Phenotypic and Genotypic Characterization of Carbapenem-resistant<i>Enterobacteriaceae</i>: Data From a Longitudinal Large-scale CRE Study in China (2012–2016)

Wang, Qi; Wang, Xiaojuan; Wang, Juan; Ouyang, Ping; Jin, Chi; Wang, Ruobing; Zhang, Yawei; Jin, Longyang; Chen, Hongbin; Wang, Zhanwei; Zhang, Feifei; Cao, Bin; Xie, Liangyi; Liao, Kang; Gu, Bing; Yang, Chunxia; Liu, Zhiwu; Ma, Xiaoxuan; Jin, Liang; Zhang, Xiaoqian; Man, Sijin; Li, Wei; Pei, Fengyan; Xu, Xiuli; Jin, Yan; Ji, Ping; Wang, Hui

doi:10.1093/cid/ciy660

Cited by 281 publications

(297 citation statements)

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“…found five different carbapenemase types among Citrobacter spp. isolates collected from Spain (14), and similar results were also demonstrated in a study of carbapenemase-producing Enterobacterales in China (15). It has been suggested that carbapenemase diversity depends on local geography (46), and future studies of larger populations may confirm or refute this notion.…”

Section: Discussionsupporting

confidence: 79%

“…This is similar to previous analyses of CNSC from non-US centers that used more classical molecular typing methods (14, 47, 48). Among Citrobacter species , C. freundii is most commonly associated with both clinical disease (44) and multidrug-resistant phenotypes (14, 15, 49). Our findings were consistent with these prior reports – C. freundii was the most frequent CNSC species we observed, though we also found CNSC belonging to four additional species.…”

Section: Discussionmentioning

confidence: 99%

“…(CNSC) have become increasingly recognized as a healthcare-associated pathogen (9–13). CNSC isolates have been found to be both genotypically and phenotypically diverse (14, 15), and their resistance to carbapenems is frequently caused by plasmid-encoded carbapenemases, which can be readily acquired through horizontal gene transfer (12, 16).…”

Section: Introductionmentioning

confidence: 99%

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Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Babiker

Evans

Griffith

et al. 2020

Preprint

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22Carbapenem-non-susceptible Citrobacter spp. (CNSC) are increasingly recognized as healthcare-23 associated pathogens. Information regarding their clinical epidemiology, genetic diversity, and 24 mechanisms of carbapenem resistance is lacking. We examined microbiology records of adult 25 patients at the University of Pittsburgh Medical Center (UMPC) Presbyterian Hospital (PUH) from 26 2000-2018 for CNSC, as defined by ertapenem non-susceptibility. Over this timeframe, the 27 proportion of CNSC increased from 4% to 10% (P=0.03), as did carbapenem daily defined 28 doses/1000 patient days (6.52 to 34.5, R 2 =0.831, P<0.001), which correlated with the observed 29 increase in CNSC (lag=0 years, R 2 =0.660). Twenty CNSC isolates from 19 patients at PUH and 30 other UPMC hospitals were available for further analysis, including whole-genome short-read 31 sequencing and additional antimicrobial susceptibility testing. Of the 19 patients, nearly all 32 acquired CNSC in the healthcare setting and over half had polymicrobial cultures containing at 33 least one other organism. Among the 20 CNSC isolates, C. freundii was the predominant species 34 identified (60%). CNSC genomes were compared with genomes of carbapenem-susceptible 35Citrobacter spp. from UPMC, and with other publicly available CNSC genomes. Isolates encoding 36 carbapenemases (blaKPC-2, blaKPC-3, and blaNDM-1) were also long-read sequenced, and their 37 carbapenemase-encoding plasmid sequences were compared with one another and with publicly 38 available sequences. Phylogenetic analysis of 102 UPMC Citrobacter spp. genomes showed that 39 CNSC from our setting did not cluster together. Similarly, a global phylogeny of 64 CNSC 40 genomes showed a diverse population structure. Our findings suggest that both local and global 41 CNSC populations are genetically diverse, and that CNSC harbor carbapenemase-encoding 42 plasmids found in other Enterobacterales. 43 isolated from a specimen collected within 72 hours following hospital admission; isolates collected 91 after 72 hours were considered healthcare-associated (22). Clinical characteristics and outcomes 92 of patients with CNSC isolates that underwent further characterization were collected through 93 retrospective chart review. The primary clinical outcome was in-hospital mortality and/or transfer 94 to hospice. 95 96 CNSC isolate characterization 97 Initial species assignment was performed using standard clinical microbiology laboratory 98 methods, and was confirmed or modified after whole-genome sequencing. Carbapenem non-99 susceptibility was initially determined by standard clinical microbiology laboratory methods, and 100 was confirmed by the Kirby-Bauer disk diffusion method as per the 2017 Clinical Laboratory 101 Standards Institute (CLSI) interpretative criteria (20). Susceptibility to additional agents was 102 determined by the broth microdilution method (20). Presence of carbapenemase enzyme activity 103 was assessed by modified carbapenem inactivation (mCIM) test (23). 104 105 Genome sequencing and a...

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Babiker

Evans

Griffith

et al. 2020

Preprint

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“…As a semisynthetic parenteral glycylcycline with a broad spectrum of antimicrobial activity, tigecycline can circumvent tetracycline resistance mediated by active efflux pumps or ribosomal protection in Enterobacteriaceae (9). However, tigecycline-resistant Enterobacteriaceae are increasingly reported following the widespread clinical use of tigecycline, especially against carbapenem-resistant Klebsiella pneumoniae (CRKP), the most common type of CRE (10). Importantly, the prevalence of CRKP has increased steadily worldwide over the last decade (11,12).…”

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confidence: 99%

Emergence of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump Conferring Resistance to Multiple Drugs, Including Tigecycline, in Klebsiella pneumoniae

Lv¹,

Wan²,

Wang³

et al. 2020

mBio

178

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Transporters belonging to the chromosomally encoded resistance-nodulation-division (RND) superfamily mediate multidrug resistance in Gram-negative bacteria. However, the cotransfer of large gene clusters encoding RND-type pumps from the chromosome to a plasmid appears infrequent, and no plasmid-mediated RND efflux pump gene cluster has yet been found to confer resistance to tigecycline. Here, we identified a novel RND efflux pump gene cluster, designated tmexCD1-toprJ1, on plasmids from five pandrug-resistant Klebsiella pneumoniae isolates of animal origin. TMexCD1-TOprJ1 increased (by 4- to 32-fold) the MICs of tetracyclines (including tigecycline and eravacycline), quinolones, cephalosporins, and aminoglycosides for K. pneumoniae, Escherichia coli, and Salmonella. TMexCD1-TOprJ1 is closely related (64.5% to 77.8% amino acid identity) to the MexCD-OprJ efflux pump encoded on the chromosome of Pseudomonas aeruginosa. In an IncFIA plasmid, pHNAH8I, the tmexCD1-toprJ1 gene cluster lies adjacent to two genes encoding site-specific integrases, which may have been responsible for its acquisition. Expression of TMexCD1-TOprJ1 in E. coli resulted in increased tigecycline efflux and in K. pneumoniae negated the efficacy of tigecycline in an in vivo infection model. Expression of TMexCD1-TOprJ1 reduced the growth of E. coli and Salmonella but not K. pneumoniae. tmexCD1-toprJ1-positive Enterobacteriaceae isolates were rare in humans (0.08%) but more common in chicken fecal (14.3%) and retail meat (3.4%) samples. Plasmid-borne tmexCD1-toprJ1-like gene clusters were identified in sequences in GenBank from Enterobacteriaceae and Pseudomonas strains from multiple continents. The possibility of further global dissemination of the tmexCD1-toprJ1 gene cluster and its analogues in Enterobacteriaceae via plasmids may be an important consideration for public health planning. IMPORTANCE In an era of increasing concerns about antimicrobial resistance, tigecycline is likely to have a critically important role in the treatment of carbapenem-resistant Enterobacteriaceae, the most problematic pathogens in human clinical settings—especially carbapenem-resistant K. pneumoniae. Here, we identified a new plasmid-borne RND-type tigecycline resistance determinant, TMexCD1-TOprJ1, which is widespread among K. pneumoniae isolates from food animals. tmexCD1-toprJ1 appears to have originated from the chromosome of a Pseudomonas species and may have been transferred onto plasmids by adjacent site-specific integrases. Although tmexCD1-toprJ1 still appears to be rare in human clinical isolates, considering the transferability of the tmexCD1-toprJ1 gene cluster and the broad substrate spectrum of TMexCD1-TOprJ1, further dissemination of this mobile tigecycline resistance determinant is possible. Therefore, from a “One Health” perspective, measures are urgently needed to monitor and control its further spread. The current low prevalence in human clinical isolates provides a precious time window to design and implement measures to tackle this.

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“…Most of the characterized STs were different from those of human sources in China. Yet, there were clones shared by isolates from humans and retail meat, such as E. coli ST10, ST167, ST410, ST641, ST744, and ST5229 and K. pneumoniae ST1, ST11, ST35, and ST45 (12)(13)(14). Conjugation and transformation experiments were performed on 52 NDM producers collected in 2016 to 2017.…”

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confidence: 99%

Rapid Increase in Carbapenemase-Producing Enterobacteriaceae in Retail Meat Driven by the Spread of the bla _NDM-5 -Carrying IncX3 Plasmid in China from 2016 to 2018

Zhang

Huang

et al. 2019

Antimicrob Agents Chemother

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The presence and molecular characteristics of carbapenemase-producing Enterobacteriaceae (CPE) among meat products in China were investigated. A total of 110 carbapenem-resistant Enterobacteriaceae (CRE) isolates, including 94 Escherichia coli and 10 Klebsiella pneumoniae isolates, were identified from 105 of 794 (13.2%) samples. The positive rates markedly increased from 2016 (9.4%) to 2018 (22.2%). Only bla NDM genes were detected; 79.1% of bla NDM genes were carried by IncX3 plasmids. Routine monitoring of carbapenemase-producing Enterobacteriaceae in the animal food supply is highly recommended.

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Phenotypic and Genotypic Characterization of Carbapenem-resistantEnterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012–2016)

Cited by 281 publications

References 42 publications

Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Emergence of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump Conferring Resistance to Multiple Drugs, Including Tigecycline, in Klebsiella pneumoniae

Rapid Increase in Carbapenemase-Producing Enterobacteriaceae in Retail Meat Driven by the Spread of the bla _NDM-5 -Carrying IncX3 Plasmid in China from 2016 to 2018

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Phenotypic and Genotypic Characterization of Carbapenem-resistantEnterobacteriaceae: Data From a Longitudinal Large-scale CRE Study in China (2012–2016)

Cited by 281 publications

References 42 publications

Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Clinical and genomic epidemiology of carbapenem-non-susceptibleCitrobacterspp. at a tertiary healthcare center over two decades

Emergence of a Plasmid-Encoded Resistance-Nodulation-Division Efflux Pump Conferring Resistance to Multiple Drugs, Including Tigecycline, in Klebsiella pneumoniae

Rapid Increase in Carbapenemase-Producing Enterobacteriaceae in Retail Meat Driven by the Spread of the bla NDM-5 -Carrying IncX3 Plasmid in China from 2016 to 2018

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Rapid Increase in Carbapenemase-Producing Enterobacteriaceae in Retail Meat Driven by the Spread of the bla _NDM-5 -Carrying IncX3 Plasmid in China from 2016 to 2018