We report the first outbreak of carbapenem-resistant NDM-1-producing Acinetobacter baumannii in Europe, in a French intensive-care unit in January to May 2013. The index patient was transferred from Algeria and led to the infection/colonisation of five additional patients. Concurrently, another imported case from Algeria was identified. The seven isolates were genetically indistinguishable, belonging to ST85. The blaNDM-1 carbapenemase gene was part of the chromosomally located composite transposon Tn125. This report underscores the growing concern about the spread of NDM-1-producing A. baumannii in Europe

Anais, L.

Bonnin, R. A.

Decousser, J. W.

Emirian, A .

Jansen, C.

Merle, J. C.

Nordmann, Patrice

Poirel, Laurent

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1www.eurosurveillance.orgRapid communicationsOutbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013J W Decousser (jean-winoc.decousser@hmn.aphp.fr)1,2, C Jansen2,3, P Nordmann4,5, A Emirian1,2, R A Bonnin4, L Anais1, J C Merle6, L Poirel4,51. Department of Virology, Bacteriology - Infection Control, Parasitology –Mycology, Assistance Publique – Hôpitaux de Paris (AP-HP), University Hospital Henri Mondor, Créteil, France2. University Paris East Créteil (UPEC), Faculty of Medicine, Créteil, France 3. Infection Control, Prevention and Epidemiology Unit, AP-HP, University Hospital Henri Mondor, Créteil, France4. INSERM U914 ‘Emerging Antibiotic Resistance’, Le-Kremlin-Bicêtre, France5. Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science, University of Fribourg, Fribourg, Switzerland6. Department of Anaesthesiology, AP-HP, University Hospital Henri Mondor, Créteil, FranceCitation style for this article: Decousser JW, Jansen C, Nordmann P, Emirian A, Bonnin RA, Anais L, Merle JC, Poirel L. Outbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013 . Euro Surveill. 2013;18(31):pii=20547. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20547Article submitted on 23 July 2013 / published on 01 August 2013We report the first outbreak of carbapenem-resistant NDM-1-producing Acinetobacter baumannii in Europe, in a French intensive-care unit in January to May 2013. The index patient was transferred from Algeria and led to the infection/colonisation of five additional patients. Concurrently, another imported case from Algeria was identified. The seven isolates were geneti-cally indistinguishable, belonging to ST85. The blaNDM-1 carbapenemase gene was part of the chromosom-ally located composite transposon Tn125. This report underscores the growing concern about the spread of NDM-1-producing A. baumannii in Europe.Background The emergence and spread of New-Delhi metallo-beta-lactamase (NDM)-producing Gram negative isolates constitutes a new wave of multidrug-resistant (MDR) bacteria [1]. First identified from Enterobacteriaceae, the blaNDM gene has since been identified in non-fer-menting bacterial species such as Pseudomonas aerug-inosa and Acinetobacter baumannii [2,3]. Considering its ability to be the source of nosocomial outbreaks, carbapenem-resistant A. baumannii (AB) represents a threat for critically ill hospitalised patients [4]. We report here the first outbreak of NDM-1-producing AB in Europe, which occurred in a French surgical inten-sive-care unit in January to May 2013.Outbreak descriptionThe index case (Patient 1) was a female patient in her early 80s suffering from end-stage cirrhosis. She origi-nated from Algeria but lived mostly in France. During a stay in Algeria in December 2012, she was admit-ted into a private hospital in the city of Tizi Ouzou following renal failure, which required dialysis. After one month in hospital, she was repatriated to France due to liver decompensation. On 18 January 2013, she was admitted to a 15-bed surgical intensive-care unit of a tertiary care university hospital in a Paris sub-urb. In accordance with local and national policy, she was screened on admission for carriage of MDR bac-teria. Rectal screening revealed MDR-A. baumannii (MDR-AB) (Isolate 1) that was susceptible only to ami-kacin, netilmicin and colistin (Table). The same day, she was intubated for respiratory failure. Protected distal bronchial brushing yielded a culture of MDR-AB with the same antibiotic resistance profile. A combina-tion of intravenous tigecycline and amikacin was given. On 24 January, she developed multivisceral failure and died four days later. During the following days, three additional patients with MDR-AB infection and/or colo-nisation were identified in the same unit. A cirrhotic male patient in his mid-60s (Patient 2) – who had been hospitalised since 3 January 2013 and confirmed free of MDR bacteria on admission – developed a ventila-tor-associated pneumonia on 26 January. Culture of a distal protected specimen yielded MDR-AB (Isolate 2). This patient was successfully treated by a combination of tigecycline and amikacin and was extubated two days later. Patient 3 was a male liver-transplant patient in his mid-60s who was not colonised on admission but developed a dialysis catheter-related bloodstream infection due to a MDR-AB on 28 January (Isolate 3). Imipenem and amikacin combination was prescribed but the patient died of haemorrhagic shock before antibacterial susceptibility results could be obtained. Patient 4 was a dual renal- and liver-transplant female patient in her late 40s from whom an abdominal drain yielded an MDR-AB culture on 2 February (Isolate 4). This patient recovered without receiving any antibiotic therapy and was discharged from the hospital on 11 February. Two weeks after the admission of the index case, a woman in her early 80s (Patient 5) suffered from a cer-ebrovascular accident and was repatriated from the 2 www.eurosurveillance.orgsame Algerian county that Patient 1 was repatriated from (but from a different healthcare facility) to the emergency unit of our hospital. A screening test per-formed on admission identified MDR-AB (Isolate 5).Two months after this first cluster of five patients with MDR-AB, two additional patients free of MDR bacte-ria on admission to the surgical intensive-care unit described acquired a MDR-AB during their stay in this unit. A woman in her late 50s (Patient 6) was admit-ted to the surgical intensive-care unit on 6 April and placed in the room where the index case had stayed. This patient was found positive for MDR-AB on 15 April in specimens from a catheter and the respiratory tract (Isolate 6). She was treated with intravenous tigecy-cline and aerosolised colistin. She underwent success-ful liver transplantation on 22 April and recovered well. The last patient (Patient 7) was a man in his late 50s admitted to the surgical intensive-care unit on 3 April for a liver transplant and from whom a rectal swab yielded MDR-AB a month later (Isolate 7). The patients’ duration of hospital stay, time of infection and/or col-onisation and location in the hospital are reported in Figure 1.Laboratory analysisIdentification of the seven MDR-AB strains at the spe-cies level was confirmed by 16S RNA sequencing (data not shown). Their antimicrobial susceptibilities were tested by minimum inhibitory concentration (MIC) determination (Etest, bioMérieux, France) (Table) and interpreted according to EUCAST guidelines [5]. All isolates exhibited a high level of resistance to penicil-lins, broad-spectrum cephalosporins, carbapenems, fluoroquinolones and trimethoprim-sulfamethoxazole. Those isolates remained susceptible only to netilmicin, colistin and amikacin. The production of a class B car-bapenemase was suspected by the positive results of the imipenem/imipenem plus EDTA test using MIC dou-ble strips (Etest, bioMérieux, France) (Table 1) and con-firmed by UV spectrophotometry [6]. Carbapenemase genes were screened by PCR as described and the blaNDM-1 gene was amplified in the seven isolates [7]. Genotypic comparison by pulsed-field gel electro-phoresis using restriction enzyme SmaI revealed an indistinguishable profile (data not shown). Diversilab (bioMérieux, France) analysis and multilocus sequence typing (MLST) typing confirmed that these isolates were clonally related and belonged to the same sequence type, ST85 (Figure 2) [8]. The genetic environment of blaNDM-1 was investigated as previously described [8] and showed that it was located in the composite trans-poson Tn125 made of two copies of insertion sequence (IS) ISAba125.Discussion Carbapenem-resistant A. baumannii are a source of deep concern due to their multidrug resistance pat-tern and the ability of this bacterial species to persist in the environment [4,9,10]. Intensive-care units are particularly susceptible to outbreaks associated with Table Antimicrobial susceptibility of carbapenem-resistant  NDM-1-producing Acinetobacter baumannii isolates, France, January–May 2013 (n=7)AntibioticIsolatesMIC [µg/mL] (S/I/Ra)b1 2 3 4 5 6 7Ampicillin-sulbactam 16 24 16 24 24 32 192Ticarcillin-clavulanic acid >256 >256 >256 >256 >256 >256 >256Piperacillin >256 >256 >256 >256 >256 >256 >256Piperacillin-tazobactam >256 >256 >256 >256 >256 >256 >256Aztreonam >256 >256 >256 >256 >256 >256 192Ceftazidime >256 >256 >256 >256 >256 >256 >256Cefepime >256 >256 >256 >256 >256 >256 >256Meropenem >32(R)>32(R)>32(R)>32(R)>32(R)>32(R)>32(R)Imipenem >32(R)>32(R)>32(R)>32(R)>32(R)>32(R)>32(R)Imipenem/imipenem + EDTA  ratiob96 96 64 128 96 64 128Doripenem >32(R)>32(R)>32(R>32(R)>32(R)>32(R)>32(R)Ciprofloxacin >32(R)>32(R)>32(R)>32(R)>32(R)>32(R)>32(R)Gentamicin 32(R)24(R)24(R)32(R)24(R)32(R)64(R)Amikacin 8(S)12(I)8(S)8(S)8(S)8(S)64(R)Tobramycin 24(R)32(R)24(R)24(R)24(R)32(R)64(R)Netilmicin 0.75(S)1.5(S)0.5(S)0.75(S)0.75(S)0.75(S)1(S)Tetracycline 4 2 2 2 2 2 2Tigecycline 0.75 1 1 1 1 0.25 0.38Colistin 0.125(S)0.19(S)0.38(S)0.25(S)0.38(S)0.25(S)0.38(S)Trimethoprim-sulfamethoxazole>32(R)>32(R)>32(R)>32(R)>32(R)>32(R)>32(R)Fosfomycin 256 384 384 192 256 256 192Rifampicin 6 6 6 6 6 32 8MIC: mimimum inhibitory concentration; NDM: New-Delhi metallo-beta-lactamase.a  Susceptible/Intermediary Resistant/Resistant categories from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines [5], if determined.b  Except for the imipenem/imipenem + EDTA ratio. The ratio was considered significant if >4. 3www.eurosurveillance.orgMDR-AB: it is sometimes difficult for them to adhere strictly to infection control measures when patients require a high and persistent care-load. Four years ago, the same hospital faced a hospital-wide outbreak of MDR-AB colonisations and infections due to the importation of an index case from Tahiti [11]. Despite this experience and the implementation in 2010 at the national and local level of strict measures on hospital admission to detect, screen and place under contact-isolation precautions repatriated patients, another outbreak linked to the admission of a patient previ-ously hospitalised abroad again occurred [12]. Since 2010, NDM-producing MDR-AB has been iden-tified in various parts of the world, in particular in North Africa and the Middle East [8,13-17]. A series of imported cases have been identified recently in Europe, such as in the Czech Republic, Germany, Slovenia, Switzerland and Belgium [8,13,14,17]. In France, the emergence of an NDM-1-producing MDR-AB strain originating from North Africa was recently highlighted [15,17]. We describe here the first outbreak associ-ated with the importation of this NDM-1-producing A. baumannii clone ST85 in Europe. This report under-lines the need for dedicated measures for patients previously treated in a hospital located in a ‘high risk’ geographical area. Such measures (e.g. screening for colonisation/infection with MDR organisms and isola-tion nursing) should be maintained until the screen-ing for colonisation/infection (e.g. using rectal, throat and wound swabs) has shown that these patients are free of MDR organisms. Because of intermittent car-riage or lack of sensitivity of the current culture-based screening methods, repeated specimen collection and Figure 1Timeline of patients infected/colonised with carbapenem-resistant NDM-1-producing Acinetobacter baumannii hospitalised in a surgical intensive-care unit, Créteil, France, January–May 2013 (n=6)Rectal swabPatient 7 Bed 19colonisationPatient 6 Bed 30infectionPatient 4 Bed 18colonisation Catheter-associated bacteremiaPatient 3 Bed 28infection Bronchial protected specimenPatient 2 Bed 26infection Rectal swab and bronchial protected specimenPatient 1infectionNegative culturesPositive cultures Surgical intensive-care unit Other wardDeathBed 30Jan             Feb             Mar       Apr     May17  18  19 20 21  22 23 24  25 26 27 28 29 30 31   1    2    3    4    5   6    7    8   9    10  11         15  16 17  18       30  31        6    7   8    9    10  11  12  13 14  15  16  17  18 19 20 21         1    2    3   4    5    6    7   8    Date (2013)First A. baumannii isolationCatheter, bronchial protected specimenAbdominal fluid and drain cultureDischargedNDM: New-Delhi metallo-beta-lactamase.Figure 2Results of Diversilab and multilocus sequence typing analysis of isolates from patients infected/colonised with carbapenem-resistant NDM-1-producing Acinetobacter baumannii hospitalised in a surgical intensive-care unit, Créteil, France, January–May 2013 (n=6)NDM: New-Delhi metallo-beta-lactamase.The isolates from the hospitalised patients were compared with a collection of characterised strains [8,17]. A similarity line (89.4%) shows the cut-off to separate different clones.Similarity (%)A. baumannii Ora-1A. baumannii StNA. baumannii 5A. baumannii 7A. baumannii 8A. baumannii 3A. baumannii 6A. baumannii 4A. baumannii Patient 1A. baumannii Patient 2A. baumannii Patient 3A. baumannii Patient 4A. baumannii Patient 6A. baumannii Patient 7A. baumannii SloA. baumannii 161/07A. baumannii ANC4097A. baumannii JHST85ST25ST14 www.eurosurveillance.orgmolecular-based methods of detection may help to control such outbreaks. Taking in account the relationship between North African countries and many European countries, it is possible that the spread of NDM-1 carbapenemase may occur rapidly, mostly through A. baumannii rather than Enterobacteriacae, since A. baumannii may become much more difficult to eradicate.Acknowledgements We thank J M Le Glaunec for technical assistance. Conflict of interestNone declared.Authors’ contributionsJean-Winoc Decousser: laboratory work, manuscript prepa-ration. Chloé Jansen: infection control, manuscript prepa-ration. Aurélie Emirian: laboratory and clinical work. Rémy Bonnin: laboratory work. Leslie Anais: laboratory work. Jean-Claude Merle: clinical work. Patrice Nordmann: manuscript preparation, analysis of data. Laurent Poirel: manuscript preparation, analysis of data.References1. Nordmann P, Poirel L, Walsh TR, Livermore DM. The emerging NDM carbapenemases. Trends Microbiol. 2011;19(12):588-95. http://dx.doi.org/10.1016/j.tim.2011.09.005 PMid:22078325 2. Karthikeyan K, Thirunarayan MA, Krishnan P. Coexistence of blaOXA-23 with blaNDM-1 and armA in clinical isolates of Acinetobacter baumannii from India. J Antimicrob Chemother. 2010;65(10):2253-4. http://dx.doi.org/10.1093/jac/dkq273 PMid:20650909 3. Jovcic B, Lepsanovic Z, Suljagic V, Rackov G, Begovic J, Topisirovic L, et al. Emergence of NDM-1 metallo-β-lactamase in Pseudomonas aeruginosa clinical isolates from Serbia. 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Outbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013

Outbreak of NDM-1-producing Acinetobacter baumannii in France, January to May 2013

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