Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015

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Original article

Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015 Surveillance des Entérobactéries productrices de carbapénémases dans l’océan Indien de 2010 à 2015 A.M. Holman a , J. Allyn a , G. Miltgen b , N. Lugagne c , N. Traversier b , S. Picot d , A. Lignereux e , C. Oudin f , O. Belmonte b , N. Allou a,∗ a

Réanimation polyvalente, centre hospitalier universitaire Felix-Guyon, allée des Topazes, 97405 Saint-Denis, Réunion b Bacteriologie, centre hospitalier universitaire Felix-Guyon, allée des Topazes, 97405 Saint-Denis, Réunion c Unité d’hygiène et de lutte contre les infections hospitalières, centre hospitalier universitaire Felix-Guyon, allée des Topazes, 97405 Saint-Denis, Réunion d Bactériologie, centre hospitalier universitaire Sud Réunion, 97410 Saint-Pierre, Réunion e Biologie, centre hospitalier Gabriel-Martin, 97460 Saint-Paul, Réunion f Comité de lutte contre les infections nosocomiales, groupe hospitalier Est Réunion, 97470 Saint-Benoît, Réunion Received 20 September 2016; accepted 12 April 2017

Abstract Background. – The aim of this study was to trace the emergence of carbapenemase-producing Enterobacteriaceae (CPE) on Reunion Island, a French overseas territory well suited for the surveillance of CPE emergence in patients from the entire Indian Ocean Region. Methods. – This retrospective multicenter study was conducted on Reunion Island between 2010 and 2015. Results. – A total of 43 CPEs were isolated during the course of the study, in 36 patients (50% in the last year alone). Among these patients, 21 had a link with a foreign country (58%), mainly Mauritius (47.6%). Over the same period, CPEs were isolated from 13 of 1735 (0.7%) repatriated patients to Reunion Island from another country of the Indian Ocean Region. The incidence of isolation of CPEs in the repatriated patients treated in Mauritius was higher (9.2%) than in patients treated in Madagascar or the Comoros Islands (< 1%, P < 0.001). The most commonly isolated microorganism was Klebsiella pneumoniae (39.5%). The most frequently identified carbapenemase was NDM-1 (81.4%); 100% and 56% of the NDM-1 strains were susceptible to tigecycline and colistin, respectively. In-hospital mortality rate was higher in patients presenting with CPE infection than in patients without CPE infection (75% vs. 25%, P = 0.04). Conclusion. – As elsewhere in the world, the number of CPE cases on Reunion Island is on the rise. Most cases involve patients from Mauritius, which justifies screening and isolating CPE in patients from that country. © 2017 Elsevier Masson SAS. All rights reserved. Keywords: Carbapenemase-producing Enterobacteriaceae; Indian Ocean region; Reunion Island; Klebsiella pneumoniae

Résumé Objectifs. – Point épidémiologique sur l’émergence des entérobactéries productrices de carbapénémases (EPC) sur l’Île de La Réunion, département franc¸ais d’outre-mer bien situé pour la surveillance de l’émergence des EPC dans la zone océan Indien. Patients et méthodes. – Étude rétrospective et multicentrique réalisée sur l’Île de La Réunion (2010–2015). Résultats. – Pendant la période, 43 EPC ont été isolées chez 36 patients (50 % la dernière année). Vingt et un patients avaient un lien avec un séjour à l’étranger (58 %), principalement avec Maurice (47,6 %). Pendant la même période, 13 EPC ont été isolées parmi les 1735 (0,7 %) patients ayant bénéficié d’une évacuation sanitaire d’un pays de l’océan Indien vers La Réunion. L’incidence de l’isolement des EPC des patients rapatriés de Maurice (9,2 %) était supérieure à celle des patients rapatriés de Madagascar et de l’archipel des Comores (< 1 %, p < 0,001). Les germes les ∗

Auteur correspondant. Réanimation polyvalente, hôpital Felix-Guyon, Bellepierre, 97405 Saint-Denis, France. E-mail address: [email protected] (N. Allou).

http://dx.doi.org/10.1016/j.medmal.2017.04.007 0399-077X/© 2017 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Holman AM, et al. Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.04.007

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plus fréquemment isolés étaient des Klebsiella pneumoniae (39,5 %). Le mécanisme de résistance aux carbapénèmes le plus fréquent était de type NDM-1 (81,4 %) ; 100 % et 56 % des souches portant le gène NDM-1 étaient respectivement sensibles à la tigécycline et à la colimycine. La mortalité intra-hospitalière était plus élevée dans le groupe infecté par une EPC (25 %) que dans le groupe colonisé (75 %, p = 0,04). Conclusion. – Le nombre de cas d’EPC répertoriés à l’Île de La Réunion suit la tendance mondiale à l’augmentation. La plupart des cas d’EPC proviennent des patients de Maurice, qui devraient être dépistés et isolés. © 2017 Elsevier Masson SAS. Tous droits r´eserv´es. Mots clés : Entérobactérie productrice de carbapénémases ; Océan Indien ; Île de la Réunion ; Klebsiella pneumoniae

1. Introduction Carbapenemase-producing Enterobacteriaceae (CPEs) are a major public health concern worldwide. The association between the global spread of antibiotic resistance and international travel is now well-established. Resistance of Enterobacteriaceae strains to carbapenems in France is limited and mostly concerns patients with a history of hospitalization abroad [1]. The first outbreak of CPEs in metropolitan France occurred in 2004, following the transfer of a patient from Greece [2]. A sharp increase in the number of CPE cases has since been observed in the country [3]. Reunion Island is a French overseas territory with a population of 850,000 inhabitants located in the Indian Ocean. It is well suited for the medical evacuation of patients from the entire Indian Ocean Region (Madagascar, Mauritius, Comoros Islands, and Seychelles), both for reasons of proximity, and because its medical infrastructure meets European standards (coronarography, all types of surgeries, and circulatory assistance). While studies have been conducted on the emergence of CPEs in countries all over the world [4,5], data collected for the Indian Ocean Region is limited to only a few case reports [6–9]. The first reported case of CPE (a strain of Klebsiella pneumoniae) on Reunion Island resulted from the transfer of a patient from a Mauritius hospital in 2010 [6]. The aim of this study was to trace the emergence of CPEs on Reunion Island between 2010 (year of the first reported case) and December 2015, and to determine how the repatriation of patients from the Indian Ocean Region has contributed to this development.

acronym CLIN) or the Federation for nosocomial infection control (French acronym FELIN) on Reunion Island between January 2010 and December 2015 (Félix Guyon University Hospital, Saint-Pierre University Hospital, Gabriel-Martin Hospital, Saint-Benoît Hospital, Les Orchidées Care Clinic, and SainteClotilde Care Clinic). 2.2. Definitions We defined a case patient as a patient infected or colonized with CPE, as confirmed by our expert laboratory. An episode was defined as one or several case patients in a well-identified chain of transmission. A chain of transmission was established when two or more case patients were found to have been in contact – including through sharing the same healthcare workers (nurse, auxiliary staff, or physician) – and/or following molecular comparison of bacterial strains by repetitive sequence-based PCR. 2.3. Data collection Demographic and clinical data was collected from consecutive patients presenting with CPE infection. We collected the following data: patients’ demographic characteristics, number of infected or colonized patients, site of infection/colonization, number of reported deaths, bacterial species, as well as existence of an epidemiological link between the index case and a foreign country, including name of the country and nature of the link (i.e., previous stay or hospitalization abroad within one year of hospitalization on Reunion Island).

2. Material and methods

2.4. Microbiological investigations

This observational study was approved by the Bordeaux University Hospital Ethics Committee (DC 2016/104). The requirement for informed consent was waived given the retrospective nature of the study. This study complies with the Strengthening the Reporting of Observational studies in Epidemiology recommendations statement for reporting [10].

All Enterobacteriaceae isolates were identified at species ® level using biochemical identification galleries (API 20E, bioMérieux, Marcy l’Etoile, France) or MALDI-TOF spectrometric identification system (Bruker Daltonics, Breme, Germany/bioMérieux, La Balme-les-Grottes, France). Screening for carbapenemase-producing strains without associated extended-spectrum beta-lactamase was performed using an ertapenem disk on Drigalski agar or selective agar (chromID CARBA SMART, bioMérieux, Marcy l’Étoile, France) [11]. In carbapenem-resistant strains, carbapenemase production was detected using phenotypic and/or genotypic (carbapenemase gene amplification and sequencing) methods. Carbapenemase ® production was detected using the Carba NP test (RAPIDEC

2.1. Selection of the study sample We performed a multicenter retrospective review of all consecutive patients identified as carriers of CPE and reported either to the Committee for nosocomial infection control (French

Please cite this article in press as: Holman AM, et al. Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.04.007

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2.5. Statistical analysis Results were expressed as total numbers and percentage for categorical variables and median and 25th–75th percentiles for continuous variables. Continuous variables were compared with the non-parametric (Mann–Whitney) test. Categorical variables were compared with the Chi2 test or Fisher’s exact test, as appropriate. A P value < 0.05 was considered significant. Analysis was performed using SAS statistical software (8.2, Cary, NC, USA). 3. Results 3.1. Number and location of CPE case patients and episodes The first case patient of CPE on Reunion Island was reported in 2010. Another 36 case patients were reported during the course of the study, with a sharp increase in the number of case patients the last year (Fig. 1). A total of four episodes were observed. All episodes occurred in intensive care units, with three episodes involving two patients, and one episode involving three patients. The characteristics of study patients are depicted in Table 1. Patients presenting with CPE infection were mainly hospitalized in the intensive care unit (n = 20), surgical ward (n = 5), and hematology/malignancy ward (n = 3). Twenty-three (63.9 %) patients received antibiotics before isolation of CPE, including carbapenems for nine patients (25 %), fluoroquinolones for four patients (11.1 %), and third-generation cephalosporins for seven patients (19.4 %). Thirty-five strains were isolated from rectal swabs (81.4 %), nine from urine samples (20.9 %), three from blood cultures (7 %), two from bronchoalveolar lavage (4.6 %), one from central venous catheter (2.3 %), and one from peritoneal catheter (2.3 %).

20 18 Carbapenemase-producing Eterobacteriaceae case patients

CARBA NP, bioMérieux, La Balme-les-Grottes, France), based on in vitro hydrolysis of imipenem demonstrated by a chromogenic test. Genotypic detection was performed using two different methods (BD Max, Check-MDR Carba kit, Check points, Wageningen, The Netherlands and GeneXpert System, Cepheid, Sunnyvale, USA). Enterobacteriaceae isolates were sent to the Associated French National Reference Centre for Antibiotic Resistance for confirmation by sequencing of carbapenemase genes: blaNDM , blaOXA , blaVIM , blaIMP , blaIMI . Isolates from clinical samples and rectal swabs were tested for susceptibility to antibiotics according to guidelines issued by the Antibiogram committee of the French microbiology society (French acronym CA-SFM) and by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) [12]. Susceptibilities to the following antibiotics were determined by disk diffusion on Mueller–Hinton agar (Bio-Rad, Marnes-la-Coquette, France): imipenem, ertapenem, meropenem, amikacin, gentamicin, tobramycin, cefotaxime, ceftazidime, cefepime, quinolones, fosfomycin, colistin, and tigecycline. Minimum inhibitory concentrations (MIC) were determined by gradient strips (Etest, bioMérieux, Marcy l’Étoile, France) for meropenem, tigecycline, and colistin.

3

16 14

No link with foreign country

12 Link with foreign country 10 8 6 4 2 0 2010

2011

2013

2012

2014

2015

Years

Fig. 1. Number of carbapenemase-producing Enterobacteriaceae case patients (2010–2015). Cas d’entérobactéries productrices de carbapénémases de 2010 à 2015.

In 15 of the 36 patients (41.7 %), CPE carriage was isolated not on admission, but during hospitalization after a median of two screening swabs in the absence of cross-transmission. 3.2. Association with cross-border transfer A link with a foreign country was established for 21 of 36 patients (58.3 %) presenting with CPE infection. Overall, 19 patients had stayed in one foreign country and two in ≥ 2 foreign countries, with a total of 24 different stays abroad: Mauritius in 10 cases (40 %), Comoros Islands in four cases (16 %), Madagascar in four cases (16 %), India in four cases (16 %), and the Seychelles in one case (4 %). Between 2010 and 2012, 71.4 % (5/7) of patients presenting with CPE infection had a link with a foreign country versus 55.2 % (16/29) between 2013 and 2015 (P = 0.43) (Fig. 1). During the study period, CPEs were isolated in 13 of 1735 (0.7 %) repatriated patients who had received medical assistance in another country of the Indian Ocean Region. The incidence

Table 1 Clinical characteristics. Caractéristiques cliniques. Variable

n = 36

Age (years) Male Body mass index > 27 kg/m2 Medical admission Admission to the Intensive Care Unit Cancer Liver cirrhosis Chronic obstructive pulmonary disease Immunosuppression Alcohol abuse Chronic renal failure with dialysis History of congestive heart failure Diabetes mellitus Link with a foreign country Prior antibiotic therapy

26 (72.2) 8 (22.2) 20 (55.6) 20 (55.6) 9 (25) 1 (2.8) 5 (13.9) 3 (8.3) 6 (16.7) 3 (8.3) 9 (25) 5 (13.9) 21 (58.3) 23 (63.9)

Results are expressed as mean ± standard deviation.

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Table 2 Forty-three bacterial species and carbapenemase type in 36 patients presenting with carbapenemase-producing Enterobacteriaceae infection. Caractéristiques des 43 entérobactéries productrices de carbapénémases isolées chez les 36 patients. Bacterial species

Klebsiella pneumoniae Escherichia coli Enterobacter cloacae Citrobacter freundii Morganella morganii Enterobacter aerogenes Proteus mirabilis Salmonella enteritidis Total

Number of microorganisms by type of carbapenemases NDM-1

NDM-4

NDM-5

NDM-6

OXA-48

OXA-242

IMI-1

Total

17 10 2 2 2 0 1 1 35

0 1 0 0 0 0 0 0 1

0 1 0 0 0 0 0 0 1

0 1 0 0 0 0 0 0 1

0 1 0 0 0 1 0 0 2

0 1 0 0 0 0 0 0 1

0 0 2 0 0 0 0 0 2

17 15 4 2 2 1 1 1 43

Results are expressed as number; NDM: New Delhi metallo-beta-lactamase; OXA: oxacillinase; IMI: imipenem hydrolyzing beta-lactamase.

of CPE isolation in the repatriated patients treated in Mauritius was higher (6/65, 9.2 %) than in patients treated in Madagascar (3/487, 0.6 %, P < 0.0001) or the Comoros Islands (2/1,169, 0.2 %, P < 0.0001). The incidence of CPE isolation was similar in patients repatriated with medical assistance from Mauritius and in patients repatriated from India (1/7, 14.3 %, P = 0.67) or the Seychelles (1/6, 16.7 %, P = 0.56). 3.3. Carbapenemase-producing Enterobacteriaceae, resistance mechanisms and susceptibility of microorganisms The study observed 43 CPE strains in 36 patients (seven patients had two different CPE strains). The main species involved were: K. pneumoniae in 17 patients (34.9 %) and Escherichia coli in 15 patients (34.9 %) (Table 2). The carbapenemases identified were NDM-1 (n = 35, 81.4 %), OXA-48 (n = 2, 4.6 %), IMI-2 (n = 2, 4.6 %), OXA-242 (n = 1, 2.3 %), NDM-6 (n = 1, 2.3 %), NDM-4 (n = 1, 2.3 %), and NDM-5 (n = 1, 2.3 %) (Tables 2 and 3). In the study cohort, most isolated CPE strains carrying blaNDM and blaOXA genes were resistant to antibiotic therapy (Tables 4 and 5). The two CPE strains carrying the blaIMI-2 gene were susceptible to amikacin, colistin, cefotaxime, and tigecycline (Tables 4 and 5). 3.4. Outcome Four of the 36 patients (11.1 %) contracted infections. The sources of sepsis were catheter-related infection for one patient, urinary tract infection for another one, and unknown for two patients. Bacteremia was observed in three patients. Eleven of the 36 patients (30.6 %) died during hospitalization, including three of the four patients (75 %) presenting with CPE infection versus eight of the 32 patients (25 %) without CPE infection (P = 0.04). 4. Discussion This is the first study assessing the epidemiology of CPEs on Reunion Island and its Indian Ocean Region origin. There has been a rise in the number of CPE case patients observed

on the island since 2010. This increase is in line with studies conducted on the epidemiology of CPEs in metropolitan France and in the rest of the world [2,5]. Studying the epidemiology of CPEs on Reunion Island is relevant as it provides information on the spread of CPEs in the entire Indian Ocean Region. In our study, most CPE case patients had a link with another country of the region (58.3 %). Similarly, in metropolitan France, nearly 50 % of CPE case patients reported between 2004 and 2015 had a link with a foreign country [1]. On Reunion Island, this link most certainly results from the growing number of repatriated patients (95 in 2010 versus > 300/year in 2014 and 2015). Most of the non-local CPE case patients observed in our study had a link with Mauritius. Indeed, despite a relatively small number of repatriated patients from Mauritius, a high rate of CPE carriage was observed among them. By contrast, the number of CPE case patients and the incidence of CPE carriage were low (< 1 %) among patients from Madagascar and the Comoros Islands, even though the number of repatriated patients from these two countries was high. Our results also reveal an increase in the number of local CPE case patients. These patients with no link with a foreign country may be associated with the rise in antibiotic consumption – especially carbapenems [13]. Indeed, carbapenems are increasingly used as a first-line antibiotic therapy in patients severely infected or colonized with extended-spectrum betalactamase producing Enterobacteriaceae [14]. The consumption of carbapenems increased by 145 % between 2000 and 2013 in France [15]. The prescription of carbapenems may be leading to selective pressure, thereby favoring the emergence of carbapenem-resistant strains like CPEs. Twenty-five per cent of our patients and three of the eight local patients had received carbapenems before the isolation of CPE. The spread of CPEs (such as extended-spectrum beta-lactamase-producing Enterobacteriaceae) may also be explained by the prolonged duration of carriage. This is suggested by the study of Zimmerman et al., which reported a mean time to carbapenem-resistant Enterobacteriaceae negativity of 387 days [16]. Local carriage and spread of CPEs seem to be on the rise on Reunion Island. This is also the case in metropolitan France, where 26 % of reported CPE case patients had no link with a foreign country in 2011 vs. 45 % in 2013, 49 % in 2014, and 52 % in 2015 [17]. Similarly,

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Table 3 Forty-three bacterial species and carbapenemase type in 36 patients presenting with carbapenemase-producing Enterobacteriaceae infection, and link with foreign country. Caractéristiques des 43 entérobactéries productrices de carbapénémases isolées chez les 36 patients en fonction d’un lien avec un séjour à l’étranger. Bacterial species

Number of microorganisms by type of carbapenemases

Comoros Islands Madagascar Mauritius Seychelles India No link with foreign country Total

NDM-1

NDM-4

NDM-5

NDM-6

OXA-48

OXA-242

IMI-2

Total

2 3 8 1 3 18 35

0 1 0 0 0 0 1

0 0 1 0 0 0 1

0 0 0 0 1 0 1

0 0 1 0 0 1 2

0 0 1 0 0 0 1

2 0 0 0 0 0 2

4 4 11 1 4 19 43

Results are expressed as number; NDM: New Delhi metallo-beta-lactamase; OXA: oxacillinase; IMI: imipenem hydrolyzing beta-lactamase. Table 4 Antimicrobial susceptibilities of strains carrying blaNDM , blaOXA , and blaIMI-2 genes. Sensibilités aux antibiotiques des souches d’entérobactéries productrices de carbapénémases portant les gènes blaNDM , blaOXA , et blaIMI-2 . Antibiotics

% resistant blaNDM (n = 38)

% resistant blaOXA (n = 3)

% resistant blaIMI-2 (n = 2)

Ertapenem Imipenem Meropenem Cefotaxime Ceftazidime Cefepime Amikacin Gentamicin Tobramycin Ciprofloxacin Colistin Tigecycline

100 85 100 100 100 95 52 85 100 96 0 56

100 100 100 100 100 100 0 0 0 100 0 0

100 100 100 0 0 0 0 0 0 100 0 0

in Reunion Island, the proportion of CPE case patients with no link with a foreign country seems to be on the rise: 29 % in 2012, 39 % in 2013 and 2014, and 42 % in 2015. Most of the non-local CPE case patients observed in our study had a link with Mauritius. Although no exhaustive data on CPEs in Mauritius is available, two factors seem to be favoring the spread of CPEs in this country:

As in metropolitan France, the most frequently isolated microorganisms on Reunion Island were K. pneumoniae (39.5 %) and E. coli (34.9 %) [2]. Yet the most common carbapenemases are OXA-48 in metropolitan France [2] and NDM-1 (81.4 %) on Reunion Island – the latter finding being also reported in India [5]. French national guidelines suggest systematic admission screening and contact isolation pending screening results for all patients recently hospitalized abroad [18]. In 41.7 % of our patients, CPE carriage was isolated not on admission but during hospitalization after a median of two screening swabs in the absence of cross-transmission. This could be explained by two hypotheses: a false-negative test on admission, or a late onset due to antibiotic pressure. Overall, 63.9 %

• close ties with India, which lead to numerous exchanges between the two populations; • a management of antibiotic therapy that is very different from that prevailing on Reunion Island, with evidence of widespread self-medication without medical instruction.

Table 5 Cumulative proportions of CPE isolates inhibited by increasing concentrations of antimicrobial agents. Pourcentage des souches d’entérobactéries productrices de carbapénémases dont la croissance est inhibée par des concentrations croissantes d’antibiotiques. Antimicrobial agent

Colistin Meropenem Tigecycline

% of strains per susceptibility category 0.12

0.25

0.5

0 0 0

27.8 0 14.3

72.2 0 35.7

1 83.3 10 50

2

4

8

16

32

S

I

R

100 10 64.3

100 40 78.6

100 40 78.6

100 50 85.7

100 100 100

100 7.1 50

0 21.4 14.3

0 71.4 35.7

CPE: carbapenemase-producing Enterobacteriaceae; S: susceptible; I: intermediate; R: resistant.

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of our patients received antibiotics before the isolation of CPE. The prolonged isolation of high-risk patients is therefore highly recommended, even if admission screening results are negative [19]. Carbapenemase-producing Enterobacteriaceae is a major public health problem. First, at the collective level, there is a risk of CPE dissemination in the local population: our study revealed an increased proportion of CPE case patients with no link with a foreign country, which may lead to an endemic situation on Reunion Island, as is the case in India, Greece, or Italy [5]. Second, at the individual level, there is a risk of colonization and infection with microorganisms that are difficult to treat [20]. This study has several limitations. The retrospective nature of the analysis is obviously a weakness, as only a small number of CPE case patients were identified. Even though CPE detection in patients coming from abroad is strongly advised in Reunion Island hospitals, not all patients in our study underwent CPE screening during hospitalization. The real number of CPE case patients was therefore certainly underestimated. Comparing the incidence of CPE isolation over the years is difficult because the number of rectal swabs for multidrug-resistance Gram-negative Bacilli detection likely increased during the study period. The foreign countries where our patients had stayed are all located in the Indian Ocean Region, that is, far from Europe. Thus, even though some geographic locations are known for their high prevalence of multidrug-resistant bacteria, the origin of the patient was sometimes difficult to determine due to a lack of epidemiologic data or poorly updated information. Nevertheless, immigration is known to play an important role in the dissemination of CPEs, as shown by studies conducted in the United Kingdom and in India [21]. Given that our study focused on patients who stayed in another country of the Indian Ocean Region, our results are most likely relevant to address this worldwide problem. The incidence of CPE is growing on Reunion Island, as is the case elsewhere in the world. This increase can mainly be observed in repatriated patients from Mauritius, which justifies screening and isolating CPEs in patients from that country. The most frequently identified carbapenemase on Reunion Island is NDM-1 (81.4 %). This finding has also been reported in India, a country with close ties with Mauritius. The number of case patients with no link with foreign countries increased during the study period, suggesting a potential dissemination of CPEs in the local population. Funding This work was internally funded. Contribution of authors AMH, NA, JA, and NL had full access to data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: AMH, NA, JA, NL, OB, NT, GM Acquisition of data: AMH, NL, OB, NT, GM

Analysis and interpretation of data: AMH, NA, JA, NL, OB, NT, GM. Drafting of the article: AMH, NA, JA, NL, OB, NT. Critical revision of the article for important intellectual content: AMH, NA, JA, NL, OB, NT, GM. Statistical analysis: NA, JA. Administrative, technical, or material support: AMH, NA, JA, NL, OB, NT. Study supervision: AMH, NA, JA, NL, OB, NT, GM. Disclosure of interest The authors declare that they have no competing interest. References [1] Fournier S, Lepainteur M, Kassis-Chikhani N, Huang M, Brun-Buisson C, Jarlier V. Link between carbapenemase-producing Enterobacteria carriage and cross-border exchanges: eight-year surveillance in a large French multihospitals institution. J Travel Med 2012;19:320–3. [2] Fournier S, Monteil C, Lepainteur M, Richard C, Brun-Buisson C, Jarlier V. Long-term control of carbapenemase-producing Enterobacteriaceae at the scale of a large French multihospital institution: a nine-year experience, France, 2004 to 2012. Euro Surveill 2014:19. [3] Vaux S, Carbonne A, Thiolet JM, Jarlier V, Coignard B. Emergence of carbapenemase-producing Enterobacteriaceae in France, 2004 to 2011. Euro Surveill 2011:16. [4] Glasner C, Albiger B, Buist G, Andraˇsevi´c AT, Canton R, Carmeli Y, et al. Carbapenemase-producing Enterobacteriaceae in Europe: a survey among national experts from 39 countries. February 2013. Euro Surveill 2013:18. [5] Nordmann P, Poirel L. The difficult-to-control spread of carbapenemase producers among Enterobacteriaceae worldwide. Clin Microbiol Infect 2014;20:821–30. [6] Cabanes F, Lemant J, Picot S, Simac C, Cousty J, Jalin L, et al. Emergence of Klebsiella pneumoniae and Salmonella metallo-beta-lactamase (NDM-1) producers on reunion island. J Clin Microbiol 2012;50:3812. [7] Chereau F, Herindrainy P, Garin B, Huynh BT, Randrianirina F, Padget M, et al. Colonization of extended-spectrum-beta-lactamase- and NDM-1producing Enterobacteriaceae among pregnant women in the community in a low-income country: a potential reservoir for transmission of multiresistant Enterobacteriaceae to neonates. Antimicrob Agents Chemother 2015;59:3652–5. [8] Poirel L, Lascols C, Bernabeu S, Nordmann P. NDM-1-producing Klebsiella pneumoniae in Mauritius. Antimicrob Agents Chemother 2012;56:598–9. [9] Hall JM, Corea E, Sanjeewani HD, Inglis TJ. Molecular mechanisms of beta-lactam resistance in carbapenemase-producing Klebsiella pneumoniae from Sri Lanka. J Med Microbiol 2014;63:1087–92. [10] von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;370:1453–7. [11] Nordmann P, Gniadkowski M, Giske CG, Poirel L, Woodford N, Miriagou V, et al. Identification and screening of carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 2012;18:432–8. [12] Jehl F, Bonnet R, Bru JP, Caron F, Cattoen C, Cattoir V, et al. Comité de l’antibiogramme de la Société franc¸aise de microbiologie. European Commitee on antimicrobial susceptibility testing. Recommandations. V.1.0 février; 2016 http://www.sfm-microbiologie.org,. Accessed on May 2016. [13] Gharbi M, Moore LS, Gilchrist M, Thomas CP, Bamford K, Brannigan ET, et al. Forecasting carbapenem resistance from antimicrobial consumption surveillance: lessons learnt from an OXA-48-producing Klebsiella pneumoniae outbreak in a West London renal unit. Int J Antimicrob Agents 2015;46:150–6.

Please cite this article in press as: Holman AM, et al. Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.04.007

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[14] Gauzit R, Pean Y, Alfandari S, Bru JP, Bedos JP, Rabaud C, et al. Carbapenem use in French hospitals: a nationwide survey at the patient level. Int J Antimicrob Agents 2015;46:707–12. [15] Cavalié P, Djeraba A. L’évolution des consommations d’antibiotiques en France entre 2000 et 2013. ANSM; 2014 www.ansm.sante.fr. [16] Zimmerman FS, Assous MV, Bdolah-Abram T, Lachish T, Yinnon AM, Wiener-Well YT, et al. Duration of carriage of carbapenem-resistant Enterobacteriaceae following hospital discharge. Am J Infect Control 2013;41:190–4. [17] http://www.invs.sante.fr/Dossiers-thematiques/Maladiesinfectieuses/Infections-associees-aux-soins/Surveillancedes-infections-associees-aux-soins-IAS/Enterobacteriesproductrices-de-carbapenemases-EPC/Episodes-impliquantdes-enterobacteries-productrices-de-carbapenemases-en-France. -Situation-epidemiologique-du-4-septembre-2015. Accessed on February 2016.

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[18] Lepelletier D, Berthelot P, Lucet JC, Fournier S, Jarlier V, Grandbastien B. French recommendations for the prevention of emerging extensively drug-resistant bacteria (eXDR) cross-transmission. J Hosp Infect 2015;90:186–95. [19] Allyn J, Angue M, Belmonte O, Lugagne N, Traversier N, Vandroux D, et al. Delayed diagnosis of high drug-resistant microorganisms carriage in repatriated patients: three cases in a French intensive care unit. J Travel Med 2015;22:215–7. [20] Tzouvelekis LS, Markogiannakis A, Piperaki E, Souli M, Daikos GL, et al. Treating infections caused by carbapenemase-producing Enterobacteriaceae. Clin Microbiol Infect 2014;20:862–72. [21] Hidalgo L, Hopkins KL, Gutierrez B, Ovejero CM, Shukla S, Douthwaite S, et al. Association of the novel aminoglycoside resistance determinant RmtF with NDM carbapenemase in Enterobacteriaceae isolated in India and the UK. J Antimicrob Chemother 2013;68:1543–50.

Please cite this article in press as: Holman AM, et al. Surveillance of carbapenemase-producing Enterobacteriaceae in the Indian Ocean Region between January 2010 and December 2015. Med Mal Infect (2017), http://dx.doi.org/10.1016/j.medmal.2017.04.007