Molecular Dissection of an Outbreak of Carbapenem-Resistant Enterobacteriaceae Reveals Intergenus KPC Carbapenemase Transmission through a Promiscuous Plasmid

Mathers, Amy J; Cox, Heather; Kitchel, Brandon; Bonatti, Hugo; Brassinga, Ann Karen C.; Carroll, Joanne; Scheld, W. Michael; Hazen, Kevin C.; Sifri, Costi D.

doi:10.1128/mbio.00204-11

Cited by 163 publications

(172 citation statements)

References 29 publications

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“…Given that bla KPC is found on plasmids that are transmissible among Enterobacteriaceae and can produce novel CRKP strains (24,25) The heterogeneity in wzi types and bla KPC variants among ST258 isolates encountered in our study is consistent with emerging literature on variability in capsule types and associated resistance determinants in this ST (10,11,26). We found that bla was almost entirely restricted to wzi154-positive ST258 CRKP isolates, whereas bla KPC-2 was detected in isolates with several sequence and wzi alleles.…”

Section: Discussionsupporting

confidence: 79%

Population Structure of Klebsiella pneumoniae Causing Bloodstream Infections at a New York City Tertiary Care Hospital: Diversification of Multidrug-Resistant Isolates

et al. 2015

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bDespite the growing importance of carbapenem-resistant Klebsiella pneumoniae (CRKP), the clonal relationships between CRKP and antibiotic-susceptible isolates remain unclear. We compared the genetic diversity and clinical features of CRKP, third-generation and/or fourth-generation cephalosporin-resistant (Ceph-R) K. pneumoniae, and susceptible K. pneumoniae isolates causing bloodstream infections at a tertiary care hospital in New York City between January 2012 and July 2013. Drug susceptibilities were determined with the Vitek 2 system. Isolates underwent multilocus sequence typing and PCR sequencing of the wzi and bla KPC genes. Clinical and microbiological data were extracted from patient records and correlated with molecular data. Among 223 patients, we identified 272 isolates. Of these, 194 were susceptible, 30 Ceph-R, and 48 CRKP, belonging to 144 sequence types (STs). Susceptible (127 STs) and Ceph-R (20 STs) isolates were highly diverse. ST258 dominated CRKP strains (12 STs, with 63% ST258). There was minimal overlap in STs between resistance groups. The bla KPC-3 gene (30%) was restricted to ST258/wzi154, whereas bla KPC-2 (70%) was observed for several wzi allele types. CRKP infections occurred more frequently among solid organ transplant (31%) and dialysis (17%) patients. Mortality rates were high overall (28%) and highest among CRKP-infected patients (59%). In multivariable analyses, advanced age, comorbidities, and disease severity were significant predictors of 30-day mortality rates, whereas the K. pneumoniae susceptibility phenotype was not. Among CRKP infections, we observed a borderline significant association of increased mortality rates with ST258 and the wzi154 allele. Although the clonal spread of ST258 continues to contribute substantially to the dissemination of CRKP, non-ST258 strains appear to be evolving. Further investigations into the mechanisms promoting CRKP diversification and the effects of clonal backgrounds on outcomes are warranted. Infections due to carbapenem-resistant Enterobacteriaceae have emerged as an important public health problem over the past decade and are now considered an urgent antibiotic-resistant threat by the Centers for Disease Control and Prevention (CDC), the category of greatest concern (1). In the United States, carbapenem resistance among Enterobacteriaceae is primarily attributable to the production of the Klebsiella pneumoniae carbapenemase (KPC) (2, 3), which is plasmid mediated and most commonly encountered in K. pneumoniae in nosocomial settings (4, 5). Bloodstream infections (BSIs) caused by carbapenem-resistant K. pneumoniae (CRKP) are associated with particularly high mortality rates (6-8), with previous studies reporting hospital mortality rates of 40 to 70%, compared to rates of 20 to 30% among matched patients with bacteremia due to susceptible K. pneumoniae (4, 9).A single clone, multilocus sequence type 258 (ST258), has been found to account for the majority of CRKP infections in the United States and was identified among 70% of isolates s...

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Section: Discussionsupporting

confidence: 79%

Population Structure of Klebsiella pneumoniae Causing Bloodstream Infections at a New York City Tertiary Care Hospital: Diversification of Multidrug-Resistant Isolates

et al. 2015

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“…Few clinical laboratories have the capability of identifying the mechanism of carbapenem resistance, and yet this information can be exceedingly useful to outbreak investigations by identifying patients colonized with CRE that harbor the same resistance mechanism and are thus potentially part of an outbreak. Furthermore, carbapenemase genes are harbored on highly mobile genetic elements, and the ability to detect the spread of a particular gene may aid in identifying plasmid-mediated outbreaks that occur across patients and genera of the Enterobacteriaceae (21).…”

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confidence: 99%

Commentary: Continuing Challenges for the Clinical Laboratory for Detection of Carbapenem-Resistant Enterobacteriaceae

Humphries

McKinnell

2015

J Clin Microbiol

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Over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have become an urgent threat to health in the United States and elsewhere in the world (1, 2). The Centers for Disease Control and Prevention (CDC) have reported a steady increase in the burden of disease from CRE, particularly, carbapenem-resistant Klebsiella pneumoniae, in the United States (3, 4). Surveillance data from Chicago showed that 30% of residents of long-termacute-care hospitals (LTACHs) and 3.3% of patients in hospital intensive care units (ICUs) were CRE carriers, suggesting that CRE infections are now endemic in parts of the United States (5). The spread of CRE in the U.S. health care system comes at a great cost because there are limited available treatment options and high attributable mortality from CRE (6, 7).Spread of CRE in the United States appears to be driven by movement of patients though the health care system (8, 9). For instance, the CDC epicenters program demonstrated that patient transfers led to regional spread of CRE across 26 health care facilities in four counties (8). The transfer of CRE-colonized patients not only moves these organisms between institutions but also accelerates the epidemic through subsequent patient transmission events at each institution as the incidence of CRE increases (10) (11). To this point, a study of New York hospitals found that the odds of a patient acquiring CRE increased by 15% for each 1% increase in overall patient colonization at the facility (12).Recent research has shown some promising findings for curbing the spread of CRE. Hayden and colleagues demonstrated that the use of an infection prevention bundle that included chlorhexidine bathing and strict isolation practices in a high-CRE-burden LTACH was able to significantly reduce the rates of both new CRE acquisitions and bacteremia cases (13). Computer model estimates suggest that a coordinated regional response, compared to individual hospital actions, has the potential to reduce or even eliminate CRE transmission (10, 11).Such interventions require an understanding of the prevalence of CRE at the institutional level. However, the true burden of CRE at the local, regional, or national level remains poorly understood. Our limited understanding of CRE burden is due in part to challenges faced by the clinical laboratory at identifying CRE-in both clinical and surveillance cultures. In 2010, the Clinical and Laboratory Standards Institute (CLSI) revised the carbapenem breakpoints for the Enterobacteriaceae, and the U.S. Food and Drug Administration (FDA) followed suit by revising the drug product labeling to include these revised breakpoints. However, no manufacturer of commercial automated antimicrobial susceptibility test (AST) systems has obtained FDA clearance for these new standards, despite over 5 years having passed since their approval. Almost all laboratories in the United States rely on these systems for routine AST, and few have the resources to conduct the studies required to establish the performance of these syste...

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“…In particular, Klebsiella pneumoniae sequence type 258 (ST258) and its derivatives carrying plasmid-borne bla KPC carbapenemase genes have spread to cause outbreaks globally (3)(4)(5)(6)(7)(8)(9)(10). Some evidence suggests that CRE outbreaks could alternatively involve the primary transmission of carbapenemase-encoding plasmids or other mobile elements among genetically heterogeneous populations of bacteria, although this has not been demonstrated to be a dominant epidemiologic mechanism to date (11)(12)(13)(14)(15)(16)(17)(18). In areas of high endemicity, it is also possible for multiple unrelated plasmids mediating carbapenem resistance to be present concurrently among bacterial strains circulating during a given outbreak, leading to potentially complex transmission chains.…”

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confidence: 99%

A Rapid Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Method for Single-Plasmid Tracking in an Outbreak of Carbapenem-Resistant Enterobacteriaceae

et al. 2014

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e Carbapenem-resistant Enterobacteriaceae (CRE) have spread globally and represent a serious and growing threat to public health. Rapid methods for tracking plasmids carrying carbapenemase genes could greatly benefit infection control efforts. Here, we demonstrate that real-time, direct tracking of a single plasmid in a bacterial strain responsible for an outbreak is possible using a commercial matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) system. In this case, we retrospectively tracked the bla KPC carbapenemase gene-bearing pKpQIL plasmid responsible for a CRE outbreak that occurred at the NIH Clinical Center in 2011. An ϳ11,109-Da MS peak corresponding to a gene product of the bla KPC pKpQIL plasmid was identified and characterized using a combination of proteomics and molecular techniques. This plasmid peak was present in spectra from retrospectively analyzed K. pneumoniae outbreak isolates, concordant with results from whole-genome sequencing, and absent from a diverse control set of bla KPC -negative clinical Enterobacteriaceae isolates. Notably, the gene characterized here is located adjacent to the bla KPC Tn4401 transposon on the pKpQIL plasmid. Sequence analysis demonstrates the presence of this gene in other bla KPC Tn4401-containing plasmids and suggests that this signature MS peak may be useful in tracking other plasmids conferring carbapenem resistance. Plasmid identification using this MALDI-TOF MS method was accomplished in as little as 10 min from isolated colonies and 30 min from positive (spiked) blood cultures, demonstrating the potential clinical utility for real-time plasmid tracking in an outbreak.

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Molecular Dissection of an Outbreak of Carbapenem-Resistant Enterobacteriaceae Reveals Intergenus KPC Carbapenemase Transmission through a Promiscuous Plasmid

Cited by 163 publications

References 29 publications

Population Structure of Klebsiella pneumoniae Causing Bloodstream Infections at a New York City Tertiary Care Hospital: Diversification of Multidrug-Resistant Isolates

Population Structure of Klebsiella pneumoniae Causing Bloodstream Infections at a New York City Tertiary Care Hospital: Diversification of Multidrug-Resistant Isolates

Commentary: Continuing Challenges for the Clinical Laboratory for Detection of Carbapenem-Resistant Enterobacteriaceae

A Rapid Matrix-Assisted Laser Desorption Ionization–Time of Flight Mass Spectrometry-Based Method for Single-Plasmid Tracking in an Outbreak of Carbapenem-Resistant Enterobacteriaceae

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