Carbapenemases in Gram-Negative Bacteriadownloads.hindawi.com/journals/specialissues/231314.pdf · 2 BioMedResearchInternational spp.-CphA,andS.maltophilia-L1),acquiredMBLencoding

BioMed Research International

Carbapenemases in Gram-Negative Bacteria

Guest Editors: Branka Bedenić, Vanda Plečko, Sanda Sardelić, Selma Uzunović, and Karmen Godič Torkar

BioMed Research International


Guest Editors: BrankaBedenić, VandaPlečko, Sanda Sardelić’,Selma Uzunović, and Karmen Godič Torkar

Copyright © 2014 Hindawi Publishing Corporation. All rights reserved.

This is a special issue published in “BioMed Research International.” All articles are open access articles distributed under the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the originalwork is properly cited.

Contents

Carbapenemases in Gram-Negative Bacteria: Laboratory Detection and Clinical Significance,Branka Bedenić, Vanda Plečko, Sanda Sardelić’, Selma Uzunović, and Karmen Godič TorkarVolume 2014, Article ID 841951, 3 pages

Epidemiology of Carbapenemase-Producing Enterobacteriaceae and Acinetobacter baumannii inMediterranean Countries, Nassima Djahmi, Catherine Dunyach-Remy, Alix Pantel, Mazouz Dekhil,Albert Sotto, and Jean-Philippe LavigneVolume 2014, Article ID 305784, 11 pages

Worldwide Dissemination of the NDM-Type Carbapenemases in Gram-Negative Bacteria,Laurent Dortet, Laurent Poirel, and Patrice NordmannVolume 2014, Article ID 249856, 12 pages

Performance of Quantification of Modified Hodge Test: An Evaluation with Klebsiella pneumoniaeCarbapenemase-Producing Enterobacteriaceae Isolates, Vanessa Bley Ribeiro,Adriano Rostirolla Linhares, Alexandre P. Zavascki, and Afonso Luis BarthVolume 2014, Article ID 139305, 6 pages

Detection of Carbapenemase-Producing Enterobacteriaceae in the Baltic Countries and St. PetersburgArea, Anastasia Pavelkovich, Arta Balode, Petra Edquist, Svetlana Egorova, Marina Ivanova, Lidia Kaftyreva,Irina Konovalenko, Siiri Kõljalg, Jana Lillo, Lidia Lipskaya, Jolanta Miciuleviciene, Kristiine Pai, Kristel Parv,Katri Pärna, Tiiu Rööp, Epp Sepp, Jelena Štšepetova, and Paul NaaberVolume 2014, Article ID 548960, 7 pages

Carbapenemase Genes among Multidrug Resistant Gram Negative Clinical Isolates from a TertiaryHospital in Mwanza, Tanzania, Martha F. Mushi, Stephen E. Mshana, Can Imirzalioglu,and Freddie BwangaVolume 2014, Article ID 303104, 6 pages

Antimicrobial Resistance Pattern andTheir Beta-Lactamase Encoding Genes among Pseudomonasaeruginosa Strains Isolated from Cancer Patients, Mai M. Zafer, Mohamed H. Al-Agamy,Hadir A. El-Mahallawy, Magdy A. Amin, and Mohammed Seif El-Din AshourVolume 2014, Article ID 101635, 8 pages

EditorialCarbapenemases in Gram-Negative Bacteria:Laboratory Detection and Clinical Significance

Branka BedeniT,1,2 Vanda PleIko,1,2 Sanda SardeliT,3

Selma UzunoviT,4 and Karmen GodiI Torkar5

1 Clinical Department for Clinical and Molecular Microbiology, University Hospital Center Zagreb, 10000 Zagreb, Croatia2 Department of Microbiology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia3 Department of Microbiology, University Hospital Center Split, 21000 Split, Croatia4Cantonal Public Health Institute Zenica, 72000 Zenica, Bosnia and Herzegovina5 Department for Sanitary Engineering, Faculty of Health Sciences, 1000 Ljubljana, Slovenia

Correspondence should be addressed to Branka Bedenić; [email protected]

Received 24 May 2014; Accepted 24 May 2014; Published 15 June 2014

Copyright © 2014 Branka Bedenić et al.This is an open access article distributed under the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Carbapenems are potent 𝛽-lactam antibiotics used to treatserious infections in hospital settings. In comparison to peni-cillins, cephalosporins, or 𝛽-lactam/𝛽-lactamase inhibitor,they have broad antimicrobial spectrum that includesGram-positive (e.g., imipenem, doripenem) and Gram-negative bacteria (e.g., meropenem, ertapenem). Imipenemand meropenem have better activity against P. aeruginosa,while imipenem and doripenem have better activity thanmeropenem against Acinetobacter baumannii. Doripenemhas the lowest MIC against P. aeruginosa and A. baumanniiin comparison to imipenem and meropenem, and it is leastsusceptible to hydrolysis by carbapenemases.

To act on PBPs, carbapenems have to enter the wall ofGram-negative bacteria through outer membrane proteins(porins). Binding to different PBPs, they inhibit the synthesisof cell wall finally leading to the death of bacterium [1].

Carbapenem resistance in Gram-negative bacteria can bethe consequence of the production of a 𝛽-lactamase, expres-sion of efflux pumps, porin loss, and alterations in PBPs. Since𝛽-lactams, including carbapenem-like compounds, are natu-ral products of several environmental bacteria and fungi, it issupposed that other bacteria started to produce their intrinsic𝛽-lactamase to give them selective advantage for survival.Thus, several genes encoding different carbapenemases canbe found in environmental bacteria like Bacillus anthracis,Serratia fonticola, Pseudomonas cepacia, or Acinetobacterspp. as part of their chromosome [1, 2]. Further step in

this evolution of resistance was the escape of carbapenemaseencoding genes to mobile genetic elements (plasmids, trans-posons) providing possibility of successful horizontal spreadof resistance genes even between different genera [3].

Since this discovery, carbapenemases became a globalproblem. According to the Ambler classification (based onstructural similarities), they belong to the classes A, B, andD [1]. Class A carbapenemases contain serine at their activesite and are capable of hydrolyzing all 𝛽-lactams, includingaztreonam. In this group of carbapenemases, Sme (Sme-1 toSme-3), IMI (IMI-1 to IMI-3), NmcA, and SFC-1 enzymesare mostly chromosomally encoded, while KPC (KPC-2 toKPC-13) and GES (GES-1 to GES-20) are plasmid encoded.Dominant carbapenemase from this group is KPC, identifiedin 1996 in North Caroline, USA, now causing many regionaloutbreaks, with endemicity in northeastern part of the USA,Israel, China, Porto Rico, Colombia, and Greece, and becom-ing more and more prevalent throughout Europe [4]. BesideK. pneumoniae, represented by a predominant clone (ST258),it has been found in other Enterobacteriaceae, as well asin P. aeruginosa and A. baumannii-calcoaceticus complexes.It is sometimes difficult to be recognized since MICs tocarbapenems are in many cases lower than the breakpoints[2, 5]. Class B carbapenemases are also known as metallo-𝛽-lactamase (MBL) since they contain metal ion(s) in theiractive site. Beside those chromosomally located in envi-ronmental bacteria (Bacillus cereus-BCI, BCII, Aeromonas

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014, Article ID 841951, 3 pageshttp://dx.doi.org/10.1155/2014/841951

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2 BioMed Research International

spp.-CphA, and S. maltophilia-L1), acquired MBL encodinggenes are often located in gene cassettes within integron,being part of a plasmid or chromosome. Firstly describedacquired MBLs were in Japan in 1991, so called IMP-enzymes(there are now more than 30 derivatives), and are stilldominant MBLs in Asian continent causing mainly sporadicoutbreaks [6]. VIM-enzymes (there are now more than 30derivatives) were firstly described in P. aeruginosa but lateremerged in Enterobacteriaceae as well and fastly spread overwhole Europe, causing outbreaks in many Mediterraneancountries (like Greece, Italy, and Turkey). VIM metallo-𝛽-lactamase is now the most prevalent carbapenemase spread-ing globally and, although largely connected to P. aeruginosa,is now reported more often from Enterobacteriaceae fromMediterranean countries, particularly Greece and Turkey,with the description of many panresistant strains [6, 7].Anotherworrisomemetalloenzyme arose from India in 2008,namely, New-Delhi MBL (NDM-1; until now more thanten variants are described) and spread fastly over Indiansubcontinent in the following few years. NDM-enzymes aremostly not only associatedwith nonclonally related isolates ofK. pneumoniae and E. coli but also described in P. aeruginosaandA. baumannii [8]. Beside proven facts that those enzymesexist in isolates spreading in environment and are carriedin general population by enteric flora, the magnitude ofthe problem potentiates the huge population reservoir fromIndian subcontinent and Middle Asia that moves across theworld spreading further the resistance genes [9–11]. Anothernew source of those enzymes could be the Balkan region[12, 13]. Oxacillinases from molecular class D demonstratingcarbapenemase activity are often found in Acinetobacter spp.They are divided into themost globally spreadOXA-23 group,found also in environmental isolate of Acinetobacter spp.suggesting the possible natural and not nosocomial source ofthese genes, OXA-24 group, not so widespread as OXA-23,mostly described in Europe and USA, and OXA-58 group,described in several outbreaks all over the world [14]. Theproblem became more global with the discovery of OXA-48 in Enterobacteriaceae, particularly in K. pneumoniae andto lesser extent in E. coli, spreading all around the worldbut specifically in countries close to the Mediterranean Sea[14–16].

Carbapenemase producing Gram-negative bacteria cancause a wide spectrum of infections including bacteraemia,nosocomial pneumonia, wound infections, endocarditis, andurinary tract infections.Those infections are often associatedwith treatment failures, long hospital stay, and high mortalityrates; for example, attributable mortality for carbapenemresistant P. aeruginosa infections ranged between 51.2% and95% [17, 18].

Ideally, methods for determining carbapenemase shouldhave a short turn-around time to ensure timely implemen-tation of control measures. This could be challenged by dif-ficulties in detecting carbapenemase producers, since MICsto carbapenems could be elevated but within susceptiblerange or even low, as described in Enterobacteriaceae and A.baumannii [19].

However, relevant methodology with specific laboratorytest has not yet been standardized. Modified Hodge test is

the only test recommended by CLSI for the phenotypicdetection of carbapenemase producers but often lacks sen-sitivity and specificity. There are also several inhibitor basedtests using different inhibitors (EDTA and phenanthrolineas inhibitors of MBLs, phenylboronic acid as inhibitor ofKPC) in combination with carbapenem (e.g., meropenem)or cephalosporin (e.g., ceftazidime) in different format-diskdiffusion or broth dilution or 𝐸-test [19].

There is no specific inhibitor that could be used indetection of class D carbapenemases, but there are reports onusing temocillin disk (or combined with avibactam) for thispurpose [20].

Carba NP test is a simple biochemical test based onhydrolysis of imipenem detectable by a change of colourof indicator due to decrease of pH. It is applicable inmost microbiological laboratories, although the referencestandard in detection of carbapenemase production is spec-trophotometric measurement of carbapenem hydrolysis inthe presence or absence of inhibitor, but it is still reservedfor reference laboratories [19]. Recently, the use of mass spec-trometry (MALDI-TOFF) based on analysis of degradationof carbapenem molecule enabled rapid detection of KPCcarbapenemase (in 45 minutes) or MBL (in 150 minutes)[20, 21]. Finally, simplex or multiplex PCR, real-time PCR,or hybridization tests could significantly improve detectionof carbapenemase genes in clinical laboratory bypassing thesensitivity and specificity problems with phenotypic tests.However, molecular methods require expensive equipmentand trained laboratory staff.

There are still debates in optimizing possible treatmentapproach in infections caused by carbapenemase producingstrain. It is strongly suggested that combination therapy,including colistin, tigecycline, aminoglycosides, aztreonam,and carbapenems in different combination schemes, is stillsuperior to monotherapy and that carbapenem-containingregimens were superior to others when appropriate dose isapplied [17].

Controlling transmission of resistant microorganismsin healthcare setting, which includes carbapenem resistantEnterobacteriaceae (CRE), has several steps. It is importantto recognize these bacteria as epidemiologically significant, toknow the prevalence in specific region, to be able to identifyinfected and colonized patients, and to implement measuresfor stopping the transmission of CRE [22].

There is a bundle of measures which are usually imple-mented. These include proper hand hygiene, contact isola-tion, education, strict use of devices, cohorting of patients andstaff, laboratory notification, antimicrobial stewardship, anddifferent screening strategies. The best results are achievedonly when all measures are simultaneously implemented[23]. Screening of patients at risk is crucial for control ofCRE spreading. Screening can be restricted to contacts orto patients that were previously hospitalized in CRE positiveinstitutions. Samples which are usually taken are rectal swabs,stool, or urine. Environmental samples are not useful exceptfor control of disinfection and cleaning. Microbiologicallaboratory must have guidelines for CRE detection andprocedures for rapid notification of CRE positive results.Guidelines from CDC and HICPAC (Healthcare Infection

BioMed Research International 3

Control Practices Advisory Committee) suggest searchingin laboratory data for unrecognized CRE. If positive CREare found, it is advised to do the point prevalence study onspecific departments. After that, it is suggested to performactive surveillance till negative results are obtained. It isnecessary to monitor resistance to carbapenems in acutehealthcare settings and in long-term care facilities [24].

In conclusion, facing the global crisis in antibioticresistance, presented by rapid dissemination of carbapene-mase producing Gram-negative bacteria, many issues remaincontroversial, especially detection methods and treatmentoptions. However, active surveillance, hand hygiene, contactprecautions, and appropriate antibiotic usage are part ofeffective approach in reducing incidence of colonization andinfections caused by these life treating microorganisms.

Branka BedenićVanda PlečkoSanda Sardelić

Selma UzunovićKarmen Godič Torkar

References

[1] K. M. Papp-Wallace, A. Endimiani, M. A. Taracila, and R. A.Bonomo, “Carbapenems: past, present, and future,” Antimicro-bial Agents and Chemotherapy, vol. 55, no. 11, pp. 4943–4960,2011.

[2] A. M. Queenan and K. Bush, “Carbapenemases: the versatile𝛽-lactamases,” Clinical Microbiology Reviews, vol. 20, no. 3, pp.440–458, 2007.

[3] S. M. Diene and J. M. Rolain, “Carbapenemase genes andgenetic platforms in Gram-negative bacilli: Enterobacteri-aceae, Pseudomonas, andAcinetobacter species (E.P.A),”ClinicalMicrobiology and Infection, 2014.

[4] L. S. Munoz-Price, L. Poirel, R. A. Bonomo et al., “Clinicalepidemiology of the global expansion of Klebsiella pneumoniaecarbapenemases,” The Lancet Infectious Diseases, vol. 13, no. 9,pp. 785–796, 2013.

[5] L. S. Tzouvelekis, A. Markogiannakis, M. Psichogiou, P. T.Tassios, and G. L. Daikos, “Carbapenemases in Klebsiellapneumoniae and other Enterobacteriaceae: an evolving crisis ofglobal dimensions,” Clinical Microbiology Reviews, vol. 25, no.4, pp. 682–707, 2012.

[6] T. R. Walsh, “Emerging carbapenemases: a global perspective,”International Journal of Antimicrobial Agents, vol. 36, supple-ment 3, pp. S8–S14, 2010.

[7] R. Cantón, M. Akóva, Y. Carmeli et al., “Rapid evolutionand spread of carbapenemases among Enterobacteriaceae inEurope,” Clinical Microbiology and Infection, vol. 18, no. 5, pp.413–431, 2012.

[8] L. Poirel, C. Hombrouck-Alet, C. Freneaux, S. Bernabeu, and P.Nordmann, “Global spread of New Delhi metallo-𝛽-lactamase1,”The Lancet Infectious Diseases, vol. 10, no. 12, p. 832, 2010.

[9] P. Espina, L. Poirel, Y. Carmeli et al., “Spread of NDM-2-producingAcinetobacter baumannii in theMiddle East,” Journalof Antimicrobial Chemotherapy, vol. 68, no. 8, Article ID dkt109,pp. 1928–1930, 2013.

[10] Y. Nakazawa, R. Ii, T. Tamura et al., “A case of NDM-1-producing Acinetobacter baumannii transferred from India to

Japan,” Journal of Infection and Chemotherapy, vol. 19, no. 2, pp.330–332, 2013.

[11] T. R. Walsh, J. Weeks, D. M. Livermore, and M. A. Toleman,“Dissemination of NDM-1 positive bacteria in the New Delhienvironment and its implications for human health: an environ-mental point prevalence study,” The Lancet Infectious Diseases,vol. 11, no. 5, pp. 355–362, 2011.

[12] B. Jovcic, Z. Lepsanovic, V. Suljagic et al., “Emergence of NDM-1 metallo-𝛽-lactamase in Pseudomonas aeruginosa clinical iso-lates from Serbia,”Antimicrobial Agents and Chemotherapy, vol.55, no. 8, pp. 3929–3931, 2011.

[13] A. Mazzariol, Z. Bošnjak, P. Ballarini et al., “NDM-1-producingKlebsiella pneumoniae, Croatia,” Emerging Infectious Diseases,vol. 18, no. 3, pp. 532–534, 2012.

[14] B. A. Evans and S. G. Amyes, “OXA 𝛽-lactamases,” ClinicalMicrobiology Reviews, vol. 27, no. 2, pp. 241–263, 2014.

[15] L. Poirel, C. Héritier, V. Tolün, and P. Nordmann, “Emergenceof oxacillinase-mediated resistance to imipenem in Klebsiellapneumoniae,” Antimicrobial Agents and Chemotherapy, vol. 48,no. 1, pp. 15–22, 2004.

[16] G. Cuzon, J. Ouanich, R. Gondret, T. Naas, and P. Nord-mann, “Outbreak of OXA-48-positive carbapenem-resistantKlebsiella pneumoniae isolates in France,” Antimicrobial Agentsand Chemotherapy, vol. 55, no. 5, pp. 2420–2423, 2011.

[17] M. Akova, G. L. Daikos, L. Tzouvelekis, and Y. Carmeli,“Interventional strategies and current clinical experience withcarbapenemase-producing Gram-negative bacteria,” ClinicalMicrobiology and Infection, vol. 18, no. 5, pp. 439–448, 2012.

[18] V. Miriagou, G. Cornaglia, M. Edelstein et al., “Acquired car-bapenemases in Gram-negative bacterial pathogens: detectionand surveillance issues,”ClinicalMicrobiology and Infection, vol.16, no. 2, pp. 112–122, 2010.

[19] P. Nordmann, M. Gniadkowski, C. G. Giske, L. Poirel, N.Woodford, and V. Miriagou, “Identification and screening ofcarbapenemase-producing Enterobacteriaceae,” Clinical Micro-biology and Infection, vol. 18, no. 5, pp. 432–438, 2012.

[20] T. D. Huang, C. Berhin, P. Bogaerts, and Y. Glupczynski,“Evaluation of avibactam-supplemented combination disk testsfor the detection of OXA-48 carbapenemase-producing Enter-obacteriaceae,” Diagnostic Microbiology and Infectious Diseases,vol. 79, no. 2, pp. 252–254, 2014.

[21] A. Johansson, J. Ekelöf, C. G. Giske, and M. Sundqvist, “Thedetection and verification of carbapenemases using ertapenemand Matrix Assisted Laser Desorption Ionization-Time ofFlight,” BMCMicrobiology, vol. 14, no. 1, article 89, 2014.

[22] “Risk assessment on the spread of carbapenemase-producingEnterobacteriaceae (CPE),” (Klebsiella pneumoniae in Health-care Settings), http://www.cdc.gov.

[23] J. D. Siegel, E. Rhinehgart, M. Jackson, and L. Chiarello,Healthcare Infection Control Practices Advisory Committee.Managment of Multidrug Resistant Organisms in HealthcareSettings, CDC, Atlanta, Ga, USA, 2006.

[24] Guidance for Control of Carbapenem-Resistant Enterobacteri-acae (CRE), CRE Toolkit, National Center for Emerging andZoonotic Infectious Diseases, Division of Healthcare Promo-tion, CDC, Atlanta, Ga, USA, 2012.

Review ArticleEpidemiology of Carbapenemase-Producing Enterobacteriaceaeand Acinetobacter baumannii in Mediterranean Countries

Nassima Djahmi,1,2 Catherine Dunyach-Remy,1,3 Alix Pantel,1,3 Mazouz Dekhil,2

Albert Sotto,1,4 and Jean-Philippe Lavigne1,3

1 National Institute of Health and Medical Research, U1047, Faculty of Medicine, Montpellier 1 University,30908 Nı̂mes Cedex 02, France

2Department of Microbiology, University Hospital Ibn Rochd, 23000 Annaba, Algeria3 Department of Microbiology, University Hospital Caremeau, 30029 Nı̂mes Cedex 9, France4Departement of Infectious Diseases, University Hospital Caremeau, 30029 Nı̂mes Cedex 9, France

Correspondence should be addressed to Jean-Philippe Lavigne; [email protected]

Received 8 December 2013; Accepted 22 April 2014; Published 13 May 2014

Academic Editor: Selma Uzunović

Copyright © 2014 Nassima Djahmi et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The emergence and global spread of carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii are of greatconcern to health services worldwide. These 𝛽-lactamases hydrolyse almost all 𝛽-lactams, are plasmid-encoded, and are easilytransferable among bacterial species. They are mostly of the KPC, VIM, IMP, NDM, and OXA-48 types. Their current extensivespread worldwide in Enterobacteriaceae is an important source of concern. Infections caused by these bacteria have limitedtreatment options and have been associated with high mortality rates. Carbapenemase producers are mainly identified amongKlebsiella pneumoniae, Escherichia coli, and A. baumannii and still mostly in hospital settings and rarely in the community. TheMediterranean region is of interest due to a great diversity and populationmixing.The prevalence of carbapenemases is particularlyhigh, with this area constituting one of the most important reservoirs. The types of carbapenemase vary among countries, partiallydepending on the population exchange relationship between the regions and the possible reservoirs of each carbapenemase. Thisreview described the epidemiology of carbapenemases produced by enterobacteria and A. baumannii in this part of the worldhighlighting the worrisome situation and the need to screen and detect these enzymes to prevent and control their dissemination.

1. Introduction

Carbapenems are 𝛽-lactam group of drugs that are oftenused as antibiotics of last resort for treating infection dueto multidrug-resistant Gram-negative bacilli. They are alsostable even in response to extended-spectrum (ESBL) andAmpC 𝛽-lactamases. However, this scenario has changedwith the emergence in the last few years of carbapenemresistant bacteria both in nonfermenters (Acinetobacter bau-mannii and Pseudomonas aeruginosa) and in fermenters(Enterobacteriaceae) Gram-negative bacilli [1].

Resistance to carbapenems is mediated mostly by twomain mechanisms: (i) production of a 𝛽-lactamase (dere-pressed cephalosporinase or ESBL) with nonsignificant

carbapenemase activity combined with decreased perme-ability due to porin loss or alteration; (ii) production of acarbapenem-hydrolyzing 𝛽-lactamase [2].

Carbapenemases have now become a major concernworldwide [3, 4]. They are an increasing concern for globalhealthcare due to their association with resistance to 𝛽-lactam antibiotics and to other classes of antibiotics suchas aminoglycosides, fluoroquinolones, and cotrimoxazole[5]. Thus they reduce the possibility of treating infectionsdue to multidrug-resistant strains [6]. The first descriptionof carbapenemase-producing enterobacteria (NmcA) wasin 1993 [7]. Since then, large varieties of carbapenemaseshave been identified belonging to three molecular classes:the Ambler class A, B, and D 𝛽-lactamases [8]. They have


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emerged and diffused in different parts of the world, includ-ing Mediterranean countries, in recent years [2–6, 9]. Theseenzymes are carried either on chromosome or acquired viaplasmids [10].

The aim of this review is to describe the epidemiology ofthe main carbapenemases circulating in the Mediterraneancountries, a region of theworldwith a great diversity andpop-ulation mixing. This region includes 11 European countries(Albania, Bosnia, and Herzegovina, Croatia, Spain, France,Greece, Italia, Malta, Montenegro, Monaco and Slovenia),5 Asian countries (Cyprus, Israel, Lebanon, Syria, Turkey)and 5 African countries (Algeria, Egypt, Libya, Morocco,Tunisia).

2. Class A Carbapenemases

2.1. Enterobacteriaceae. A variety of class A carbapene-mases have been described: some are chromosome encoded(NmcA, Sme, IMI-1, SFC-1) and others are plasmid encoded(KPC, IMI-2, GES derivatives such as GES-1, GES-2, GES-4,and GES-5) but all effectively hydrolyze carbapenems and arepartially inhibited by clavulanic acid [8].

KPCs (acronym for K. pneumoniae carbapenemase) arethe most frequently encountered enzymes in this group [2].Since the first report of this enzyme in 1996 isolated from aclinical Klebsiella pneumonia strain in North Carolina, USA[11], the KPC producers had spread around the world and arebecoming a major clinical and public health concern [12].

Several KPC clones are disseminating harboring differentmultilocus sequence type, 𝛽-lactamase content, and plas-mids. However the 𝑏𝑙𝑎KPC genes are flanked by the sametransposon Tn4401 located on conjugative plasmids andare horizontally transferred [13]. This gives to this enzymean extraordinary spreading capacity [14]. They have beendetected more often in Klebsiella spp. [2] but have also beenreported in other Enterobacteriaceae [15]. Thirteen variantsof KPC are known so far; KPC-2 and KPC-3 are the mostfrequent worldwide variants [16]. The mortality rate due toinfection with a KPC producer ranged from 25% to 69%[2, 17].

The first outbreak of KPC-producing K. pneumoniaeoutside the United States was described in Israel in 2006 [18].This strain belonged to the pandemic clone ST258, suggestingan importation from the USA [19]. Moreover, a large rangeof enterobacteria producing these variants was describedin Israel [20–26]. Since then, many studies have reportedoutbreaks of KPC producers in enterobacterial isolates inmany Mediterranean countries (Figure 1), in which mostcases have been reported so far in Greece, where the situationcan be described as endemic [27, 28].Moreover a recent studyshowed a wide dissemination of KPC-producing strains tomany healthcare institutions in Italy [2, 29]. KPC producersbecame the most prevalent carbapenemase found in thiscountry [30]. Spain and France have recently described arapid increase of cases [31, 32]. Single or sporadic hospitaloutbreaks caused by KPCs isolated from various species werereported [32–34]. KPC-2 is clearly the most prevalent variantin Europe [12, 35]. In most of the cases reported from France,

the patients had been transferred from a country where KPCenzymes are endemic (e.g., Israel, Greece, USA, or Italy) [34].Croatia is another Mediterranean country affected [36].

To date, there is no description of class A carbapenemasesfromNorthAfrican countries. However, KPCproducers havealready been isolated in an E. coli strain inAlgeria (N. Djahmiet al., unpublished data).

2.2. Acinetobacter baumannii. Among the class A carbapen-emases, KPCs and GES-type have been described in A.baumannii [37]. KPC-2, KPC-3, KPC-4, and KPC-10 variantswere identified in 10 A. baumannii clinical isolates collectedin 2009 from 17 hospitals in Puerto Rico [38].

In Mediterranean countries, only GES-type carbapene-mase was reported. A GES-14-producing A. baumannii clini-cal strainwas isolated in France.This strainwas demonstratedto confer resistance to all 𝛽-lactams, including carbapenems[39]. Very recently, an emergence of GES-11 was reportedfrom Turkey [40]. Some strains coexpressed both OXA-23 and GES-11. They belonged to ST2, being part of theworldwide distributed clone II group.

3. Class B Carbapenemases

3.1. Enterobacteriaceae. Class B metallo-𝛽-lactamases(MBLs) are mostly of the Verona integron-encoded metallo-𝛽-lactamase (VIM) and IMP types and, more recently, ofthe New Delhi metallo-𝛽-lactamases-1 (NDM-1) type [8, 41].MBLs can hydrolyze all 𝛽-lactams except monobactam (e.g.,aztreonam) [41]. Their activity is inhibited by EDTA but notby clavulanic acid [41].

IMP-1 was the first MBL reported in Serratia marcescensfrom Japan in 1991 [42]. Since then, MBLs have beenobserved worldwide [8, 41]. The most commonly found classB carbapenemases are of the VIM type [43], which has beenidentified in all continents [44]. The death rates associatedwith MBL producers are high (18% to 67%) [2, 45].

Italy was the first Mediterranean country to reportacquired metallo-𝛽-lactamases, with sporadic isolates ofVIM-4-producing K. pneumoniae and Enterobacter cloacae[8, 46]. Since then, single or sporadic hospital outbreakscaused by VIM-1 like enzymes were described from vari-ous regions in this country [47, 48]. However, such VIM-producing Enterobacteriaceae have not undergone widedissemination, unlike that observed in Greece during thesame period [49]. Endemicity of VIM- and IMP-producingKlebsiella pneumoniae strains has now been noted in Greece[8, 41]. Additionally, outbreaks and single reports of VIM- orIMP-type producers have been reported in several countriesof Mediterranean area, such as France [50, 51], Spain [33],Morocco [52], Egypt [53, 54], Algeria [55], and Tunisia [56].

Most recently reported, NDM-1 enzyme is spreadingrapidly worldwide [44] notably Central and South Americathat represented the last zone without description of thisenzyme [57, 58]. NDM-1 was initially identified in E. coliand K. pneumoniae in a patient returning to Sweden fromIndia in 2008 [59]. Most of the outbreaks indicated a linkwith the Indian subcontinent, in some cases with the Balkancountries [60], and the Middle East [61]. Five minor variants


SloveniaFrance

Italy

Spain

Algeria

Morocco

Libya

CroatiaTunisia

Greece

EgyptTurkey

Lebanon

PIsrael500km

300mi© Daniel Dalet

Figure 1: Geographic distribution of KPC enzymes in Mediterranean countries. White, no case reported; yellow, single KPC-producingisolates; green, some outbreaks of KPC-producing isolates; orange, several outbreaks of KPC-producing isolates; red, endemicity of KPC-producing isolates.

of NDM-1 (NDM-2 to NDM-6) have been now identifiedin enterobacteria and very recently, a novel variant NDM-7 was detected in E. coli in France [62]. Contrarily to othercarbapenemase genes, 𝑏𝑙𝑎NDM-1 is not associated with a singleclone.ThusNDM-1 has been identifiedmostly in nonclonallyrelated E. coli and K. pneumoniae and to a lesser extentin other enterobacterial species [63]. These enzymes areencoded on highly transmissible plasmids that spread rapidlybetween bacteria, rather than relying on clonal proliferation.The strains harboring NDM are broadly resistant to manyother drug classes in addition to 𝛽-lactams and carry adiversity of other resistance mechanisms, which leaves fewtreatment options (tigecycline or colistin) [63, 64]. NDM-1producers have been reported in the environment and in thecommunity [2, 63].They have been identified in Enterobacte-riaceae species around the world [59] highlighting the abilityof this gene to disseminate in bacteria [65]. Moreover NDM-1 has been identified in E. coli ST131, a well-known source ofcommunity infections [66, 67].

Single or sporadic hospital outbreaks caused by NDM-1producing enterobacterial strains were reported from manycountries in Mediterranean area (Figure 2): France [68, 69],Italy [70], Lebanon [71], Morocco [52, 72], Spain [33, 73–75], Tunisia [76], and Turkey [77, 78]. Very recently, NDM-5was identified in E. coli in Algeria (Sassi et al., unpublisheddata). There are no published data yet from Libya, but avery recent study has reported identification of NDM-1 inK. pneumoniae frompatient transferred fromLibya toTunisia

[76], indicating the emergence of this enzyme resistance inMediterranean countries. Finally an emergence of NDM-producing K. pneumoniae was recently reported in Greece[79].

3.2. Acinetobacter baumannii. To date, four groups of MBLshave been identified in A. baumannii: IMP-like, VIM-like,SIM-like, and recently the NDMs [80].

The first MBL identified in A. baumannii strains wasIPM-2 reported in 2000 from Italy [81]. Since then, IMP-like, VIM-like, and SIM-like have been sporadically reportedin some parts of the world [82], including Mediterraneancountries, especially in Greece and Italy [81–85]. ConcerningNDM producers, A. baumannii bacteria harboring theseenzymes were increasingly observed around the world [86]notably in Mediterranean countries. They were detected inNorth Africa: Algeria [87, 88] and Libya (isolated from apatient transferred from Libya to Denmark) [89]; in Europa:France [87, 90, 91] and Slovenia [86]; and in Turkey [92].The isolation of an NDM-1-producing A. baumannii in aCzech patient repatriated in 2011 from Egypt was described[93]. In France, the emergence of imported cases of NDM-1-producing A. baumannii was linked with Algeria [87, 90].The strains belonged to ST85, the main clone isolated inMediterranean countries [90, 91]. Finally, another cloneNDM variant, NDM-2, was found in A. baumannii isolatesin Egypt [94] and Israel [95].


Slovenia

France

Italy

Spain

Algeria

Morocco

Libya

Croatia Tunisia

Greece

Egypt Turkey

Lebanon

Israel500km300mi

© Daniel Dalet

Figure 2: Geographic distribution of NDM type producers in Mediterranean countries. White, no case reported; yellow, sporadic NDM-producing isolates; green, emerging outbreak of NDM-producing isolates; orange, single hospital outbreaks of NDM-producing isolates.

4. Class D Carbapenemases

4.1. Enterobacteriaceae. Class D 𝛽-lactamases, also namedOXAs for oxacillinases include 232 enzymes with few vari-ants, possessing the same carbapenemase activity [96]. Ini-tiallyOXA𝛽-lactamaseswere reported fromP. aeruginosabutuntil now, these carbapenemases have been detected in manyother Gram-negative bacteria, including Enterobacteriaceae[16].

OXA-48 represents the main enzyme isolated aroundthe world. This enzyme hydrolyses penicillins but has aweak activity against carbapenems or extended-spectrumcephalosporins (third generation cephalosporin, aztreonam)[2]. However, its frequent association with ESBL (notablyCTX-M-15 enzyme) increases the level of resistance to car-bapenem. Its activity is not inhibited by EDTA or clavulanicacid [2], tazobactam, and sulbactam, whereas its activitymay be inhibited by NaCl in vitro [96, 97]. Its high level ofresistance to temocillin is interesting to detect this enzyme[98, 99]. Apointmutant analog ofOXA-48, namely,OXA-181,with similar carbapenemase activity, has been identified inenterobacterial strains from India [100, 101] and frompatientswith a link to the Indian subcontinent [100, 102]. Furtheranalysis of theOXA-48-producing isolates demonstrated thatthis enzyme was not exclusively linked with a single clone,and the 𝑏𝑙𝑎OXA-48 gene was associated with either trans-poson Tn1999 or transposon Tn1999.2 within transferablenontypable plasmids of 70 or 150 kb [103]. The death ratesassociated with OXA-producers are unknown.

OXA-48 was initially identified in K. pneumoniae isolatefrom Turkey in 2001 [104]. Since then, OXA-48 producing

strains have been extensively reported as sources of noso-comial outbreaks in many parts of the world notably inMediterranean countries [105–110] (Figure 3): Croatia [111],Egypt [54], France [109], Greece [112], Israel [113, 114], Italy[53], Lebanon [71, 115, 116], Libya [117], Slovenia [118], Spain[33, 119], Tunisia [120], and Turkey [106]. Moreover, thisenzyme disseminated in various Enterobacteriaceae species[2, 96]. To date OXA-48 represents the most commoncarbapenemase type circulating in this part of the worldnotably in Spain [33] and France [109]. The Middle Eastand North Africa are considered as reservoirs of OXA-48 producers [121]. In the last few years, a nosocomialdissemination of OXA-48-producing Enterobacteriaceae hasbeen reported in different hospitals in Morocco [122]. Thisproblem was exacerbated by the occurrence of this enzymein community [123] and in environment [124] suggesting thatOXA-48 is endemic in this country [122]. More recently, theidentification of the 𝑏𝑙𝑎OXA-48 gene in aK. pneumoniae isolatehas been reported in Algeria (N. Djahmi, personal data).

4.2. Acinetobacter baumannii. The class D carbapenemases(oxacillinases) are by far the most prevalent carbapenemasesin A. baumannii [125, 126]. They can be grouped intosix subclasses: intrinsic chromosomal OXA-51-like, amongwhich there are over 70 variants and the acquired OXA-23-like, OXA-24/40-like, OXA-58-like, OXA-143-like, andOXA-235-like 𝛽-lactamases [97, 127].

The first case of OXA-type enzyme was reported froma clinical A. baumannii isolate detected in Scotland in1985. It was initially named ARI-1 (Acinetobacter resistantto imipenem) [128] and renamed OXA-23 after sequencing


500km300mi

Slovenia

France

Italy

Spain

Algeria

Morocco

Libya

CroatiaTunisia

Greece

EgyptTurkey

Lebanon

Israel

© Daniel Dalet

Figure 3: Geographic distribution of OXA-48 type producers in Mediterranean countries. White, no case reported; yellow, single OXA-48-producing isolates; orange, several outbreaks of OXA-48-producing isolates; red, nationwide distribution of OXA-48-producing isolates.

[129]. A. radioresistens was identified as the progenitor of the𝑏𝑙𝑎OXA23-like gene [130].

Nosocomial outbreaks or sporadic cases caused bycarbapenem-resistant A. baumannii producing these OXA-enzymes have been reported worldwide [80, 131–133]. A.baumannii epidemic strains were assigned to internationalclonal lineages I or II [134], with recent studies reportingthe spread of genetically related epidemic clone of OXA-23-producing A. baumannii and belonging to IC-II withinthe Mediterranean region [135–137]. The 𝑏𝑙𝑎OXA-23 gene waseither located on the chromosome or on plasmids and wasassociated with four different genetic structures, with themost frequent being transposons Tn2006 [134].

The emergence and spread of several outbreak or sporadicA. baumannii strains producing OXA-23-like enzymes havebeen reported around the world [134]. During a long period,the 𝑏𝑙𝑎OXA-58 carbapenemase gene has been predominatedamong carbapenem-resistant A. baumannii isolates in vari-ous Mediterranean countries [85]. Since 2009, a replacementof 𝑏𝑙𝑎OXA-58 gene with 𝑏𝑙𝑎OXA-23 gene has been reported andit became the most prevalent carbapenemase-encoding genecirculating in the Mediterranean region: Algeria [88, 136],Croatia [111], Egypt [138], France [139], Greece [140], Italy[135, 141], Israel [132], Spain [137, 142], Tunisia [143], andTurkey [83, 144]. The replacement of OXA-58 by OXA-23might be explained by the selective advantage associated withthe higher carbapenemase activity ofOXA-23 [37, 142] and/oracquisition of carbapenem resistance through horizontalgene transfer [37].

Concerning other OXA-producers, outbreaks of OXA-72-producing A. baumannii were described in Croatia [145]and OXA-69 or OXA-97 in Tunisia [146, 147].

5. Conclusion

In recent years the emergence of carbapenem-resistantGram-negative bacilli inMediterranean region is an alarmingproblem. This part of the world is the cradle of westerncivilization representing nearly 475 million inhabitants (6.3%of world population). It is the location of a large populationmixing explaining the importance of the dissemination ofcarbapenemase producers. This situation imposes a seriesof measures as soon as possible. These need the over-the-counter sale of indistinctly antibiotics, improving basic andextended knowledge on hygiene, the reinforcement of infec-tion control measures, and the early and accurate detection,with restriction of the usage of carbapenems, to control thespread of these multidrug resistant organisms.

Conflict of Interests

The authors state that there is no conflict of interests.

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Review ArticleWorldwide Dissemination of the NDM-Type Carbapenemases inGram-Negative Bacteria

Laurent Dortet,1 Laurent Poirel,1,2 and Patrice Nordmann1,2

1 INSERM U914 “Emerging Resistance to Antibiotics”, 78 Avenue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France2Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg,3 Rue Albert Gockel, 1700 Fribourg, Switzerland

Correspondence should be addressed to Patrice Nordmann; [email protected]

Received 7 December 2013; Accepted 15 February 2014; Published 26 March 2014

Academic Editor: Karmen Torkar

Copyright © 2014 Laurent Dortet et al.This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The emergence of one of the most recently described carbapenemases, namely, the New Delhi metallo-lactamase (NDM-1),constitutes a critical and growingly important medical issue. This resistance trait compromises the efficacy of almost all lactams(except aztreonam), including the last resort carbapenems.Therapeutical optionsmay remain limitedmostly to colistin, tigecycline,and fosfomycin. The main known reservoir of NDM producers is the Indian subcontinent whereas a secondary reservoir seemsto have established the Balkans regions and the Middle East. Although the spread of 𝑏𝑙𝑎NDM-like genes (several variants) isderived mostly by conjugative plasmids in Enterobacteriaceae, this carbapenemase has also been identified in P. aeruginosa andAcinetobacter spp.Acinetobacter sp.may play a pivotal role for spreading 𝑏𝑙𝑎NDM genes for its natural reservoir to Enterobacteriaceae.Rapid diagnostic techniques (Carba NP test) and screening of carriers are the cornerstone to try to contain this outbreak whichthreatens the efficacy of the modern medicine.

1. Introduction

During the last decade the emergence of carbapenemase-producing strains among Enterobacteriaceae, Pseudomonasspp., and Acinetobacter baumannii is remarkable. A varietyof carbapenemases have been reported such as the Amblerclass A KPC-type (mostly identified in Enterobacteriaceaeand Pseudomonas aeruginosa) and GES-type (mostly in A.baumannii), the Ambler class B metallo-𝛽-lactamases (MBL)of VIM-, IMP-, GIM-, and NDM-types, and the Ambler classD carbapenemases of the OXA-48 type in Enterobacteriaceaeand of OXA-23, OXA-24/-40, OXA-58, and OXA-143 typesin Acinetobacter spp. The emergence of the most recentlydescribed carbapenemase, namely, the New Delhi metallo-𝛽-lactamase (NDM-1), constitutes a critical medical issue.Indeed, this enzyme compromises the efficacy of almostall 𝛽-lactams (except aztreonam), including the last resortcarbapenems. Although most of the NDM-producing strainsidentified are Enterobacteriaceae, this carbapenemase hasalso been reported from Acinetobacter spp. and more rarelyfrom P. aeruginosa, both species causing severe nosocomial

infections, including urinary tract infections, peritonitis, sep-ticemia, and pulmonary infections.The Indian subcontinent,the Balkans regions, and theMiddle East are considered to bethe main reservoirs of NDM producers. Since therapeuticaloptions are limited to very few antibiotics such as col-istin, tigecycline, and fosfomycin, hospital- and community-acquired infections caused by NDM-1 producers are difficultto eradicate. Isolation of infected patients and carriers andrapid diagnostic techniques are the key factors that contributeto contain this outbreak that threatens the efficacy of themodern medicine.

2. Clinical Impact of the AntibioticResistance Patterns of NDM Producers forthe Treatment

Currently, one of the most clinically significant carbapene-mase is the recently described NDM-1 (New Delhi metallo-𝛽-lactamase). This carbapenemase belongs to the class B ofAmbler 𝛽-lactamases classification that includes the metallo-𝛽-lactamases (MBLs). NDM-1 shares very little identity with


http://dx.doi.org/10.1155/2014/249856


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SSS SXT C NET

GM AN TM RA

Figure 1: Antibiogram of a NDM-1-producing K. pneumoniae isolate. The 𝑏𝑙𝑎NDM-1 gene was located onto a IncHIIB plasmid of ca.∼200 kb in that strain that also harbored two additional 𝛽-lactamase genes (𝑏𝑙𝑎CTX-M-15, 𝑏𝑙𝑎SHV-12, 𝑏𝑙𝑎OXA-1) and an aminoglycoside methylase(armA) responsible for high-level resistance to all aminoglycosides. PTZ, piperacillin + tazobactam; PIP, piperacillin; TIC, ticarcillin; AMX,amoxicillin; ETP, ertapenem; TCC, ticarcillin + clavulanic acid; CAZ, ceftazidime; CF, cefalotin; FOX, cefoxitin; IMP, imipenem; AMC,amoxicillin + clavulanic acid; CTX, cefotaxime; CMX, cefuroxime; MEM, meropenem; ATM, aztreonam; FEP, cefepime; FT, nitrofurantoin;NOR, norfloxacin; OFX, ofloxacin; CIP, ciprofloxacin; FOS, fosfomycin; TGC, tigecycline; TE, tetracycline; CS, colistin; SSS, sulfonamide;SXT, sulfamethoxazole + trimethoprim; C, chloramphenicol; NET, netilmicin; GM, gentamicin; AN, amikacin; TM, tobramycin; RA,rifampicin.

other MBLs, the most similar being VIM-1/VIM-2 with only32.4% amino acid identity. Compared to VIM-2, NDM-1displays tighter binding tomost cephalosporins, in particularto cefuroxime (𝐾mNDM-1 = 8 𝜇M, 𝐾mVIM-2 = 22 𝜇M),cefotaxime (𝐾mNDM-1 = 10 𝜇M, 𝐾mVIM-2 = 32 𝜇M),cephalothin (𝐾mNDM-1 = 10 𝜇M, 𝐾mVIM-2 = 44 𝜇M), andpenicillins (𝐾mNDM-1 = 16 𝜇M, 𝐾mVIM-2 = 49 𝜇M). Like allother MBLs, NDM-1 efficiently hydrolyses a broad rangeof 𝛽-lactams including penicillins, cephalosporins, andcarbapenems, just sparing monobactams such as aztreonam.NDM-1 does not bind to carbapenems as tightly as IMP-1 orVIM-2 does, and the turnover rate of carbapenem hydrolysisis similar to that of VIM-2 (𝑘cat/𝐾m are 0.21, 1.2, and0.99 s−1 ⋅ 𝜇M−1 for NDM-1, IMP-1, and VIM-2, resp.). Similarto the other MBLs, the active site of NDM-1 contains twometal ion binding sites: the His and Cys sites. Accordingly, a3D-structure modelling of the NDM-1 enzyme showed thattwo zinc ions were present at both the His and Cys sites witha distance of 4.20 Å [1]. Indeed, the hydrolysis activity ofMBLs depends on the interaction of the 𝛽-lactam moleculewith Zn2+ ion(s) in their active site. Consequently, theiractivity is inhibited by chelators of divalent cations, such asEDTA. Accordingly, the efficacy of EDTA (Ca-EDTA) hasbeen evaluated in a mouse model of sepsis caused by anNDM-1-producing Escherichia coli. It has been shown thata combination therapy using imipenem/cilastatin sodium(IPM/CS) and Ca-EDTA reduced the bacterial inoculum,as compared to IPM/CS alone suggesting the possibility touse Ca-EDTA in clinical therapeutics [2]. Comparison ofIMP-1, VIM-2, and NDM-1 by an in silico approach revealedthat NDM-1 might have greater drug profile and catalyticefficiency than IMP-1 and VIM-2 due to a larger pocketopening and a lower distance between the Zn-I ion and𝛽-lactam oxygen of the carbapenem [3].

It is noteworthy that a quite systematic associationwith other antibiotic resistance determinants is observedin almost all NDM producers (Enterobacteriaceae, Acine-tobacter, and Pseudomonas). Those associated resistancedeterminants are AmpC cephalosporinases, clavulanic acidinhibited expanded-spectrum 𝛽-lactamases (ESBLs), othertypes of carbapenemases (OXA-48-, VIM-, and KPC-types),and resistance to aminoglycosides (16S RNA methylases), toquinolones (Qnr), to macrolides (esterases), to rifampicin(rifampicin-modifying enzymes), to chloramphenicol, and tosulfamethoxazole [4–9]. Consequently, most of the NDM-1producers remain susceptible only to two bactericidal antibi-otics (colistin and fosfomycin) and a single bacteriostaticantibiotic (tigecycline) [10, 11] (Figure 1). In vitro synergycombination assays performed with NDM-1 producers withthose three antibiotic molecules showed a synergistic activityof colistin and fosfomycin, of colistin and tigecycline in rarecases, whereas most of the antibiotic associations remainneutral for most of the tested isolates [12]. Since NDM-1 doesnot hydrolyze aztreonam, a combination therapy includingaztreonamand avibactam (also namedNXL-104), a novel ser-ine𝛽-lactamase inhibitor inhibiting themost frequent broad-spectrum hydrolyzing-𝛽-lactamases hydrolyzing aztreonamhas been suggested as a possible strategy against NDM-1-producing Enterobacteriaceae.This therapeutic option seemsto be a very efficient combination therapy in vitro [13, 14].

3. Infections Caused by NDM Producers

Since NDM producers were mainly described in Enter-obacteriaceae, infections caused by NDM producers includeurinary tract infections, peritonitis, septicemia, pulmonaryinfections, soft tissue infections, and device-associated infec-tions. As observed for other multidrug-resistant bacteria,


it is highly probable that colonization of the gut floramight precede the infection by NDM producers and orofecaltransmission in the community might occur mostly throughhand contamination, food, and water. Among the NDM-1-producing Enterobacteriaceae, Klebsiella pneumoniae andE. coli are the most often described species. Both hospital-and community-acquired infections have been reported.However, this carbapenemase is also frequently describedin other enterobacterial species including Klebsiella oxytoca,Enterobacter cloacae, Citrobacter freundii, Proteus mirabilis,Salmonella spp., and Providencia spp. Although most ofNDM-producing bacteria are Enterobacteriaceae, this car-bapenemase was also reported from Acinetobacter spp. [15–32] and in rare cases Pseudomonas aeruginosa [33, 34].

Since, no specific virulence factor is known to be asso-ciated with 𝑏𝑙𝑎NDM-1-carrying plasmids [6, 35–39], thereis no evidence that NDM-producing bacteria are morevirulent than other strains [40–42]. However, some rareisolates of NDM-1-producing virulent enteric bacteria suchas Salmonella [43–45] and Vibrio cholerae [46, 47] have beendescribed.

4. Epidemiology of NDM-Producing Bacteria

NDM-1 was first identified in 2008 in aK. pneumoniae isolaterecovered from a Swedish patient who has been previouslyhospitalized in New Delhi, India [48]. Since then, NDMcarbapenemases are the focus of worldwide attention due tothe rapid dissemination of the corresponding gene amongEnterobacteriaceae and Acinetobacter spp. mainly (Figure 2).Rapidly, a link between NDM-producing Enterobacteriaceaeand the Indian subcontinent has been pointed out [49–51],and prevalence rates of NDM-producing Enterobacteriaceaewere found to range from 5 to 18.5% in Indian and Pakistanhospitals [52–55]. In addition, the 𝑏𝑙𝑎NDM-1 gene was detectednot only in patient samples, but also in drinking water andseepage samples in NewDelhi [47].The occurrence of NDM-1-producing bacteria in environmental samples in New Delhiis significant for people living in the city who often relyonto public water and poor sanitation facilities. A secondaryreservoir of NDM-1 producers was then highlighted throughseveral studies reporting patients colonized or infected withNDM-1 producers originating from the Balkan states [50, 56–61]. Recent reports also suggested that the Middle East mightbe an additional reservoir of NDM producers [62–67]. Thisdissemination of NDM producers in the Middle East couldmostly be linked to the populat

Carbapenemases in Gram-Negative Bacteriadownloads.hindawi.com/journals/specialissues/231314.pdf · 2 BioMedResearchInternational spp.-CphA,andS.maltophilia-L1),acquiredMBLencoding

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