Tigecycline activity tested against carbapenem-resistant Enterobacteriaceae from 18 European nations: results from the SENTRY surveillance program (2010–2013)

    Tigecycline Activity Tested against Carbapenem-Resistant Enterobacteriaceae from 18 European Nations: Results from the SENTRY Antimicrobial Surveillance Program (2010–2013) Helio S. Sader, Mariana Castanheira, Robert K. Flamm, Rodrigo E. Mendes, David J. Farrell, Ronald N. Jones PII: DOI: Reference:

S0732-8893(15)00214-X doi: 10.1016/j.diagmicrobio.2015.06.011 DMB 13846

To appear in:

Diagnostic Microbiology and Infectious Disease

Received date: Revised date: Accepted date:

10 March 2015 15 June 2015 19 June 2015

Please cite this article as: Sader Helio S., Castanheira Mariana, Flamm Robert K., Mendes Rodrigo E., Farrell David J., Jones Ronald N., Tigecycline Activity Tested against Carbapenem-Resistant Enterobacteriaceae from 18 European Nations: Results from the SENTRY Antimicrobial Surveillance Program (2010–2013), Diagnostic Microbiology and Infectious Disease (2015), doi: 10.1016/j.diagmicrobio.2015.06.011

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Tigecycline Activity Tested against Carbapenem-Resistant Enterobacteriaceae from 18 European Nations:

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Results from the SENTRY Antimicrobial Surveillance Program (2010-2013)

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Helio S. Sader,

Mariana Castanheira, Robert K. Flamm,

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Rodrigo E. Mendes,

and

Ronald N. Jones

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David J. Farrell,

JMI Laboratories, North Liberty, Iowa, USA

Key words: Carbapenem resistance, KPC, VIM, beta-lactamases.

Contact Information:

Helio S. Sader, M.D., PhD JMI Laboratories 345 Beaver Kreek Ctr, Ste A North Liberty, Iowa, 52317, USA Phone: 319-665-3370 Fax: 319-665-3371 [email protected]

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Abstract

We evaluated the in vitro activity of tigecycline and selected comparator agents tested against

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carbapenem-resistant Enterobacteriaceae (CRE) isolated from European medical centres. A total of 14,286 clinically-significant non-duplicate Enterobacteriaceae isolates were collected from 18 European countries in 2010-2013. Susceptibility testing was performed by CLSI broth microdilution method and isolates with a

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meropenem or imipenem MIC at ≥4 μg/mL were categorized as CRE. Selected CRE strains were screened for

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acquired carbapenemases by multiplex PCR and sequencing. Overall, 2.0% (280/14,286) of Enterobacteriaceae strains were CRE. The highest CRE occurrence was observed in Poland (17.3%; 70/405), followed by Italy

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(7.5%, 130/1,743), Greece (7.4%; 45/605) and Romania (5.0%; 8/157). The most common CRE species were Klebsiella pneumoniae (242; 86.4%) and Enterobacter cloacae (22; 7.9%), and the most common carbapenemases were KPC-2/3 (85.4%) and VIM-type (12.5%). Only tigecycline (88.6% susceptible) and

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colistin (73.9%) exhibited good in vitro activity (>70.0%) against CRE strains.

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1. Introduction

The prevalence of carbapenem-resistant Enterobacteriaceae (CRE) remained extremely low for many

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years after the approval of the first carbapenem for clinical use in 1985. However, in recent years the occurrence of carbapenemase-producing Enterobacteriaceae has increased rapidly in some geographic regions (ECDC, 2013) (Glasner et al., 2013; Magiorakos et al., 2013). In particular, clonal Klebsiella pneumoniae strains

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with KPC (class A carbapenemases) have disseminated widely in the United States, Israel, and some European countries (Munoz-Price et al., 2013).

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CRE are often resistant to all β-lactams currently available for clinical use and frequently co-resistant to

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most other antimicrobial agents, leaving very few treatment options. The epidemiology of CRE is very complex since it involves a diversity of carbapenem-hydrolyzing enzymes and the ability of these genes to disseminate (Glasner et al., 2013; Gupta et al., 2011; Swaminathan et al., 2013). Some of these resistance genes are

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associated with successful clonal lineages which have selective advantages in hospitals with high use of antimicrobial agents, whereas others are more often related to transmissible plasmids (Tzouvelekis et al., 2012).

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Tigecycline is a glycylcycline with broad-spectrum antimicrobial activity that was initially approved by the

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European Medicines Agency in 2006 for the treatment of adults with complicated skin and soft tissue (SSTI) and intra-abdominal infections (IAI)(Tygacil®, 2013; Yahav et al., 2011). This derivative of minocycline has

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demonstrated potent activity against many difficult-to-treat organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Acinetobacter spp. and Enterobacteriaceae strains that produce extended-spectrum β-lactamases (ESBL) and/or carbapenemases (CRE)(Castanheira et al., 2008; Sader et al., 2013; Stein and Babinchak, 2013). We evaluated the in vitro activity of tigecycline and comparators agents tested against Enterobacteriaceae, including CRE, isolated from European medical centres.

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2. Materials and Methods

2.1. Organism collection: A total of 14,286 clinically significant, non-duplicate Enterobacteriaceae isolates were

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collected from 58 medical centers located in 18 European countries (January 2010 to November 2013). The number of medical centers surveyed in each country ranged from one to 10 and is listed in Table 1. Isolates were collected from patients with bloodstream (BSI; 42.1%), community-acquired and nosocomial respiratory

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tract (RTI; 18.2%), SSTI (16.6%), urinary tract (UTI; 15.4%), IAI (4.6%) and other (3.1%) infections. The

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Enterobacteriaceae species/genus included in this investigation were: Citrobacter spp., Enterobacter spp.,

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Escherichia coli, Klebsiella spp. and Serratia marcescens.

2.2. Methods: Susceptibility testing was performed by reference broth microdilution method in a central monitoring laboratory (JMI Laboratories, North Liberty, Iowa, USA) according to Clinical Laboratory and

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Standards Institute (CLSI) methods using validated broth microdilution panels produced by Thermo Fisher Scientific Inc. (Cleveland, Ohio, USA). Susceptibility interpretations were performed using EUCAST breakpoint

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criteria (version 5.0, January 2015)(EUCAST, 2014) and CLSI (M100-S15, 2015)(CLSI, 2014). Isolates with a

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meropenem or imipenem MIC at ≥4 μg/mL (non-susceptible by EUCAST criteria or resistant by CLSI criteria) were categorized as CRE. Forty-eight randomly selected CRE strains collected in 2010-2011 from the countries

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with the highest CRE rates (Greece [13 strains], Italy [20] and Poland [15]) were screened for the presence of the following acquired carbapenemases in four separate multiplex polymerase chain reactions (PCR): blaKPC, blaOxa-48, blaSME, blaGES, blaNMC-A, blaIMI, blaIMP, blaVIM, blaSPM-1, blaGIM-1, blaSIM-1, blaAIM-1, blaKHM-1, blaNDM, blaDIM-1 and blaBIC-1 (Castanheira et al., 2011). Quality control was performed according to CLSI (M100-S25) guidelines 14

using E. coli ATCC 25922 and 35218, and Pseudomonas aeruginosa ATCC 27853 .

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3. Results

Overall, 2.0% (280/14,286) of Enterobacteriaceae strains sampled in Europe were categorized as CRE.

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The most common CRE strains were found among Klebsiella pneumoniae (242 strains; 86.4%) and Enterobacter cloacae (22; 7.9%; Table 1). CRE were isolated mainly from BSI (38.9%), RTI (24.3%), SSTI (13.6%), UTI (13.2%) and IAI (5.0%). Moreover, the highest CRE rate was observed among isolates from RTI

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(2.6%), followed by IAI (2.1%), BSI (1.8%), UTI (1.7%) and SSTI (1.6%).

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The highest CRE frequency was observed in Poland (17.3%; 70/405), followed by Italy (7.5%, 130/1,743), Greece (7.4%; 45/605) and Romania (5.0%; 8/157). However, this data should be interpreted with

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caution since the numbers of medical centers surveyed in Poland, Italy, Greece and Romania were limited to four, seven, two and three, respectively. Greece, Italy and Poland accounted for 88.4% of CRE strains (Table 1). No CRE (0.0%) was found in Portugal (529 isolates tested), Slovakia (113), Slovenia (237), Sweden (418)

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and the United Kingdom (1,180). CRE rates were 0.1-2.6% in Belgium, Bulgaria, Czech Republic, France, Hungary, Ireland, Netherlands and Spain (Table 1).

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Tigecycline (MIC50/90, 0.12/0.5 μg/mL; 98.3% susceptible at ≤1 μg/mL [current EUCAST susceptible

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breakpoint]), imipenem (MIC50/90, ≤0.12/0.5 μg/mL; 98.2% susceptible at ≤2 μg/mL [EUCAST]) and meropenem (MIC50/90, ≤0.12/≤0.12 μg/mL; 98.1% susceptible at ≤2 μg/mL [EUCAST]) were the most active agents tested

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against Enterobacteriaceae overall. Susceptibility rates for amikacin (MIC50/90, 2/4 μg/mL) and colistin (MIC50/90, ≤0.5/2 μg/mL) were 95.7 and 91.8%, respectively, applying EUCAST breakpoint criteria (Table 2). Tigecycline was the only compound that demonstrated good in vitro activity against CRE (MIC50/90, 0.5/2 μg/mL; 88.6% susceptible at ≤1 μg/mL [EUCAST]). Colistin, the second most active compound, inhibited only 73.9% of CRE strains at the EUCAST susceptible breakpoint of ≤2 μg/mL. Gentamicin (MIC50/90, 2/>8 μg/mL) inhibited 61.8% at the EUCAST susceptible breakpoint of ≤2 μg/mL; whereas only 19.8% of strains were susceptible (EUCAST) to amikacin at ≤8 μg/mL (MIC50/90, 32/>32 μg/mL; Table 2). Among carbapenem-non-susceptible K. pneumoniae (242 strains), 91.3% were susceptible to tigecycline (MIC50/90, 0.5/1 μg/mL) and 81.0% were susceptible to gentamicin (MIC50/90, 2/>8 μg/mL); whereas colistin (MIC50/90, ≤0.5/>8 μg/mL) was active against only 72.3% of strains. When tested against carbapenemnon-susceptible E. cloacae (n=22), colistin (MIC50/90, 0.5/8 μg/mL; 90.9% susceptible) was the most active

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compound, followed by tigecycline (MIC 50/90, 1/2 μg/mL; 59.1% susceptible [EUCAST]) and amikacin (MIC50/90, 8/>32 μg/mL; 54.5% susceptible [EUCAST]; data not shown). The carbapenemases identified among 48 selected CRE strains (17.1% of all CRE strains) collected

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from Greece, Italy and Poland in 2010-2011 were KPC-2/3 (41/48 or 85.4%), VIM-type (6/48 or 12.5%) and IMP-19 (one strain or 2.1%). KPC-2/3 accounted for 84.6, 95.0 and 73.3% of carbapenemases identified in Greece, Italy and Poland, respectively, and the largest variety of carbapenemases was observed among CRE

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from Poland (KPC-2/3 [11 strains], VIM-1 [two], VIM-4 [one] and IMP-19 [one]). Tigecycline was the most active compound tested against KPC-2/3-producing strains (n=41, all K. pneumoniae) with MIC50/90 of 0.5/1 μg/mL and

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70.7, 90.2 and 100.0% inhibited at tigecycline MIC of ≤0.5, ≤1 and ≤2 μg/mL, respectively. Colistin (MIC50/90,

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0.5/4 μg/mL) and amikacin (MIC50/90 of 32/>32 μg/mL) inhibited 87.8 and 12.2% of KPC-producing strains at the EUCAST susceptible breakpoints, respectively. Six VIM-producing strains were identified, four E. cloacae (Italy [1] and Poland [3]) and two K. pneumoniae (both from Greece), and the most active antimicrobial tested against

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these strains was colistin (MIC50, ≤0.25 μg/mL; 100.0% susceptible), followed by tigecycline (MIC50, 0.5 μg/mL;

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highest MIC, 2 μg/mL; 50.0% susceptible) and amikacin (MIC50, 8 μg/mL; 50.0% susceptible, data not shown).

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4. Discussion

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The occurrence of infections caused by CRE has increased significantly in many geographic regions in

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the last years (Tavares et al., 2015; Vasoo et al., 2015; Xu et al., 2015), and the optimal treatment of infections caused by these organisms remains unknown (Hirsch and Tam, 2010; Kelesidis et al., 2008; Zavascki et al., 2013). Their evolving resistance mechanisms and the lack of agents active against multidrug-resistant Gram-

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negative organisms represent a major treatment dilemma for physicians. Although, CRE are still rare in most

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regions of the world, these organisms have been observed with increasing frequency in some geographic areas and have become endemic in multiple countries (ECDC, 2013; Edelstein et al., 2013; Giani et al., 2013; Glasner

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et al., 2013; Gupta et al., 2011; Magiorakos et al., 2013; Miyakis et al., 2011; Munoz-Price et al., 2013). Considering its in vitro activity against many CRE, tigecycline has been used for the treatment of CRE infections, usually as part of combination regimens(Hirsch and Tam, 2010; Kelesidis et al., 2008; Tzouvelekis et

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al., 2012; Zavascki et al., 2013).

The results presented here provide valuable information on the activity of tigecycline and various

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comparator agents tested against a large collection of Enterobacteriaceae, including CRE strains. However, the

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limitations of the study should be considered when interpreting the data, and the small number of participant centers in some of the countries represents the main limitation of this investigation. Although five to ten medical

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centers were surveyed in the five major Western European countries (i.e. France, Germany, Italy, Spain and United Kingdom), some countries had only one or two medical centers contributing to the study (Table 1). Thus, it is important to note that the antimicrobial resistance profile observed in a few participant centers may not completely reflect the profile of the entire country, and may fail to detect resistance problems that are restrict to other medical centers or geographic areas not included in this surveillance investigation. On the other hand, the results of this investigation corroborate other studies showing that CRE has emerged and become a major problem of antimicrobial resistance in some European nations, mainly Greece, Italy, Poland and Romania (ECDC, 2013) (Edelstein et al., 2013; Giani et al., 2013; Glasner et al., 2013; Miyakis et al., 2011; Munoz-Price et al., 2013). Data from the 2013 European Antimicrobial Resistance Surveillance network (EARS-net) also cited high rates of CRE (K. pneumoniae) in Poland, Greece and Italy (but not in Romania), and indicated that the occurrence of carbepanem-resistant K. pneumoniae increased substantially in many other European countries,

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including Austria, France, Czech Republic, Norway, Portugal, Spain and United Kingdom in the 2010 to 2013 time period(ECDC, 2013; Eurosurveillance editorial, 2013). Of particular concern is the dissemination of KPCproducing strains (Giani et al., 2013; Glasner et al., 2013; Munoz-Price et al., 2013). In summary, we evaluated

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a large collection of Enterobacteriaceae isolates (n=14,286) from multiple types of infections collected from 18 European countries over a four-year period (2010 - 2013), and our results indicate that CRE remains uncommon in most European countries, but has become endemic in a few countries, as has been shown by other European

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surveillance programs (ECDC, 2013)(Glasner et al., 2013; Magiorakos et al., 2013).

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Another limitation of the study is the restricted number of CRE selected for molecular characterization. We focused the selection of CRE strains to the three countries with the highest rates of CRE (i.e. Greece, Italy

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and Poland), and characterized only approximately half of the CRE strains (48 of 101; randomly selected) collected in the first two years of the investigation (2010 and 2011). Although the number of characterized strains was limited, the results revealed a great variety of carbapenemase among CRE from those three

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countries. Furthermore, our results confirm that KPC has become the predominant carbapenemase among CRE in Europe, like the United States (Giani et al., 2013; Glasner et al., 2013; Magiorakos et al., 2013; Munoz-Price

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et al., 2013).

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Clinical data on the treatment of CRE infections are very limited and consist primarily of small case series, case reports, retrospective analyses and observational studies (Brust et al., 2014; Hirsch and Tam,

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2010; Kelesidis et al., 2008; van Duin et al., 2013; Zavascki et al., 2013). Monotherapy is not recommended due to increased rates of clinical failure, and aminoglycosides, polymyxins and tigecycline are usually the cornerstone agents in combination schemes (Hirsch and Tam, 2010; Kelesidis et al., 2008; Tzouvelekis et al., 2012; Zavascki et al., 2013). Furthermore, the lack of novel agents and increasing rates of resistance make selection of empirical therapy very difficult, and several studies have indicated that inadequate empirical therapy is associated with increased mortality(Retamar et al., 2012). In the present study, only tigecycline (88.4% susceptible at ≤1 μg/mL) and colistin (73.9% susceptible at ≤2 μg/mL) exhibited reasonable in vitro activity against CRE strains collected in European hospitals. The aminoglycosides showed more limited activity against these organisms, and gentamicin (61.8% susceptible) exhibited greater activity than amikacin (21.4% susceptible [EUCAST]; Table 2)(EUCAST, 2014).

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It is important to note that selection of appropriate antimicrobials should consider local microbial epidemiology, patient risk factors for multidrug-resistant organisms and patient-specific characteristics that may influence treatment options. Results from a large, well monitored surveillance network, such as those presented

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here, can provide useful information by detecting trends in antimicrobial resistance mechanisms as well as signs of emerging resistance patterns. Furthermore, our data indicates that tigecycline continues to demonstrate in vitro activity against many Enterobacteriaceae strains isolated from European hospitals, including most CRE.

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Based on the potency and spectrum, tigecycline remains an important option for treating of infections caused by

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indicated CRE Enterobacteriaceae organisms in Europe. However, expanded clinical studies are necessary to

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establish the role of candidate agents or combinations in the treatment of CRE infections.

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Acknowledgements

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The authors would like to thank all participating centers for contributing isolates to this surveillance

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protocol. All co-authors are employees of JMI Laboratories who were paid consultants to Pfizer in connection with the development of this manuscript. Laboratory testing of clinical isolates was performed by JMI

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Laboratories via the SENTRY Antimicrobial Surveillance Program platform and funded by Pfizer Inc.

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Disclosures

JMI Laboratories, Inc. has received research and educational grants in 2012-2014 from Achaogen, Actelion, Affinium, American Proficiency Institute (API), AmpliPhi Bio, Anacor, Astellas, AstraZeneca, Basilea,

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BioVersys, Cardeas, Cempra, Cerexa, Cubist, Daiichi, Dipexium, Durata, Exela, Fedora, Forest Research Institute, Furiex, Genentech, GlaxoSmithKline, Janssen, Johnson & Johnson, Medpace, Meiji Seika Kaisha,

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Melinta, Merck, Methylgene, Nabriva, Nanosphere, Novartis, Polyphor, Rempex, Roche, Seachaid, Shionogi,

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Synthes, The Medicines Co., Theravance, Thermo Fisher, Venatorx, Vertex, Waterloo, Wockhardt and some other corporations. Some JMI employees are advisors/consultants for Astellas, Cubist, Pfizer, Cempra, Cerexa-

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Forest, and Theravance. In regards to speakers bureaus and stock options-none to declare.

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Table 1. Frequency of occurrence of carbapenem-resistant Enterobacteriaceae (CRE) by country (Europe

Country

No. of isolates tested

No. of medical centers

No. (%) of CRE

Belgium

549

1

4 (0.9)

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2010-2013)

Bulgaria

79

2

1 (1.3)

KPN (1)

Czech Republic

306

2

1 (0.3)

KPN (1)

France

2,052

5

Germany

1,965

10

Greece

605

2

Hungary

187

2

Italy

1,743

Poland

405

Portugal

529

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KPN (7)

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ECL (1), KPN (3)

2 (1.1)

KPN (2)

2

1 (0.1)

KPN (1)

7

130 (7.5)

EAE (1), ECL (3), EC (1), KPN (125)

1

1 (2.6)

4

70 (17.3)

1

0

157

3

8 (5.0)

113

1

0

-

237

1

0

-

1,956

7

6 (0.3)

993

2

0

-

UK

1,180

5

0

-

Overall

14,286

58

280 (2.0)

Slovakia Slovenia Spain Sweden

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Romania

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38

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Netherlands

4 (0.4)

EAE (1), ECL (1), KPN (43)

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1,192

b

CF (1), EAE (1), KOX (2)

45 (7.4)

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Ireland

CRE Species (no. of strains)

KPN (1) CF (2), ECL (13), KOX (2), KPN (51), SM (2) ECL (3), KPN (4), SM (1)

EAE (1), ECL (1), KPN (3), SM (1)

a. CRE= carbapenem-resistant Enterobacteriaceae (imipenem or meropenem MIC of ≥4μg/mL)(EUCAST, 2014) Abbreviations: CF = Citrobacter freundii, EAE = Enterobacter aerogenes, ECL = Enterobacter cloacae, EC = Escherichia coli, KOX = Klebsiella oxytoca, KPN = Klebsiella pneumoniae and SM = Serratia marcescens.

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Table 2. Activity of tigecycline and comparator antimicrobial agents when tested against of Enterobacteriaceae, including carbapenem-resistant strains, from European hospitals. a

a

MIC90

EUCAST %S / %I / %R

Tigecycline

0.12

0.5

98.3 / 1.4 / 0.3

99.7 / 0.3 / <0.1

Ceftriaxone

≤0.06

>8

79.3 / 0.8 / 19.9

79.3 / 0.8 / 19.9

Ceftazidime

0.25

32

Cefepime

≤0.5

16

Imipenem

≤0.12

0.5

Meropenem

≤0.12 2

Piperacillin/tazobactam

≤0.5

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84.0 / 2.3 / 13.7

83.9 / 4.1 / 12.0

89.6 / 1.7 / 8.7

98.2 / 0.5 / 1.3

97.5 / 0.7 / 1.8

≤0.12

98.1 / 0.5 / 1.4

98.0 / 0.1 / 1.9

64

82.2 / 4.5 / 13.3

86.7 / 6.1 / 7.2

>4

77.0 / 1.2 / 21.8

78.2 / 2.6 / 19.2

4

95.7 / 2.2 / 2.1

97.9 / 1.5 / 0.6

2

Gentamicin

≤1

≤1

87.9 / 0.9 / 11.2

88.8 / 0.5 / 10.6

≤0.5

2

91.8 / 0.0 / 8.2

--

0.5

2

88.6 / 8.2 / 3.6

96.8 / 3.2 / 0.0

>8

>8

0.4 / 0.4 / 99.3

0.4 / 0.4 / 99.3

>32

>32

0.0 / 0.7 / 99.3

0.7 / 1.1 / 98.2

>16

>16

0.7 / 1.4 / 97.9

1.1 / 3.2 / 95.7

Piperacillin/tazobactam

>64

>64

0.4 / 0.7 / 98.9

1.1 / 1.8 / 97.1

Levofloxacin

>4

>4

5.3 / 3.2 / 91.4

8.6 / 2.5 / 88.9

Amikacin

32

>32

21.4 / 15.7 / 62.9

37.1 / 48.2 / 14.6

Gentamicin

2

>8

61.8 / 10.4 / 27.9

72.1 / 1.4 / 26.4

≤0.5

>8

73.9 / 0.0 / 26.1

--

ED

Amikacin

PT

Levofloxacin

CLSI %S / %I / %R

80.7 / 3.3 / 16.0

NU

b

RI P

a

MA

Enterobacteriaceae (14,286)

T

MIC50

Antimicrobial agent

Colistin

Carbapenem-resistant Enterobacteriaceae (280) b

Ceftriaxone Ceftazidime

AC

Cefepime

CE

Tigecycline

Colistin

c

a. Includes: Citrobacter freundii (332 strains), C. koseri (300 strains), Enterobacter aerogenes (416 strains), E. cloacae (1350 strains), Escherichia coli (7604 strains), Klebsiella oxytoca (738 strains), Klebsiella pneumoniae (2670 strains) and Serratia marcescens (876 strains). b. Criteria as published by the CLSI(CLSI, 2014) and EUCAST(EUCAST, 2014). c. Meropenem or imipenem MIC of ≥4 μg/mL. Includes: Citrobacter freundii (three strains), Enterobacter aerogenes (four strains), E. cloacae (22 strains), Escherichia coli (one strain), Klebsiella oxytoca (four strains), K. pneumoniae (242 strains) and Serratia marcescens (four strains).

ACCEPTED MANUSCRIPT 16

DMID-15-193 - Highlights

The occurrence of carbapenem-resistant Enterobacteriaceae (CRE) has increased rapidly in some

T



RI P

geographic regions.

Overall, 2.0% (280/14,286) of Enterobacteriaceae strains sampled in Europe were categorized as CRE.



Tigecycline, imipenem and meropenem were the most active agents tested against Enterobacteriaceae

SC



overall.

Tigecycline was the only compound that demonstrated good in vitro activity against CRE (MIC 50/90, 0.5/2

NU



AC

CE

PT

ED

MA

μg/mL; 88.6% susceptible at ≤1 μg/mL).