TY - JOUR
AU - Wang,, Hui
AB - Abstract Background Carbapenem-resistant Enterobacteriaceae (CRE) strains are a major threat to global health. The development of effective control measures requires more detailed phenotypic and genotypic characterization of CRE. Methods CRE isolates were collected from 65 hospitals in 25 provinces across China between January 1, 2012, and December 31, 2016. The isolates were characterized by antimicrobial susceptibility testing and multilocus sequence typing. Genes encoding carbapenemases, mobilized colistin resistance (mcr-1), and β-lactamases were detected by polymerase chain reaction and DNA sequencing. Results A total of 1801 independent CRE isolates (1201 Klebsiella pneumoniae, 282 Escherichia coli, and 179 Enterobacter cloacae) were collected during the study period. Overall, 96.9%, 89.7%, 54.5%, 49.9%, and 40% of CRE strains were susceptible to colistin, tigecycline, amikacin, minocycline, and fosfomycin, respectively. Notably, 1091/1201 (91%) K. pneumoniae, 225/282 (80%) E. coli, and 129/179 (72%) E. cloacae harbored carbapenemase gene. K. pneumoniae carbapenemase (KPC) was predominant in K. pneumoniae (77%), whereas New Delhi metallo-β-lactamase (NDM) was predominant in E. coli (75%) and E. cloacae (53%). The mcr-1 gene was detected in 13 NDM-carrying E. coli isolates (4.6%). Sequence type (ST)11 and ST167 were predominant among the 100 K. pneumoniae and 47 E. coli STs, respectively. KPC-ST11, which accounted for 64% of K. pneumoniae isolates, had higher levels of resistance than non-ST11 strains to aztreonam, fosfomycin, and amikacin (P < .001). The proportions of KPC and NDM enzymes in CRE increased from 2012 to 2016 (54%–59% and 12%–28%, respectively). Conclusions The number of CRE strains harboring carbapenemase is increasing. KPC-ST11 K. pneumoniae, the predominant strain, shows a reduced susceptibility to most available antibiotics. carbapenem-resistant Enterobacteriaceae, molecular epidemiology, KPC-2, NDM, carbapenemases Enterobacteriaceae are opportunistic pathogens that cause severe nosocomial infections, including bloodstream and abdominal infections and pneumonia. The emergence of carbapenem-resistant Enterobacteriaceae (CRE) poses a global healthcare challenge. Infections caused by these so-called superbugs are associated with high mortality because therapeutic options are limited [1–4]. In recent decades, sporadic CRE events and outbreaks have been reported in many countries and regions, including China [5–7]. There are 2 major carbapenem-resistance mechanisms in Enterobacteriaceae: the production of carbapenemase or of extended-spectrum β-lactamase (ESBL) and/or AmpC cephalosporinase (AmpC) in combination with membrane impermeability and active efflux [8–10]. The first blaKPC-positive Klebsiella pneumoniae isolate recorded in China was identified in 2004 in Zhejiang Province [11]. Since then, blaKPC-positive Enterobacteriaceae have been reported in different regions of China. Our surveillance during 2004–2008 showed that the main resistance mechanism of CRE was the loss or reduced expression of porin proteins, along with ESBL or AmpC production [12]. However, in the last 10 years, the prevalence of CRE strains producing carbapenemase has increased, especially among K. pneumoniae and Escherichia coli [13, 14]. In the United States and in European countries, K. pneumoniae ST258 has contributed significantly to the dissemination of blaKPC-positive K. pneumoniae [5], although sequence type (ST)11 is predominant in China [15]. Currently, there is no comprehensive CRE monitoring network in China for CRE epidemiology and antimicrobial resistance surveillance. A longitudinal large-scale CRE study can be useful for controlling nosocomial infections, as it can provide a basis for the development of new detection methods and treatment measures. In the present study, we investigated the status of the major strains, carbapenemase types, STs, and antimicrobial resistance characteristics of CRE strains in China. MATERIALS AND METHODS CRE Network Our research group established a CRE network to investigate the epidemiology of CRE in China starting from 2014. There were 2 stages to this study: first, from 2012 to 2013, we collected 150 CRE isolates from 16 tertiary hospitals, and second, starting in 2014, we expanded the collection area. The number of participating hospitals increased from 25 in 2014 to 65 in 2016. Peking University People’s Hospital was the lead unit in this project and was responsible for the collection, identification, and sorting of isolates. Bacterial Isolates From January 1, 2012, to December 31, 2016, we collected 1801 non-repetitive clinical CRE isolates from 65 hospitals in 25 provinces and municipalities across China. During the study period, Enterobacteriaceae isolates resistant to any carbapenem (imipenem, meropenem, or ertapenem), as determined by standard methods, were obtained from individual patients at participating hospitals. The provinces and municipalities were distributed throughout Northern China (including Inner Mongolia, Beijing, Shanxi, Hebei, and Tianjin), Eastern China (including Anhui, Jiangsu, Shandong, Fujian, Shanghai, and Zhejiang), Southern China (including Guangdong), Central China (including Hunan, Hubei, and Henan), Northeastern China (including Jilin, Liaoning, and Heilongjiang), Northwestern China (Gansu, Ningxia, Xinjiang, and Shaanxi), and Southwestern China (including Chongqing and Yunnan). All isolates were reidentified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (Bruker Daltonik, Bremen, Germany) at Peking University People’s Hospital and were stored at −80°C for antimicrobial susceptibility testing and investigation of resistance mechanisms. Antimicrobial Susceptibility Testing Antimicrobial susceptibility was evaluated by the agar dilution and microdilution methods at Peking University People’s Hospital according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (M07-A9, 2012), and the results were interpreted according to CLSI categories and minimum inhibitory concentration (MIC) breakpoints [16]. The breakpoint of tigecycline for Enterobacteriaceae was based on the US Food and Drug Administration standard. The breakpoint of cefoperazone/sulbactam for Enterobacteriaceae was referred to cefoperazone in CLSI. The antibiotics cefoxitin, cefotaxime, ceftriaxone, ceftazidime, cefepime, piperacillin/tazobactam, cefoperazone/sulbactam, ertapenem, imipenem, meropenem, amikacin, ciprofloxacin, colistin, fosfomycin, chloramphenicol, and levofloxacin were tested by the agar dilution method. Tigecycline was tested by the broth microdilution method. Pseudomonas aeruginosa ATCC 27853 and E. coli ATCC 25922 were used as quality control standards for antimicrobial susceptibility testing. Investigation of Resistance Mechanisms For all CRE strains, polymerase chain reaction (PCR) was used to detect genes encoding carbapenemases (blaKPC, blaNDM, blaIMP, blaVIM, blaSIM, and blaOXA-48), ESBLs, and AmpC β-lactamases (blaCTX-M, blaDHA, and blaCMY), as previously described [17–23]. The colistin resistance gene mcr-1 was also detected by PCR, as previously described [24]. PCR products were purified with a QIAquick PCR Purification Kit (Qiagen, Valencia, CA, USA) and sequenced by Sanger sequencing on an ABI PRISM 3730XL system (Applied Biosystems, Foster City, CA, USA). Multilocus Sequence Typing (MLST) MLST of K. pneumoniae was performed according to the protocol described on the Pasteur Institute MLST website (http://www.pasteur.fr/recherche/genopole/PF8/mlst/Kpneumoniae.html). E. coli MLST was performed as described on the EnteroBase website (http://mlst.warwick.ac.uk/mlst/dbs/Ecoli). Enterobacter cloacae MLST was performed as described on the E. cloacae MLST databases website (https://pubmlst.org/ecloacae/). The sequences of 7 housekeeping genes were compared with those in the MLST databases. Statistical Analysis Data were analyzed using SPSS v.19.0 software (SPSS Inc., Chicago, IL, USA). For categorical data, different groups were compared using the χ2 test. A P value < .05 was considered statistically significant. Susceptibility data were analyzed using WHONET v.5.6 (http://www.whonet.org/contact.html). RESULTS Distribution of Isolates Of the 1801 CRE isolates, K. pneumoniae was the most abundant species (n = 1201), followed by E. coli (n = 282), E. cloacae (n = 179), Citrobacter freundii (n = 44), Klebsiella oxytoca (n = 29), Serratia marcescens (n = 28), Enterobacter aerogenes (n = 24), Raoultella ornithinolytica (n = 6), Citrobacter braakii (n = 3), Citrobacter koseri (n = 3), and Raoultella planticola (n = 2). The proportion of K. pneumoniae was 78% in 2012, and it increased from 46.8% in 2013 to 70.9% in 2016 (Supplementary Figure S1). The abundance of other species changed little over the years. K. pneumoniae accounted for the highest proportion of all specimen types, ranging from 44.4% from wounds to 74.4% from the respiratory tract (Supplementary Table S1). Most of the isolates were obtained from the respiratory tract (47.6%, 858/1801), followed by blood (16.9%, 304/1801), urine (16.8%, 303/1801), and abdominal fluid (6.5%, 117/1801). Antimicrobial Susceptibility Testing Results Antimicrobial susceptibility findings of the major species are shown in Table 1. The 1801 CRE isolates showed high susceptibility to colistin (96.9%), followed by tigecycline (89.7%), amikacin (54.5%), minocycline (49.9%), fosfomycin (40%), and chloramphenicol (26.9%). The tested strains showed low susceptibility to carbapenem (<12.7%). Fewer than 7.6% of the CRE strains were susceptible to third- or fourth-generation cephalosporins and β-lactam combination agents (eg, cefoperazone/sulbactam and piperacillin/tazobactam). There were clear interspecies variations in susceptibility; for example, E. coli was less susceptible to colistin than other species (93.9% vs 97.1%–98.5%). The susceptibility rate of K. pneumoniae to amikacin was 42.2%, compared with >74% for E. coli, E. cloacae, and C. freundii. Only 21% of K. pneumoniae isolates were susceptible to fosfomycin, compared with >76% of the E. coli, E. cloacae, and C. freundii isolates. Table 1. Antimicrobial Susceptibility Testing Results of CRE Isolates Antibiotic Name All Strains (n = 1801) Klebsiella pneumoniae (n = 1201) Escherichia coli (n = 282) Enterobacter cloacae (n = 179) Citrobacter freundii (n = 42) %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 Amikacin 44.8 54.5 8 >256 57.5 42.2 >256 >256 24.4 74.9 2 >256 12.1 86.8 2 >256 14.3 78.6 2 >256 Aztreonam 89 9.6 >256 >256 95.7 3.7 >256 >256 76.6 19.7 256 >256 70.5 28.8 64 >256 71 25.8 32 >256 Cefepime 90.2 4 64 256 93.5 2.3 64 256 94.6 1.8 256 >256 75.9 10.9 32 128 83.3 2.4 64 256 Cefoperazone/Sulbactam 90.7 4.8 >256 >256 94.6 2.8 >256 >256 90.6 3.6 >256 >256 74.7 14.4 256 >256 88.1 4.8 >256 >256 Cefotaxime 98.4 1.2 256 >256 98.5 1 256 >256 99.6 0.4 >256 >256 97.1 2.9 256 >256 100 0 256 >256 Cefotaxime/Clavulanic acid 95.1 4 128 >256 95.1 4.1 128 256 96.4 3.6 >256 >256 95.4 2.9 256 >256 100 0 256 >256 Cefoxitin 96.1 2.2 >256 >256 95.4 2.7 256 >256 97.5 0.7 >256 >256 98.8 0.6 >256 >256 100 0 >256 >256 Ceftazidime 95.2 3.2 256 >256 96.1 2.6 256 >256 97.5 0.7 >256 >256 93.7 5.7 >256 >256 97.6 0 >256 >256 Ceftazidime/Clavulanic acid 91.6 6.8 128 >256 92.6 5.8 64 >256 90.9 7.6 >256 >256 93.6 6.4 >256 >256 95.2 0 >256 >256 Ceftriaxone 98.5 1.3 >256 >256 98.8 1.1 >256 >256 99.6 0.4 >256 >256 97.1 2.3 >256 >256 100 0 >256 >256 Chloramphenicol 64.5 26.9 64 >256 70.3 21.5 64 >256 57.4 36 32 >256 57 34.9 32 >256 38.1 52.4 8 256 Ciprofloxacin 80.6 16.7 64 128 86.3 12 64 128 87.8 11.5 64 128 50.9 41.6 4 128 64.3 33.3 16 64 Ertapenem 92.2 3.8 64 64 94.6 2.8 64 64 92.7 3.4 64 64 82.3 6.5 8 64 89.7 3.4 16 64 Fosfomycin 52.1 40 256 >256 69.6 21 >256 >256 21.3 76.4 2 >256 11.8 81 32 256 17.5 82.5 1 256 Imipenem 80.2 12.7 16 64 86.8 8.6 16 64 69.9 16.1 4 32 56.9 29.3 4 32 69 19 8 32 Levofloxacin 77.7 19.4 32 128 84.3 14 32 128 86.7 12.2 16 64 46 47.7 4 64 54.8 38.1 8 32 Meropenem 80.9 12.5 32 64 87.1 7.7 64 64 75.6 13.6 8 32 56.3 35.1 4 32 69 23.8 8 32 Minocycline 32.5 49.9 8 32 31.1 50.2 4 32 31.4 51.3 4 32 46 45.4 8 128 35.7 50 4 32 Piperacillin/Tazobactam 87.9 7.6 >256 >256 92.8 5.1 >256 >256 88.8 5 >256 >256 67.8 21.8 256 >256 78.6 19 >256 >256 Colistin 2.5 96.9 0.25 0.5 1.4 98.5 0.25 0.5 4 93.9 0.25 0.5 2.9 97.1 0.25 0.5 2.4 97.6 0.25 0.5 Tigecycline 3.5 89.7 1 4 3.1 89.4 1 4 0.7 96.8 0.5 1 10.3 79.9 1 6 0 95.2 0.5 1 Antibiotic Name All Strains (n = 1801) Klebsiella pneumoniae (n = 1201) Escherichia coli (n = 282) Enterobacter cloacae (n = 179) Citrobacter freundii (n = 42) %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 Amikacin 44.8 54.5 8 >256 57.5 42.2 >256 >256 24.4 74.9 2 >256 12.1 86.8 2 >256 14.3 78.6 2 >256 Aztreonam 89 9.6 >256 >256 95.7 3.7 >256 >256 76.6 19.7 256 >256 70.5 28.8 64 >256 71 25.8 32 >256 Cefepime 90.2 4 64 256 93.5 2.3 64 256 94.6 1.8 256 >256 75.9 10.9 32 128 83.3 2.4 64 256 Cefoperazone/Sulbactam 90.7 4.8 >256 >256 94.6 2.8 >256 >256 90.6 3.6 >256 >256 74.7 14.4 256 >256 88.1 4.8 >256 >256 Cefotaxime 98.4 1.2 256 >256 98.5 1 256 >256 99.6 0.4 >256 >256 97.1 2.9 256 >256 100 0 256 >256 Cefotaxime/Clavulanic acid 95.1 4 128 >256 95.1 4.1 128 256 96.4 3.6 >256 >256 95.4 2.9 256 >256 100 0 256 >256 Cefoxitin 96.1 2.2 >256 >256 95.4 2.7 256 >256 97.5 0.7 >256 >256 98.8 0.6 >256 >256 100 0 >256 >256 Ceftazidime 95.2 3.2 256 >256 96.1 2.6 256 >256 97.5 0.7 >256 >256 93.7 5.7 >256 >256 97.6 0 >256 >256 Ceftazidime/Clavulanic acid 91.6 6.8 128 >256 92.6 5.8 64 >256 90.9 7.6 >256 >256 93.6 6.4 >256 >256 95.2 0 >256 >256 Ceftriaxone 98.5 1.3 >256 >256 98.8 1.1 >256 >256 99.6 0.4 >256 >256 97.1 2.3 >256 >256 100 0 >256 >256 Chloramphenicol 64.5 26.9 64 >256 70.3 21.5 64 >256 57.4 36 32 >256 57 34.9 32 >256 38.1 52.4 8 256 Ciprofloxacin 80.6 16.7 64 128 86.3 12 64 128 87.8 11.5 64 128 50.9 41.6 4 128 64.3 33.3 16 64 Ertapenem 92.2 3.8 64 64 94.6 2.8 64 64 92.7 3.4 64 64 82.3 6.5 8 64 89.7 3.4 16 64 Fosfomycin 52.1 40 256 >256 69.6 21 >256 >256 21.3 76.4 2 >256 11.8 81 32 256 17.5 82.5 1 256 Imipenem 80.2 12.7 16 64 86.8 8.6 16 64 69.9 16.1 4 32 56.9 29.3 4 32 69 19 8 32 Levofloxacin 77.7 19.4 32 128 84.3 14 32 128 86.7 12.2 16 64 46 47.7 4 64 54.8 38.1 8 32 Meropenem 80.9 12.5 32 64 87.1 7.7 64 64 75.6 13.6 8 32 56.3 35.1 4 32 69 23.8 8 32 Minocycline 32.5 49.9 8 32 31.1 50.2 4 32 31.4 51.3 4 32 46 45.4 8 128 35.7 50 4 32 Piperacillin/Tazobactam 87.9 7.6 >256 >256 92.8 5.1 >256 >256 88.8 5 >256 >256 67.8 21.8 256 >256 78.6 19 >256 >256 Colistin 2.5 96.9 0.25 0.5 1.4 98.5 0.25 0.5 4 93.9 0.25 0.5 2.9 97.1 0.25 0.5 2.4 97.6 0.25 0.5 Tigecycline 3.5 89.7 1 4 3.1 89.4 1 4 0.7 96.8 0.5 1 10.3 79.9 1 6 0 95.2 0.5 1 Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; MIC50/90, 50%/90% minimum inhibitory concentration. Open in new tab Table 1. Antimicrobial Susceptibility Testing Results of CRE Isolates Antibiotic Name All Strains (n = 1801) Klebsiella pneumoniae (n = 1201) Escherichia coli (n = 282) Enterobacter cloacae (n = 179) Citrobacter freundii (n = 42) %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 Amikacin 44.8 54.5 8 >256 57.5 42.2 >256 >256 24.4 74.9 2 >256 12.1 86.8 2 >256 14.3 78.6 2 >256 Aztreonam 89 9.6 >256 >256 95.7 3.7 >256 >256 76.6 19.7 256 >256 70.5 28.8 64 >256 71 25.8 32 >256 Cefepime 90.2 4 64 256 93.5 2.3 64 256 94.6 1.8 256 >256 75.9 10.9 32 128 83.3 2.4 64 256 Cefoperazone/Sulbactam 90.7 4.8 >256 >256 94.6 2.8 >256 >256 90.6 3.6 >256 >256 74.7 14.4 256 >256 88.1 4.8 >256 >256 Cefotaxime 98.4 1.2 256 >256 98.5 1 256 >256 99.6 0.4 >256 >256 97.1 2.9 256 >256 100 0 256 >256 Cefotaxime/Clavulanic acid 95.1 4 128 >256 95.1 4.1 128 256 96.4 3.6 >256 >256 95.4 2.9 256 >256 100 0 256 >256 Cefoxitin 96.1 2.2 >256 >256 95.4 2.7 256 >256 97.5 0.7 >256 >256 98.8 0.6 >256 >256 100 0 >256 >256 Ceftazidime 95.2 3.2 256 >256 96.1 2.6 256 >256 97.5 0.7 >256 >256 93.7 5.7 >256 >256 97.6 0 >256 >256 Ceftazidime/Clavulanic acid 91.6 6.8 128 >256 92.6 5.8 64 >256 90.9 7.6 >256 >256 93.6 6.4 >256 >256 95.2 0 >256 >256 Ceftriaxone 98.5 1.3 >256 >256 98.8 1.1 >256 >256 99.6 0.4 >256 >256 97.1 2.3 >256 >256 100 0 >256 >256 Chloramphenicol 64.5 26.9 64 >256 70.3 21.5 64 >256 57.4 36 32 >256 57 34.9 32 >256 38.1 52.4 8 256 Ciprofloxacin 80.6 16.7 64 128 86.3 12 64 128 87.8 11.5 64 128 50.9 41.6 4 128 64.3 33.3 16 64 Ertapenem 92.2 3.8 64 64 94.6 2.8 64 64 92.7 3.4 64 64 82.3 6.5 8 64 89.7 3.4 16 64 Fosfomycin 52.1 40 256 >256 69.6 21 >256 >256 21.3 76.4 2 >256 11.8 81 32 256 17.5 82.5 1 256 Imipenem 80.2 12.7 16 64 86.8 8.6 16 64 69.9 16.1 4 32 56.9 29.3 4 32 69 19 8 32 Levofloxacin 77.7 19.4 32 128 84.3 14 32 128 86.7 12.2 16 64 46 47.7 4 64 54.8 38.1 8 32 Meropenem 80.9 12.5 32 64 87.1 7.7 64 64 75.6 13.6 8 32 56.3 35.1 4 32 69 23.8 8 32 Minocycline 32.5 49.9 8 32 31.1 50.2 4 32 31.4 51.3 4 32 46 45.4 8 128 35.7 50 4 32 Piperacillin/Tazobactam 87.9 7.6 >256 >256 92.8 5.1 >256 >256 88.8 5 >256 >256 67.8 21.8 256 >256 78.6 19 >256 >256 Colistin 2.5 96.9 0.25 0.5 1.4 98.5 0.25 0.5 4 93.9 0.25 0.5 2.9 97.1 0.25 0.5 2.4 97.6 0.25 0.5 Tigecycline 3.5 89.7 1 4 3.1 89.4 1 4 0.7 96.8 0.5 1 10.3 79.9 1 6 0 95.2 0.5 1 Antibiotic Name All Strains (n = 1801) Klebsiella pneumoniae (n = 1201) Escherichia coli (n = 282) Enterobacter cloacae (n = 179) Citrobacter freundii (n = 42) %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 %R %S MIC50 MIC90 Amikacin 44.8 54.5 8 >256 57.5 42.2 >256 >256 24.4 74.9 2 >256 12.1 86.8 2 >256 14.3 78.6 2 >256 Aztreonam 89 9.6 >256 >256 95.7 3.7 >256 >256 76.6 19.7 256 >256 70.5 28.8 64 >256 71 25.8 32 >256 Cefepime 90.2 4 64 256 93.5 2.3 64 256 94.6 1.8 256 >256 75.9 10.9 32 128 83.3 2.4 64 256 Cefoperazone/Sulbactam 90.7 4.8 >256 >256 94.6 2.8 >256 >256 90.6 3.6 >256 >256 74.7 14.4 256 >256 88.1 4.8 >256 >256 Cefotaxime 98.4 1.2 256 >256 98.5 1 256 >256 99.6 0.4 >256 >256 97.1 2.9 256 >256 100 0 256 >256 Cefotaxime/Clavulanic acid 95.1 4 128 >256 95.1 4.1 128 256 96.4 3.6 >256 >256 95.4 2.9 256 >256 100 0 256 >256 Cefoxitin 96.1 2.2 >256 >256 95.4 2.7 256 >256 97.5 0.7 >256 >256 98.8 0.6 >256 >256 100 0 >256 >256 Ceftazidime 95.2 3.2 256 >256 96.1 2.6 256 >256 97.5 0.7 >256 >256 93.7 5.7 >256 >256 97.6 0 >256 >256 Ceftazidime/Clavulanic acid 91.6 6.8 128 >256 92.6 5.8 64 >256 90.9 7.6 >256 >256 93.6 6.4 >256 >256 95.2 0 >256 >256 Ceftriaxone 98.5 1.3 >256 >256 98.8 1.1 >256 >256 99.6 0.4 >256 >256 97.1 2.3 >256 >256 100 0 >256 >256 Chloramphenicol 64.5 26.9 64 >256 70.3 21.5 64 >256 57.4 36 32 >256 57 34.9 32 >256 38.1 52.4 8 256 Ciprofloxacin 80.6 16.7 64 128 86.3 12 64 128 87.8 11.5 64 128 50.9 41.6 4 128 64.3 33.3 16 64 Ertapenem 92.2 3.8 64 64 94.6 2.8 64 64 92.7 3.4 64 64 82.3 6.5 8 64 89.7 3.4 16 64 Fosfomycin 52.1 40 256 >256 69.6 21 >256 >256 21.3 76.4 2 >256 11.8 81 32 256 17.5 82.5 1 256 Imipenem 80.2 12.7 16 64 86.8 8.6 16 64 69.9 16.1 4 32 56.9 29.3 4 32 69 19 8 32 Levofloxacin 77.7 19.4 32 128 84.3 14 32 128 86.7 12.2 16 64 46 47.7 4 64 54.8 38.1 8 32 Meropenem 80.9 12.5 32 64 87.1 7.7 64 64 75.6 13.6 8 32 56.3 35.1 4 32 69 23.8 8 32 Minocycline 32.5 49.9 8 32 31.1 50.2 4 32 31.4 51.3 4 32 46 45.4 8 128 35.7 50 4 32 Piperacillin/Tazobactam 87.9 7.6 >256 >256 92.8 5.1 >256 >256 88.8 5 >256 >256 67.8 21.8 256 >256 78.6 19 >256 >256 Colistin 2.5 96.9 0.25 0.5 1.4 98.5 0.25 0.5 4 93.9 0.25 0.5 2.9 97.1 0.25 0.5 2.4 97.6 0.25 0.5 Tigecycline 3.5 89.7 1 4 3.1 89.4 1 4 0.7 96.8 0.5 1 10.3 79.9 1 6 0 95.2 0.5 1 Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; MIC50/90, 50%/90% minimum inhibitory concentration. Open in new tab Screening for Carbapenemase and Other Antimicrobial Resistance Genes Of the 1801 CRE isolates, 1544 (85.7%) were found to produce carbapenemases (Table 2). K. pneumoniae was the most abundant carbapenemase-producing species (1091/1201, 90.8%), followed by C. freundii (38/44, 86.4%), E. coli (225/282, 79.8%), and E. cloacae (111/179, 62%). K. pneumoniae carbapenemase (KPC)-2 was the most common carbapenemase type in both K. pneumoniae (919/1201, 76.5%) and Serratia marcescens (14/28, 50%); New Delhi metallo-β-lactamase (NDM)-5 was the most common type in E. coli (147/282, 52.1%); and NDM-1 was the most common type in E. cloacae (90/179, 50.3%), C. freundii (24/44, 54.5%), and K. oxytoca (14/29, 48.3%). Only 6/1801 strains were found to express 2 types of carbapenemase (K. pneumoniae and C. freundii, n = 2; E. cloacae and K. oxytoca, n = 1). The carbapenemase OXA-48 was rare in China (2/1801, 0.1%), with only 2 K. pneumoniae isolates harboring the corresponding gene. However, 740/1201 K. pneumoniae isolates were found to harbor genes encoding ESBLs (mainly CTX-M-65 and CTX-M-14), whereas only 14.4% harbored AmpC genes (DHA-1 and ACT-20). Only 39.4% and 13.8% of E. coli, and 16.2% and 24.6% of E. cloacae isolates carried ESBL and AmpC genes, respectively. The carbapenemase types in CRE differed across regions throughout China (Supplementary Tables S2–S4). The frequency of KPC in K. pneumoniae increased from 61.5% in 2012 to 80.1% in 2016, whereas that of NDM in E. coli and E. cloacae increased from 20.8%–25% in 2013 to 84.1%–52.6% in 2016 (Figure 1). The colistin resistance gene mcr-1 was detected in 13/282 (4.6%) E. coli isolates in this study and coexisted with NDM-5 in one strain. We did not detect the mcr-1 gene in other CRE species. Table 2. Prevalence of Resistant Genes Harbored by All CRE Strains Organism No. Carbapenemase ESBL AmpC mcr-1 KPC NDM IMP Other Two types of Carbapenemase Total Klebsiella pneumoniae 1201 KPC-2 (919, 76.5%); KPC-12 (6, 0.5%); KPC-24 (1, 0.1%) NDM-1 (112, 9.3%); NDM-5 (21, 1.7%); NDM-7 (2, 0.2%); NDM-9 (1, 0.1%) IMP-1 (2, 0.2%); IMP-4 (14, 1.2%); IMP-24 (2, 0.2%); IMP-26 (3, 0.2%) OXA-48 (2, 0.2%); SIM-1 (2, 0.2%); VIM-1 (2, 0.2%); 2a, 0.2% 1091, 90.8% 740, 61.6% 173, 14.4% Escherichia coli 282 KPC-2 (9, 3.2%) NDM-1 (52, 18.4%); NDM-4 (6, 2.1%); NDM-5 (147, 52.1%); NDM-7 (1, 0.4%); NDM-9 (5, 1.8%) IMP-4 (5, 1.8%) 225, 79.8% 111, 39.4% 39, 13.8% 13, 4.6% Enterobacter cloacae 179 KPC-2 (6, 3.4%) NDM-1 (90, 50.3%); NDM-5 (4, 2.2%) IMP-1 (3, 1.7%); IMP-4 (18, 10.1%); IMP-26 (3, 1.7%) VIM-1 (4, 2.2%); 1b, 0.5% 129, 72.1% 29, 16.2% 44, 24.6% Citrobacter freundii 44 KPC-2 (5, 11.4%) NDM-1 (24, 54.5%) IMP-4 (7, 15.9%) 2c, 4.5% 38, 86.4% 16, 36.4% 21, 47.7% Klebsiella oxytoca 29 KPC-2 (5, 17.2%) NDM-1 (14, 48.3%) IMP-1 (2, 6.9%); IMP-4 (6, 20.7%) 1d, 3.4% 28, 96.6% 10, 34.5% 3, 10.3% Serratia marcescens 28 KPC-2 (14, 50%) 14, 50% 1, 3.6% 1, 3.6% Enterobacter aerogenes 24 KPC-2 (1, 4.2%) NDM-1 (5, 20.8%) 6, 25% 9, 37.5% 5, 20.8% Raoultella ornitholytica 6 KPC-2 (2, 33.3%) NDM-1 (3, 50%) 5, 83.3% 2, 33.3% 2, 33.3% Citrobacter braakii 3 NDM-1 (3, 100%) 3, 100% 2, 66.7% Citrobacter koseri 3 NDM-1 (3, 100%) 3, 100% Raoultella planticola 2 NDM-1 (2, 100%) 2, 100% 2, 100% Total 1801 961, 53.4% 495, 27.5% 65, 3.6% 10, 0.6% 6, 0.3% 1544, 85.7% 922, 51.2% 290, 16.1% 13, 0.7% Organism No. Carbapenemase ESBL AmpC mcr-1 KPC NDM IMP Other Two types of Carbapenemase Total Klebsiella pneumoniae 1201 KPC-2 (919, 76.5%); KPC-12 (6, 0.5%); KPC-24 (1, 0.1%) NDM-1 (112, 9.3%); NDM-5 (21, 1.7%); NDM-7 (2, 0.2%); NDM-9 (1, 0.1%) IMP-1 (2, 0.2%); IMP-4 (14, 1.2%); IMP-24 (2, 0.2%); IMP-26 (3, 0.2%) OXA-48 (2, 0.2%); SIM-1 (2, 0.2%); VIM-1 (2, 0.2%); 2a, 0.2% 1091, 90.8% 740, 61.6% 173, 14.4% Escherichia coli 282 KPC-2 (9, 3.2%) NDM-1 (52, 18.4%); NDM-4 (6, 2.1%); NDM-5 (147, 52.1%); NDM-7 (1, 0.4%); NDM-9 (5, 1.8%) IMP-4 (5, 1.8%) 225, 79.8% 111, 39.4% 39, 13.8% 13, 4.6% Enterobacter cloacae 179 KPC-2 (6, 3.4%) NDM-1 (90, 50.3%); NDM-5 (4, 2.2%) IMP-1 (3, 1.7%); IMP-4 (18, 10.1%); IMP-26 (3, 1.7%) VIM-1 (4, 2.2%); 1b, 0.5% 129, 72.1% 29, 16.2% 44, 24.6% Citrobacter freundii 44 KPC-2 (5, 11.4%) NDM-1 (24, 54.5%) IMP-4 (7, 15.9%) 2c, 4.5% 38, 86.4% 16, 36.4% 21, 47.7% Klebsiella oxytoca 29 KPC-2 (5, 17.2%) NDM-1 (14, 48.3%) IMP-1 (2, 6.9%); IMP-4 (6, 20.7%) 1d, 3.4% 28, 96.6% 10, 34.5% 3, 10.3% Serratia marcescens 28 KPC-2 (14, 50%) 14, 50% 1, 3.6% 1, 3.6% Enterobacter aerogenes 24 KPC-2 (1, 4.2%) NDM-1 (5, 20.8%) 6, 25% 9, 37.5% 5, 20.8% Raoultella ornitholytica 6 KPC-2 (2, 33.3%) NDM-1 (3, 50%) 5, 83.3% 2, 33.3% 2, 33.3% Citrobacter braakii 3 NDM-1 (3, 100%) 3, 100% 2, 66.7% Citrobacter koseri 3 NDM-1 (3, 100%) 3, 100% Raoultella planticola 2 NDM-1 (2, 100%) 2, 100% 2, 100% Total 1801 961, 53.4% 495, 27.5% 65, 3.6% 10, 0.6% 6, 0.3% 1544, 85.7% 922, 51.2% 290, 16.1% 13, 0.7% Abbreviations: AmpC, AmpC cephalosporinase; CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum β-lactamase; KPC, Klebsiellapneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; mcr-1, colistin resistance gene; VIM, Verona integron-encoded metallo-β-lactamase. aKPC-2 + NDM-1; bNDM-5 + IMP-26; cKPC-2 + IMP-1; dNDM-1 + IMP-26. Open in new tab Table 2. Prevalence of Resistant Genes Harbored by All CRE Strains Organism No. Carbapenemase ESBL AmpC mcr-1 KPC NDM IMP Other Two types of Carbapenemase Total Klebsiella pneumoniae 1201 KPC-2 (919, 76.5%); KPC-12 (6, 0.5%); KPC-24 (1, 0.1%) NDM-1 (112, 9.3%); NDM-5 (21, 1.7%); NDM-7 (2, 0.2%); NDM-9 (1, 0.1%) IMP-1 (2, 0.2%); IMP-4 (14, 1.2%); IMP-24 (2, 0.2%); IMP-26 (3, 0.2%) OXA-48 (2, 0.2%); SIM-1 (2, 0.2%); VIM-1 (2, 0.2%); 2a, 0.2% 1091, 90.8% 740, 61.6% 173, 14.4% Escherichia coli 282 KPC-2 (9, 3.2%) NDM-1 (52, 18.4%); NDM-4 (6, 2.1%); NDM-5 (147, 52.1%); NDM-7 (1, 0.4%); NDM-9 (5, 1.8%) IMP-4 (5, 1.8%) 225, 79.8% 111, 39.4% 39, 13.8% 13, 4.6% Enterobacter cloacae 179 KPC-2 (6, 3.4%) NDM-1 (90, 50.3%); NDM-5 (4, 2.2%) IMP-1 (3, 1.7%); IMP-4 (18, 10.1%); IMP-26 (3, 1.7%) VIM-1 (4, 2.2%); 1b, 0.5% 129, 72.1% 29, 16.2% 44, 24.6% Citrobacter freundii 44 KPC-2 (5, 11.4%) NDM-1 (24, 54.5%) IMP-4 (7, 15.9%) 2c, 4.5% 38, 86.4% 16, 36.4% 21, 47.7% Klebsiella oxytoca 29 KPC-2 (5, 17.2%) NDM-1 (14, 48.3%) IMP-1 (2, 6.9%); IMP-4 (6, 20.7%) 1d, 3.4% 28, 96.6% 10, 34.5% 3, 10.3% Serratia marcescens 28 KPC-2 (14, 50%) 14, 50% 1, 3.6% 1, 3.6% Enterobacter aerogenes 24 KPC-2 (1, 4.2%) NDM-1 (5, 20.8%) 6, 25% 9, 37.5% 5, 20.8% Raoultella ornitholytica 6 KPC-2 (2, 33.3%) NDM-1 (3, 50%) 5, 83.3% 2, 33.3% 2, 33.3% Citrobacter braakii 3 NDM-1 (3, 100%) 3, 100% 2, 66.7% Citrobacter koseri 3 NDM-1 (3, 100%) 3, 100% Raoultella planticola 2 NDM-1 (2, 100%) 2, 100% 2, 100% Total 1801 961, 53.4% 495, 27.5% 65, 3.6% 10, 0.6% 6, 0.3% 1544, 85.7% 922, 51.2% 290, 16.1% 13, 0.7% Organism No. Carbapenemase ESBL AmpC mcr-1 KPC NDM IMP Other Two types of Carbapenemase Total Klebsiella pneumoniae 1201 KPC-2 (919, 76.5%); KPC-12 (6, 0.5%); KPC-24 (1, 0.1%) NDM-1 (112, 9.3%); NDM-5 (21, 1.7%); NDM-7 (2, 0.2%); NDM-9 (1, 0.1%) IMP-1 (2, 0.2%); IMP-4 (14, 1.2%); IMP-24 (2, 0.2%); IMP-26 (3, 0.2%) OXA-48 (2, 0.2%); SIM-1 (2, 0.2%); VIM-1 (2, 0.2%); 2a, 0.2% 1091, 90.8% 740, 61.6% 173, 14.4% Escherichia coli 282 KPC-2 (9, 3.2%) NDM-1 (52, 18.4%); NDM-4 (6, 2.1%); NDM-5 (147, 52.1%); NDM-7 (1, 0.4%); NDM-9 (5, 1.8%) IMP-4 (5, 1.8%) 225, 79.8% 111, 39.4% 39, 13.8% 13, 4.6% Enterobacter cloacae 179 KPC-2 (6, 3.4%) NDM-1 (90, 50.3%); NDM-5 (4, 2.2%) IMP-1 (3, 1.7%); IMP-4 (18, 10.1%); IMP-26 (3, 1.7%) VIM-1 (4, 2.2%); 1b, 0.5% 129, 72.1% 29, 16.2% 44, 24.6% Citrobacter freundii 44 KPC-2 (5, 11.4%) NDM-1 (24, 54.5%) IMP-4 (7, 15.9%) 2c, 4.5% 38, 86.4% 16, 36.4% 21, 47.7% Klebsiella oxytoca 29 KPC-2 (5, 17.2%) NDM-1 (14, 48.3%) IMP-1 (2, 6.9%); IMP-4 (6, 20.7%) 1d, 3.4% 28, 96.6% 10, 34.5% 3, 10.3% Serratia marcescens 28 KPC-2 (14, 50%) 14, 50% 1, 3.6% 1, 3.6% Enterobacter aerogenes 24 KPC-2 (1, 4.2%) NDM-1 (5, 20.8%) 6, 25% 9, 37.5% 5, 20.8% Raoultella ornitholytica 6 KPC-2 (2, 33.3%) NDM-1 (3, 50%) 5, 83.3% 2, 33.3% 2, 33.3% Citrobacter braakii 3 NDM-1 (3, 100%) 3, 100% 2, 66.7% Citrobacter koseri 3 NDM-1 (3, 100%) 3, 100% Raoultella planticola 2 NDM-1 (2, 100%) 2, 100% 2, 100% Total 1801 961, 53.4% 495, 27.5% 65, 3.6% 10, 0.6% 6, 0.3% 1544, 85.7% 922, 51.2% 290, 16.1% 13, 0.7% Abbreviations: AmpC, AmpC cephalosporinase; CRE, carbapenem-resistant Enterobacteriaceae; ESBL, extended-spectrum β-lactamase; KPC, Klebsiellapneumoniae carbapenemase; NDM, New Delhi metallo-β-lactamase; mcr-1, colistin resistance gene; VIM, Verona integron-encoded metallo-β-lactamase. aKPC-2 + NDM-1; bNDM-5 + IMP-26; cKPC-2 + IMP-1; dNDM-1 + IMP-26. Open in new tab Figure 1. Open in new tabDownload slide Major carbapenemases found in CRE species by year. Abbreviation: CRE, carbapenem-resistant Enterobacteriaceae. Figure 1. Open in new tabDownload slide Major carbapenemases found in CRE species by year. Abbreviation: CRE, carbapenem-resistant Enterobacteriaceae. Carbapenem MIC Distribution of Different Carbapenemases The MICs of the 3 carbapenemases identified in the isolates are shown in Figure 2. The distribution of imipenem and meropenem MICs for NDM-positive strains was 8 mg/L (28.5%–28.7%), followed by 4 mg/L (22.1%–23.6%), and 16 mg/L (15.4%–18.6%). Over 96% of the NDM strains had an MIC >2 mg/L for ertapenem. The most frequently observed MIC of meropenem and ertapenem in KPC-positive strains was ≥16 mg/L (86.6%–76.7%). Fewer than 3.5% of the KPC-producing strains were in the carbapenem-susceptible range. The most frequent imipenem and meropenem MIC for IMP-positive strains was 1 mg/L (24.6%–32.3%). Only 1.5% of IMP-producing strains had high imipenem and meropenem MICs (>32 mg/L). Figure 2. Open in new tabDownload slide Carbapenem MIC distribution among strains harboring different carbapenemase genes. MIC distribution among (A) blaKPC-positive (n = 972), (B) blaNDM-positive (n = 499), and (C) blaIMP-positive (n = 67) CRE strains. Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; MIC, minimum inhibitory concentration. Figure 2. Open in new tabDownload slide Carbapenem MIC distribution among strains harboring different carbapenemase genes. MIC distribution among (A) blaKPC-positive (n = 972), (B) blaNDM-positive (n = 499), and (C) blaIMP-positive (n = 67) CRE strains. Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; MIC, minimum inhibitory concentration. Geographic Distribution of STs and Carbapenemase-producing CRE Strains A total of 100 K. pneumoniae ST types were classified (Table 3). ST11 was the most prevalent ST in China (790/1201, 65.8%), followed by ST17 (35/1201, 2.9%), ST15 (31/1201, 2.6%), and ST48 (22/1201, 1.8%). K. pneumoniae ST types were geographically diverse. ST11 was the most prevalent type in Northern (306/408, 75%), Eastern (268/416, 64.4%), Southern (94/135, 69.6%), Central (75/114, 65.8%), Northeastern (15/29, 51.7%), and Southwestern (18/26, 69.2%) China. ST17 (19/73, 26.0%) was the most prevalent ST in Northwestern China, whereas ST11 accounted for 19.2% of K. pneumoniae isolates in this area (Figure 3). Table 3. Carbapenemase Distribution Determined by CRE MLST ST No. IMP KPC NDM OXA-48 SIM-1 VIM-1 Klebsiella pneumoniae ST11 790 1 (0.1) 767 (97.1) 8 (1) (n = 1201) ST17 35 3 (8.6) 32 (91.4) ST15 31 23 (74.2) 1 (3.2) ST48 22 19 (86.4) 1 (4.5) ST37 11 7 (63.6) ST290 9 6 (66.7) 1 (11.1) ST147 7 1 (14.3) 2 (28.6) 3 (42.9) ST1 6 4 (66.7) ST895 6 6 (100) ST23 6 3 (50) 2 (33.3) Other STs 278 19 (6.8) 103 (37.1) 71 (25.5) 2 (0.7) 2 (0.7) 2 (0.7) Escherichia coli ST167 69 1 (1.4) 61 (88.4) (n = 282) ST410 31 30 (96.8) ST617 13 1 (7.7) 12 (92.3) ST131 12 3 (25) 5 (41.7) ST405 12 5 (41.7) ST361 10 8 (80) ST46 9 6 (66.7) ST10 7 7 (100) ST156 4 4 (100) ST354 4 3 (75) Other STs 111 4 (3.6) 5 (4.5) 70 (63.1) Enterobacter cloacae ST74 15 1 (6.7) 6 (40) (n = 179) ST418 12 12 (100) ST256 9 2 (22.2) 6 (66.7) 1 (11.1) ST175 6 4 (66.7) 2 (33.3) ST754 6 1 (16.7) 4 (66.7) ST88 6 5 (83.3) ST111 5 1 (20) 4 (80) ST145 5 1 (20) 4 (80) ST51 5 4 (80) ST66 3 1 (33.3) 2 (66.7) Other STs 107 18 (16.8) 5 (4.7) 43 (40.2) 1 (0.9) ST No. IMP KPC NDM OXA-48 SIM-1 VIM-1 Klebsiella pneumoniae ST11 790 1 (0.1) 767 (97.1) 8 (1) (n = 1201) ST17 35 3 (8.6) 32 (91.4) ST15 31 23 (74.2) 1 (3.2) ST48 22 19 (86.4) 1 (4.5) ST37 11 7 (63.6) ST290 9 6 (66.7) 1 (11.1) ST147 7 1 (14.3) 2 (28.6) 3 (42.9) ST1 6 4 (66.7) ST895 6 6 (100) ST23 6 3 (50) 2 (33.3) Other STs 278 19 (6.8) 103 (37.1) 71 (25.5) 2 (0.7) 2 (0.7) 2 (0.7) Escherichia coli ST167 69 1 (1.4) 61 (88.4) (n = 282) ST410 31 30 (96.8) ST617 13 1 (7.7) 12 (92.3) ST131 12 3 (25) 5 (41.7) ST405 12 5 (41.7) ST361 10 8 (80) ST46 9 6 (66.7) ST10 7 7 (100) ST156 4 4 (100) ST354 4 3 (75) Other STs 111 4 (3.6) 5 (4.5) 70 (63.1) Enterobacter cloacae ST74 15 1 (6.7) 6 (40) (n = 179) ST418 12 12 (100) ST256 9 2 (22.2) 6 (66.7) 1 (11.1) ST175 6 4 (66.7) 2 (33.3) ST754 6 1 (16.7) 4 (66.7) ST88 6 5 (83.3) ST111 5 1 (20) 4 (80) ST145 5 1 (20) 4 (80) ST51 5 4 (80) ST66 3 1 (33.3) 2 (66.7) Other STs 107 18 (16.8) 5 (4.7) 43 (40.2) 1 (0.9) Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase; MLST, multilocus sequence typing; NDM, New Delhi metallo-β-lactamase; ST, sequence type; VIM, Verona integron-encoded metallo-β-lactamase. Open in new tab Table 3. Carbapenemase Distribution Determined by CRE MLST ST No. IMP KPC NDM OXA-48 SIM-1 VIM-1 Klebsiella pneumoniae ST11 790 1 (0.1) 767 (97.1) 8 (1) (n = 1201) ST17 35 3 (8.6) 32 (91.4) ST15 31 23 (74.2) 1 (3.2) ST48 22 19 (86.4) 1 (4.5) ST37 11 7 (63.6) ST290 9 6 (66.7) 1 (11.1) ST147 7 1 (14.3) 2 (28.6) 3 (42.9) ST1 6 4 (66.7) ST895 6 6 (100) ST23 6 3 (50) 2 (33.3) Other STs 278 19 (6.8) 103 (37.1) 71 (25.5) 2 (0.7) 2 (0.7) 2 (0.7) Escherichia coli ST167 69 1 (1.4) 61 (88.4) (n = 282) ST410 31 30 (96.8) ST617 13 1 (7.7) 12 (92.3) ST131 12 3 (25) 5 (41.7) ST405 12 5 (41.7) ST361 10 8 (80) ST46 9 6 (66.7) ST10 7 7 (100) ST156 4 4 (100) ST354 4 3 (75) Other STs 111 4 (3.6) 5 (4.5) 70 (63.1) Enterobacter cloacae ST74 15 1 (6.7) 6 (40) (n = 179) ST418 12 12 (100) ST256 9 2 (22.2) 6 (66.7) 1 (11.1) ST175 6 4 (66.7) 2 (33.3) ST754 6 1 (16.7) 4 (66.7) ST88 6 5 (83.3) ST111 5 1 (20) 4 (80) ST145 5 1 (20) 4 (80) ST51 5 4 (80) ST66 3 1 (33.3) 2 (66.7) Other STs 107 18 (16.8) 5 (4.7) 43 (40.2) 1 (0.9) ST No. IMP KPC NDM OXA-48 SIM-1 VIM-1 Klebsiella pneumoniae ST11 790 1 (0.1) 767 (97.1) 8 (1) (n = 1201) ST17 35 3 (8.6) 32 (91.4) ST15 31 23 (74.2) 1 (3.2) ST48 22 19 (86.4) 1 (4.5) ST37 11 7 (63.6) ST290 9 6 (66.7) 1 (11.1) ST147 7 1 (14.3) 2 (28.6) 3 (42.9) ST1 6 4 (66.7) ST895 6 6 (100) ST23 6 3 (50) 2 (33.3) Other STs 278 19 (6.8) 103 (37.1) 71 (25.5) 2 (0.7) 2 (0.7) 2 (0.7) Escherichia coli ST167 69 1 (1.4) 61 (88.4) (n = 282) ST410 31 30 (96.8) ST617 13 1 (7.7) 12 (92.3) ST131 12 3 (25) 5 (41.7) ST405 12 5 (41.7) ST361 10 8 (80) ST46 9 6 (66.7) ST10 7 7 (100) ST156 4 4 (100) ST354 4 3 (75) Other STs 111 4 (3.6) 5 (4.5) 70 (63.1) Enterobacter cloacae ST74 15 1 (6.7) 6 (40) (n = 179) ST418 12 12 (100) ST256 9 2 (22.2) 6 (66.7) 1 (11.1) ST175 6 4 (66.7) 2 (33.3) ST754 6 1 (16.7) 4 (66.7) ST88 6 5 (83.3) ST111 5 1 (20) 4 (80) ST145 5 1 (20) 4 (80) ST51 5 4 (80) ST66 3 1 (33.3) 2 (66.7) Other STs 107 18 (16.8) 5 (4.7) 43 (40.2) 1 (0.9) Abbreviations: CRE, carbapenem-resistant Enterobacteriaceae; KPC, Klebsiella pneumoniae carbapenemase; MLST, multilocus sequence typing; NDM, New Delhi metallo-β-lactamase; ST, sequence type; VIM, Verona integron-encoded metallo-β-lactamase. Open in new tab Figure 3. Open in new tabDownload slide Distribution of STs of K. pneumoniae and E. coli and carbapenemase production in different regions of China. Distribution of (A) K. pneumoniae STs and (B) carbapenemase-producing K. pneumoniae strains (B) in different regions of China. Distribution of (C) E. coli STs and (D) carbapenemase-producing E. coli strains in different regions of China. Abbreviation: ST, sequence type. Figure 3. Open in new tabDownload slide Distribution of STs of K. pneumoniae and E. coli and carbapenemase production in different regions of China. Distribution of (A) K. pneumoniae STs and (B) carbapenemase-producing K. pneumoniae strains (B) in different regions of China. Distribution of (C) E. coli STs and (D) carbapenemase-producing E. coli strains in different regions of China. Abbreviation: ST, sequence type. There were 47 different E. coli STs (Table 3). The most prevalent type was ST167 (69/282, 24.5%), followed by ST410 (31/282, 11.0%), ST617 (13/282, 4.6%), and ST131 (12/282, 4.3%). ST167 was the most prevalent type in Northern (15/67, 22.4%), Eastern (33/105, 31.4%), Southern (5/41, 12.2%), and Northwestern (12/26, 46.2%) China. The most prevalent ST in the Northeast was ST410 (6/13, 46.0%) (Figure 3). There were 52 different E. cloacae STs (Table 3); ST74 was the most prevalent type (15/179, 8.4%), followed by ST418 (12/179, 6.7%), ST256 (9/179, 5.0%), and ST754 (6/179, 3.4%). Relationship Between ST and Carbapenemase Genes Most K. pneumoniae ST11 isolates (96.2%) produced KPC-2 carbapenemase (Table 3), whereas ST17 isolates were more likely to produce NDM carbapenemase (91.4%). ST11-KPC-2 K. pneumoniae was the most prevalent carbapenem-resistant K. pneumoniae (CRKP) strain in China. Most E. coli isolates harbored only NDM; only a few ST167 and ST 131 isolates carried KPC. ST167-NDM isolates accounted for 21.6% of all carbapenem-resistant E. coli isolates. Most E. cloacae isolates harbored NDM, and all ST418 isolates produced NDM. VIM was found in 4 E. cloacae isolates. Antimicrobial Susceptibility of K. pneumoniae ST11 and E. coli ST167 The susceptibility of K. pneumoniae ST11 to drugs other than colistin and minocycline was lower than that of non-ST11 isolates (Figure 4). The 2 groups of bacteria differed significantly in terms of susceptibility to aztreonam (0% vs 12.5%, P < .001), fosfomycin (3.6% vs 59.5%, P < .001), ciprofloxacin (0.4% vs 35.7%, P < .001), levofloxacin (0.5% vs 41.6%, P < .001), amikacin (0.3% vs 26.9%, P < .001), and chloramphenicol (9.9% vs 14.1%, P < .001). There were no statistically significant differences between ST167 E. coli isolates and non-ST167 E. coli isolates with respect to susceptibility to meropenem, chloramphenicol, minocycline, fosfomycin, colistin, and tetracycline (Figure 5). In contrast, ST167 was less susceptible than non-ST167 E. coli to amikacin (58.0% vs 80.5%, P < .001), aztreonam (9.0% vs 23.8%, P = .006), imipenem (8.7% vs 18.6%, P = .049), ciprofloxacin (0% vs 15.3%, P < .001), and levofloxacin (0% vs 16.2%, P < .001). Figure 4. Open in new tabDownload slide Comparison of susceptibility between ST11 and non-ST11 K. pneumoniae isolates. Figure 4. Open in new tabDownload slide Comparison of susceptibility between ST11 and non-ST11 K. pneumoniae isolates. Figure 5. Open in new tabDownload slide Comparison of susceptibility between ST167 and non-ST167 E. coli isolates. Figure 5. Open in new tabDownload slide Comparison of susceptibility between ST167 and non-ST167 E. coli isolates. DISCUSSION The continual emergence of CRE strains is a major threat to public health worldwide. The China Antimicrobial Resistance Surveillance Report (http://www.carss.cn/), the largest survey of antimicrobial resistance in China, reported that the rate of carbapenem resistance in K. pneumoniae increased from 6.4% in 2014 to 8.7% in 2016, whereas in E. coli, the rate remained stable at under 2% over this period. The results of our study reflect this trend, revealing that K. pneumoniae accounts for the largest percentage of domestic CRE strains and is the fastest growing species. The number of deaths attributable to CRE is not insignificant [25]; patients with CRE infection, especially bloodstream infection, have high mortality rates [26, 27]. In this study, a significant portion of isolates were obtained from blood specimens, suggesting that CRE bloodstream infection is a major problem. Treatment of CRE infections is challenging, and some of the few effective drugs, so far, such as ceftazidime-avibactam and colistin, are not available in many countries, including China. Individualized therapy must be used to treat CRE infections based on in vitro antimicrobial susceptibility profiles, molecular type, infection severity, and the patient’s health status [28]. Our study describes the antimicrobial susceptibility profiles and molecular epidemiological characteristics of CRE in China, which can inform the choice of treatment. For example, we found that colistin and tetracycline have high activity against CRE in China, which is consistent with surveillance data from the United States [29] and European countries [30]. The susceptibility of different CRE species to fosfomycin varied, with a lower rate in K. pneumoniae (21%) than in E. coli, E. cloacae, and C. freundii (>76%). Over 74% of the isolates of the latter three species were susceptible to amikacin. This result provides important data for selecting specific drug and aminoglycoside combinations for the empiric therapy of infections caused by these species. Carbapenemase-producing CRE strains carry resistance genes on mobile plasmids that can shuttle between resistant and susceptible strains [31, 32]. The dissemination of mobile resistance genes, especially those encoding KPC and NDM, is a major reason for the increase in nosocomial and community infections caused by CRE. CRKP strains harboring KPC are prevalent in the United States, Israel, Romania, Greece, Italy, and some parts of the Mediterranean region [33]. Our data showed that KPC was the main drug resistance factor of CRKP in most regions of China (found in 76% of isolates). Only CKRP from the Northwest produced a high level of NDM. CRKP strains in some European countries, such as France and Turkey, are more affected by OXA-48-like carbapenemases [5, 34]. However, OXA-48 was rare in China, with only 2 isolates from the Eastern region found to be OXA-48 carriers. It was reported that OXA-48-producing K. pneumoniae and E. coli were isolated from a female patient in Eastern China who had returned from Europe [35]. Although the positive rate of ESBL genes was >60% in CRKP in this study, we were unable to confirm this by phenotypic testing because the ESBL phenotype is no longer sensitive to carbapenemase. Accordingly, the incidence of ESBL-positive K. pneumoniae has been declining for years, according to the CHINET survey [36]. Asian countries such as India are a major reservoir of NDM producers. Our study showed that NDM was the main mechanism of carbapenem resistance in E. coli and E. cloacae. Compared with the results of previous studies in China [12, 13], the prevalence of KPC and NDM carbapenemases in CRE increased between 2012 and 2016, whereas that of IMP decreased. Particular attention should be paid to the high proportion of NDM-5 coexisting with mcr-1 in the same E. coli strain [37]. The mcr-1 gene is particularly abundant in China [38–40] and can be transferred between strains. The main ST was, and still is, derived from the clonal expansion of K. pneumoniae ST258, which has become prevalent in many parts of the world [5] since it was first detected in the United States [41]. However, our data showed that ST11 was the most abundant K. pneumoniae ST type in China. Most ST11 CRKP isolates carried KPC-2 carbapenemase. Moreover, ST11 showed a higher resistance than non-ST11 strains. We believe that the most abundant K. pneumoniae strain in China is ST11-KPC, which should be the focus of infection control measures and clinical studies. Other STs, such as ST17, are likely to harbor NDM carbapenemase and cause local epidemics. The most common clone of E. coli in China was ST167, which also showed higher resistance than non-ST167 strains. This result is in disagreement with an earlier report stating that ST131 was the most prevalent strain [15]. Moreover, E. coli ST varied across regions; specifically, ST167 was the most prevalent ST in Northern, Eastern, Southern, and Northwestern China, whereas ST167 was predominant in Northern China. Carbapenemases differ in terms of hydrolytic activity, with class B β-lactamases exhibiting the highest activity [42, 43]. However, in our study, most IMP-producing strains had imipenem and meropenem MIC values <4 mg/L. Therefore, carbapenems may be clinically effective against IMP-producing strains [44]. The cutoff for the sentinel drug for the detected carbapenemase is controversial. We found that >50% of IMP-producing strains had low imipenem and meropenem MICs (≤1 mg/l). Thus, cutoff values of 0.25 mg/L for meropenem and imipenem and 0.5 mg/L for ertapenem can be used to screen for carbapenemase in Enterobacteriaceae. This study had some limitations. Some hospitals did not preserve all CRE strains, resulting in the loss of some data. Additionally, we did not carry out a detailed analysis of drug-resistant plasmids, which should be examined at later stages by second- or third-generation sequencing. In conclusion, to our knowledge this is the first longitudinal large-scale CRE surveillance of CRE in China, covering 25 provinces and municipalities. Our major findings were as follows: (1) CRE caused by carbapenemase production is increasing; (2) KPC and NDM are the major carbapenemases produced by CRE in China, and their proportions among carbapenemases are increasing; (3) K. pneumoniae ST11 and E. coli ST167 are the most abundant CRE strains in China and have a reduced susceptibility to available antibiotics; and (4) the MICs of meropenem and imipenem (0.25 mg/L) and of ertapenem (0.5 mg/L) can serve as cutoff values for screening for carbapenemases in Enterobacteriaceae. These results provide a basis for developing more effective measures for controlling the spread of CRE. Supplementary Data Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author. Notes Acknowledgments. The main members of the CRE network: Xiaoling Ma, Anhui Provincial Hospital, Hefei, Anhui, China. Qiaozhen Cui, Shanxi Province People’s Hospital, Taiyuan, Shanxi, China. Rui Zheng, The First Chinese Hospital in Yunnan Province, Kunming, Yunnan, China. Shifu Wang, Qilu Children’s Hospital of Shandong University, Jinan, Shandong, China. Zhusheng Guo, Donghua Hospital Affiliated to Sun Yat-sen University, Dongguan, Guangdong, China. Hong Zou, Xiangtan Central Hospital, Xiangtan, Hunan, China. Meicui Zou, The First People’s Hospital of Yinchua, Yinchuan, Ningxia, China. Yumei Zhang, Zunhua People’s Hospital, Zunhua, Hebei, China. Zhidong Hu, Tianjin Medical University General Hospital, Tianjin, China. Zhijie Zhang, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. Jinjing Tian, Liaocheng Second People’s Hospital, Liaocheng, Shandong, China. Dawen Guo, First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Quan Fu, Affiliated Hospital of Inner Mongolia Medical University, Hohhot, Inner Mongolia, China. Jiaming Huang, Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China. Financial support. This study was supported by National Natural Science Foundation of China (81625014). Supplement sponsorship. This article appears as part of the supplement “Current Status and Challenge of Antimicrobial Resistance in China,”sponsored by MSD. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Nordmann P , Cuzon G , Naas T . The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria . Lancet Infect Dis 2009 ; 9 : 228 – 36 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Gupta N , Limbago BM , Patel JB , Kallen AJ . Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention . Clin Infect Dis 2011 ; 53 : 60 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Zhang Y , Wang Q , Yin Y , et al. Epidemiology of carbapenem-resistant Enterobacteriaceae infections: report from the China CRE Network . Antimicrob Agents Chemother 2018 ; 62 :doi: https://doi.org/10.1128/AAC.01882-17 . WorldCat 4. Wang Q , Zhang Y , Yao X , et al. Risk factors and clinical outcomes for carbapenem-resistant Enterobacteriaceae nosocomial infections . Eur J Clin Microbiol Infect Dis 2016 ; 35 : 1679 – 89 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Munoz-Price LS , Poirel L , Bonomo RA , et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases . Lancet Infect Dis 2013 ; 13 : 785 – 96 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Yu J , Tan K , Rong Z , et al. Nosocomial outbreak of KPC-2- and NDM-1-producing Klebsiella pneumoniae in a neonatal ward: a retrospective study . BMC Infect Dis 2016 ; 16 : 563 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Snitkin ES , Zelazny AM , Thomas PG , et al. Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with whole-genome sequencing . Sci Transl Med 2012 ; 4 : 148ra116 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Goodman KE , Simner PJ , Tamma PD , et al . Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE) . Expert Rev Anti Infect Ther 2016 ; 14 : 95 – 108 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Li XZ , Plésiat P , Nikaido H . The challenge of efflux-mediated antibiotic resistance in Gram-negative bacteria . Clin Microbiol Rev 2015 ; 28 : 337 – 418 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Tzouvelekis LS , Markogiannakis A , Psichogiou M , et al. Carbapenemases in Klebsiella pneumoniae and other Enterobacteriaceae: an evolving crisis of global dimensions . Clin Microbiol Rev 2012 ; 25 : 682 – 707 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Wei ZQ , Du XX , Yu YS , Shen P , Chen YG , Li LJ . Plasmid-mediated KPC-2 in a Klebsiella pneumoniae isolate from China . Antimicrob Agents Chemother 2007 ; 51 : 763 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Yang Q , Wang H , Sun H , et al. Phenotypic and genotypic characterization of Enterobacteriaceae with decreased susceptibility to carbapenems: results from large hospital-based surveillance studies in China . Antimicrob Agents Chemother 2010 ; 54 : 573 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Li H , Zhang J , Liu Y , et al. Molecular characteristics of carbapenemase-producing Enterobacteriaceae in China from 2008 to 2011: predominance of KPC-2 enzyme . Diagn Microbiol Infect Dis 2014 ; 78 : 63 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Zhang R , Chan EW , Zhou H , et al . Prevalence and genetic characteristics of carbapenem-resistant Enterobacteriaceae strains in China . Lancet Infect Dis 2017 ; 17 : 256 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat 15. Zhang R , Liu L , Zhou H , et al. Nationwide surveillance of clinical carbapenem-resistant Enterobacteriaceae (CRE) strains in China . EBioMedicine 2017 ; 19 : 98 – 106 . Google Scholar Crossref Search ADS PubMed WorldCat 16. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing, 26th informational supplement. CLSI document. Wayne, PA: CLSI, 2016; M100–S26. COPAC 17. Yigit H , Queenan AM , Anderson GJ , et al. Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of Klebsiella pneumoniae . Antimicrob Agents Chemother 2001 ; 45 : 1151 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat 18. Xiaojuan W , Henan L , Chunjiang Z , et al. Novel NDM-9 metallo-β-lactamase identified from a ST107 Klebsiella pneumoniae strain isolated in China . Int J Antimicrob Agents 2014 ; 44 : 90 – 1 . Google Scholar Crossref Search ADS PubMed WorldCat 19. Shibata N , Doi Y , Yamane K , et al. PCR typing of genetic determinants for metallo-beta-lactamases and integrases carried by gram-negative bacteria isolated in Japan, with focus on the class 3 integron . J Clin Microbiol 2003 ; 41 : 5407 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat 20. Poirel L , Héritier C , Tolün V , et al . Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae . Antimicrob Agents Chemother 2004 ; 48 : 15 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 21. Pérez-Pérez FJ , Hanson ND . Detection of plasmid-mediated AmpC beta-lactamase genes in clinical isolates by using multiplex PCR . J Clin Microbiol 2002 ; 40 : 2153 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat 22. Giakkoupi P , Tambic-Andrasevic A , Vourli S , et al. Transferable DHA-1 cephalosporinase in Escherichia coli . Int J Antimicrob Agents 2006 ; 27 : 77 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat 23. Armand-Lefèvre L , Leflon-Guibout V , Bredin J , et al. Imipenem resistance in Salmonella enterica serovar Wien related to porin loss and CMY-4 beta-lactamase production . Antimicrob Agents Chemother 2003 ; 47 : 1165 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 24. Liu YY , Wang Y , Walsh TR , et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study . Lancet Infect Dis 2016 ; 16 : 161 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 25. Falagas ME , Tansarli GS , Karageorgopoulos DE , et al . Deaths attributable to carbapenem-resistant Enterobacteriaceae infections . Emerg Infect Dis 2014 ; 20 : 1170 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat 26. Gutiérrez-Gutiérrez B , Salamanca E , de Cueto M , et al. ; REIPI/ESGBIS/INCREMENT Investigators . Effect of appropriate combination therapy on mortality of patients with bloodstream infections due to carbapenemase-producing Enterobacteriaceae (INCREMENT): a retrospective cohort study . Lancet Infect Dis 2017 ; 17 : 726 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat 27. Tumbarello M , Viale P , Viscoli C , et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy . Clin Infect Dis 2012 ; 55 : 943 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat 28. Rodríguezbaño J , Gutiérrezgutiérrez B , Machuca I , et al. Treatment of infections caused by extended-spectrum-beta-lactamase-, AmpC-, and carbapenemase-producing Enterobacteriaceae . Clin Microbiol Rev 2018 ; 31 : doi: https://doi.org/10.1128/CMR.00079-17 . WorldCat 29. Guh AY , Bulens SN , Mu Y , et al. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012–2013 . JAMA 2015 ; 314 : 1479 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat 30. Grundmann H , Glasner C , Albiger B , et al. European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) Working Group . Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study . Lancet Infect Dis 2017 ; 17 : 153 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat 31. Mathers AJ , Peirano G , Pitout JD . The role of epidemic resistance plasmids and international high-risk clones in the spread of multidrug-resistant Enterobacteriaceae . Clin Microbiol Rev 2015 ; 28 : 565 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat 32. Mathers AJ , Cox HL , Kitchel B , et al. Molecular dissection of an outbreak of carbapenem-resistant Enterobacteriaceae reveals intergenus KPC carbapenemase transmission through a promiscuous plasmid . MBio 2011 ; 2 : e00204 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat 33. Navon-Venezia S , Kondratyeva K , Carattoli A . Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance . FEMS Microbiol Rev 2017 ; 41 : 252 – 75 . Google Scholar Crossref Search ADS PubMed WorldCat 34. Logan LK , Weinstein RA . The epidemiology of carbapenem-resistant Enterobacteriaceae: the impact and evolution of a global menace . J Infect Dis 2017 ; 215 : 28 – 36 . Google Scholar Crossref Search ADS WorldCat 35. Yu F , Wang S , Lv J , et al. Coexistence of OXA-48-producing Klebsiella pneumoniae and Escherichia coli in a hospitalized patient who returned from Europe to China . Antimicrob Agents Chemother 2017 ; 61 : doi: https://doi.org/10.1128/AAC.02580-16 . WorldCat 36. Hu FP , Guo Y , Zhu DM , et al. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005–2014 . Clin Microbiol Infect 2016 ; 22 ( Suppl 1 ): S9 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat 37. Zhang Y , Liao K , Gao H , et al. Decreased fitness and virulence in ST10 Escherichia coli harboring blaNDM-5 and mcr-1 against a ST4981 strain with blaNDM-5 . Front Cell Infect Microbiol 2017 ; 7 : 242 . Google Scholar Crossref Search ADS PubMed WorldCat 38. Wang R , van Dorp L , Shaw LP , et al. The global distribution and spread of the mobilized colistin resistance gene mcr-1 . Nat Commun 2018 ; 9 : 1179 . Google Scholar Crossref Search ADS PubMed WorldCat 39. Wang Y , Tian GB , Zhang R , et al. Prevalence, risk factors, outcomes, and molecular epidemiology of mcr-1-positive Enterobacteriaceae in patients and healthy adults from China: an epidemiological and clinical study . Lancet Infect Dis 2017 ; 17 : 390 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 40. Mulvey MR , Mataseje LF , Robertson J , et al. Dissemination of the mcr-1 colistin resistance gene . Lancet Infect Dis 2016 ; 16 : 289 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat 41. Kitchel B , Rasheed JK , Patel JB , et al. Molecular epidemiology of KPC-producing Klebsiella pneumoniae isolates in the United States: clonal expansion of multilocus sequence type 258 . Antimicrob Agents Chemother 2009 ; 53 : 3365 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat 42. Nordmann P , Naas T , Poirel L . Global spread of carbapenemase-producing Enterobacteriaceae . Emerg Infect Dis 2011 ; 17 : 1791 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 43. Miriagou V , Cornaglia G , Edelstein M , et al. Acquired carbapenemases in Gram-negative bacterial pathogens: detection and surveillance issues . Clin Microbiol Infect 2010 ; 16 : 112 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 44. Daikos GL , Markogiannakis A . Carbapenemase-producing Klebsiella pneumoniae: (when) might we still consider treating with carbapenems ? Clin Microbiol Infect 2011 ; 17 : 1135 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Author notes Q. W. and X. W. contributed equally to this manuscript. © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Phenotypic and Genotypic Characterization of Carbapenem-resistant Enterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012–2016)
JO - Clinical Infectious Diseases
DO - 10.1093/cid/ciy660
DA - 2018-11-13
UR - https://www.deepdyve.com/lp/oxford-university-press/phenotypic-and-genotypic-characterization-of-carbapenem-resistant-xMsr5RZIH5
SP - S196
VL - 67
IS - suppl_2
DP - DeepDyve
ER -