Interestingly,herewedescribethefirstfindingof NDM-producingisolatesimportedfromAfricatoItaly,withnoobvious linktotheIndian subcontinent.In thesecases,infact, NDM-1-producingK.pneumoniaewerealreadypresentatadmissionand showedastrongcorrelationwithrecentprevioushospitalisationin Egyptianhospitals.Overall,limitedinformationisavailableforthis geographic area, although NDMdeterminants havebeen previ-ouslydescribedinK.pneumoniae,PseudomonasaeruginosaandA. baumanniiisolatedinEgypt[6,12,13].Ourdataconfirmthatthis areaisanemergentsourceofNDM-producingEnterobacteriaceae, thusrepresentingacauseofconcernforMediterraneancountries.

Table2

AntimicrobialresistanceprofileofNDM-1-producingKlebsiellapneumoniaeisolates.

Antibiotic MIC(mg/L)[susceptibilitycategorya_]

NDM-KPisolatefrompatient#1 NDM-KPisolatefrompatient#2 Amoxicillin/clavulanicacid >16[R] >16[R] Piperacillin/tazobactam >64[R] >64[R] Cefotaxime >32[R] >32[R] Ceftazidime >32[R] >32[R] Cefepime >32[R] >32[R] Ertapenem >4[R] >4[R] Imipenem 16[R] 16[R] Meropenem 16[R] 32[R] Amikacin >32[R] >32[R] Gentamicin >8[R] >8[R] Ciprofloxacin >4[R] >4[R] Tigecycline 1[S] 0.5[S] Trimethoprim/sulfamethoxazole >8[R] >8[R] Colistin "0.5[S] "0.5[S]

MIC,minimuminhibitoryconcentration;R,resistant;S,susceptible.

The uncontained spread of carbapenemase-producing bacteria mayoccurin Africaforseveral reasons,primarilyowingtothe limitedattentiontoantimicrobialstewardshipandthesuboptimal levelofinfectioncontrolpractices,withlimitedopportunityfor patient isolation or screening of high-risk individuals [6]. Of concern,thereisanincreaseinover-the-counteruseof carbape-nemsinAfrica,especiallyinEgypt,owingtothequasi-absenceof regulationsgoverningantibioticuse[14].

In Italy,arecentcountrywidesurveillanceshowedthat KPC-producing enterobacteria are now endemic in this country, whereasothercarbapenemases(e.g.MBLsandOXA-typeenzymes) aresporadicandareresponsibleforasmallpercentageofcases

[15].Inourexperience,earlydetectionofNDM-producingisolates wasperformedbyrectalswabscreeningonadmissionbasedon phenotypic and molecular methods. Further analysis by MLST evidencedthepresenceoftwo differentSTs, ofwhich ST15has beenpreviouslyreportedinAfrica(Morocco)andbelongstoCC14. ItisconsideredtobeendemicbothinHungaryandDenmarkand hasbeenassociatedwithahighcontentofvirulencefactors[16]. ST11is the major ST among K.pneumoniae strainsharbouring blaKPC from Asia, but it has been also associated with NDM determinants[17].Ofnote,thefirstNDM-1-producingK. pneumo-niaereportedfromEgyptbelongedtoST11,andisolatesofthistype haverecentlybeenfoundinthesamecountry[18,19].Both NDM-1-producingisolates exhibitedamultidrug-resistantphenotype, beingsusceptibleonlytotigecyclineandcolistin.Ofnote,patient #1wasnotappropriatelytreatedforNDM-producingK. pneumo-niae.However,thepatient’sconditionsimproved,thussuggesting probablecolonisation by NDM-producing K.pneumoniae rather than infection. In contrast, patient #2received an appropriate antimicrobialregimenbasedonseveralextended-spectrum anti-bioticsgivenduringthehospitalisationperiodintheICU.Asshown in Fig.1, colistin was administered for a long period of time (38days),mostlyincombinationwithcarbapenems(imipenemfor 30days and meropenem for 10 days). Following a 3-week antimicrobialregimen, a 1-daytreatmentwashout wasapplied thusallowingtheemergenceof pathogenscausingbloodstream infection.Followinga newcourseof antimicrobials,thepatient wasdischargedingoodconditionsafter61daysofhospitalisation. The link betweenNDMacquisition and healthcare exposure abroad has been extensively described [1,4]. This situation necessitates a series of infection control measures as soon as possible. At a local level, patients with a history of travel or originatingfromhigh-riskcountriesshouldbescreenedfor

NDM-producingbacteria[20].Notably,thepatientsinthecurrentstudy wereisolatedonadmissionowingtotheirprevioushospitalisation inacountryconsideredat-riskforCREandwerescreenedbyrectal swabs.Thisprocedureincombinationwiththeearlydetectionof NDM determinants prevented the development of onward transmission and potential outbreaks and helped to optimise antibiotic therapy. No further cases occurred in the hospital setting. Limiting patient infections and surveillance of patients colonisedwithcarbapenemase-producingEnterobacteriaceaeare of paramount importancetohospitalepidemiology and patient safety.Inthiscontext,optimaltherapeuticoptionsareverylimited. Early recognition of carbapenemase expression is the key for appropriate treatment. Ensuing availability of drugs based on specific carbapenemase inhibitors (e.g. ceftazidime/avibactam, whichis noteffectiveagainstclassBcarbapenemases) isanew reason for precise identification of carbapenem resistance determinants. Finally,it is worthnoting thatItaly is subject to strongmigrationflowsfromAfricannations andplaysapivotal role in limiting the dissemination of high-risk clones among Europeancountries. Funding None. Competinginterests Nonedeclared. Ethicalapproval Notrequired. References

[1]NordmannP,NaasT,PoirelL.Globalspreadofcarbapenemase-producing Enterobacteriaceae.EmergInfectDis2011;17:1791–8.

[2]Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, et al. Characterizationofanewmetallo-b-lactamasegene,blaNDM-1,andanovel erythromycinesterasegenecarriedonauniquegeneticstructureinKlebsiella pneumoniae sequencetype 14 fromIndia.AntimicrobAgents Chemother 2009;53:5046–54.

[3]ZouD,HuangY,ZhaoX,LiuW,DongD,LiH,etal.AnovelNewDelhi metallo-b-lactamase variant, NDM-14, isolated in a Chinese hospital possesses

Fig.1.Antimicrobialtreatmentduringthehospitalisationperiodintheintensivecareunit(ICU)forpatient#2.Boxesindicateclinicalisolatesandthedateofisolation.Rectal swabswerepositiveforAcinetobacterbaumanniiandNDM-producingKlebsiellapneumoniaeduringtheentirehospitalisationperiodintheICU(datanotshown).CVC,central venouscatheter;MEM,meropenem;LIN,linezolid;LEV,levofloxacin;CRO,ceftriaxone;SXT,trimethoprim/sulfamethoxazole;COL,colistin;IMI,imipenem;RIF,rifampicin.

increased enzymatic activity against carbapenems. Antimicrob Agents Chemother2015;59:2450–3.

[4]DortetL,PoirelL,NordmannP.WorldwidedisseminationoftheNDM-type carbapenemasesinGram-negativebacteria.BiomedResInt2014;2014:249856. [5]PoirelL,RevathiG,BernabeuS,NordmannP.DetectionofNDM-1-producing

KlebsiellapneumoniaeinKenya.AntimicrobAgentsChemother2011;55: 934–6.

[6]ManenzheRI,ZarHJ,Nicol MP,KabaM.Thespread of carbapenemase-producingbacteriainAfrica:asystematicreview.JAntimicrobChemother 2015;70:23–40.

[7]Jain A, Hopkins KL, Turton J, Doumith M, Hill R, Loy R, et al. NDM carbapenemasesintheUnitedKingdom:ananalysisofthefirst250cases.J AntimicrobChemother2014;69:1777–84.

[8]D’AndreaMM,VenturelliC,Giani T,ArenaF,ConteV,BrescianiP,etal. Persistent carriage and infection by multidrug-resistant Escherichia coli ST405producingNDM-1carbapenemase:reportonthefirstItaliancases.J ClinMicrobiol2011;49:2755–8.

[9]GaibaniP,AmbrettiS,BerlingeriA,CordovanaM,FarruggiaP,PanicoM,etal. OutbreakofNDM-1-producingEnterobacteriaceaeinnorthernItaly,Julyto August2011.EuroSurveill2011;16:[pii:20027].

[10]CoppoE, Del BonoV, VenturaF, CameraM,Orengo G, Viscoli C,et al. Identification ofa New Delhi metallo-b-lactamase-4 (NDM-4)-producing EscherichiacoliinItaly.BMCMicrobiol2014;14:148.

[11]EuropeanCommittee on Antimicrobial Susceptibility Testing. Breakpoint tablesforinterpretation ofMICsandzonediameters. Version4.0.Basel, Switzerland: EUCAST; 2014 http://www.eucast.org/clinical_breakpoints/. [Accessed29November2016].

[12] KaaseM,NordmannP,WichelhausTA,GatermannSG,BonninRA,PoirelL. NDM-2carbapenemaseinAcinetobacterbaumanniifromEgypt.JAntimicrob Chemother2011;66:1260–2.

[13]BiedenbachD,BouchillonS,HackelM,HobanD,KazmierczakK,HawserS, et al. Dissemination ofNDM metallo-b-lactamase genes among clinical isolatesofEnterobacteriaceaecollectedduringtheSMARTGlobalSurveillance Studyfrom2008to2012.AntimicrobAgentsChemother2015;59:826–30. [14]LaxminarayanR,DuseA,WattalC,ZaidiAK,WertheimHF,SumpraditN,etal.

Antibiotic resistance—the need for global solutions. Lancet Infect Dis 2013;13:1057–98.

[15]GianiT,PiniB,ArenaF,ConteV,BraccoS,MigliavaccaR,etal.Epidemic diffusionofKPCcarbapenemase-producingKlebsiella pneumoniaeinItaly: resultsofthefirstcountrywidesurvey,15Mayto30June2011.EuroSurveill 2013;18:[pii:20489].

[16]PoirelL,BenoudaA,HaysC,NordmannP.EmergenceofNDM-1-producing KlebsiellapneumoniaeinMorocco.JAntimicrobChemother2011;66:2781–3. [17]PitoutJD,NordmannP,PoirelL.Carbapenemase-producingKlebsiella pneumo-niae,akeypathogensetforglobalnosocomialdominance.AntimicrobAgents Chemother2015;59:5873–84.

[18]AbdelazizMO,BonuraC,AleoA,FascianaT,MamminaC.NDM-1-and OXA-163-producingKlebsiellapneumoniaeisolatesinCairo,Egypt,2012.JGlob AntimicrobResist2013;1:213–5.

[19]GamalD,Fernández-MartínezM,SalemD,El-DefrawyI,MontesLA, Ocampo-SosaAA,etal.Carbapenem-resistantKlebsiellapneumoniaeisolatesfromEgypt containingblaNDM-1onIncRplasmidsanditsassociationwithrmtF.IntJInfect Dis2016;43:17–20.

[20]LeblebiciogluH,Rodriguez-MoralesA,RossoliniGM,López-VélezR,ZaharJ-R, RelloJ,etal.Managementofinfectionsincriticallyillreturningtravellersin theintensivecareunit—I:considerationsoninfectioncontroland transmis-sionofresistance.IntJInfectDis2016;48:113–7.