Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals

Wright, Meredith S.; Pérez, Federico; Brinkac, Lauren; Jacobs, Michael; Kaye, Keith S.; Cober, Eric; Duin, David van; Marshall, Steven H.; Hujer, Andrea M.; Rudin, Susan D.; Hujer, Kristine M.; Adams, Mark D.

doi:10.1128/aac.00125-14

Cited by 65 publications

(68 citation statements)

References 30 publications

(29 reference statements)

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“…Although most of the colistin-resistant strains were related clones, except for Col4 and Col22, our strains did not consist of identical strains (Table 1; see also Table S2 in the supplemental material). As in a previous study (25), this study also showed correlations between capsular type and ST. The predominant capsular type of colistin-resistant K. pneumoniae in Taiwan was K64, and the MLST results revealed that about half of the colistin-resistant isolates were ST11, similar to the results of a previous report in Spain (26).…”

supporting

confidence: 71%

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Cheng

Lin

Pan

et al. 2015

Antimicrob Agents Chemother

140

103

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Colistin is one of the antibiotics of last resort for the treatment of carbapenem-resistant Klebsiella pneumoniae infection. This study showed that capsular type K64 (50%) and ST11 (53.9%) are the prevalent capsular and sequence types in the colistin-resistant strains in Taiwan. The interruption of transcripts (38.5%) and amino acid mutation (15.4%) in mgrB are the major mechanisms contributing to colistin resistance. In addition, novel single amino acid changes in MgrB (Stop48Tyr) and PhoQ (Leu26Pro) were observed to contribute to colistin resistance. Klebsiella pneumoniae is an important human pathogen that causes several hospital-acquired and community-acquired diseases (1, 2). Although carbapenem is generally used to treat infections caused by extended-spectrum ␤-lactamase (ESBL)-carrying K. pneumoniae (3), K. pneumoniae strains carrying carbapenemases or ESBL strains combined with the loss of porins can result in carbapenem-resistant K. pneumoniae (CRKP) (4-6). To eradicate CRKP, colistin and tigecycline are typically used to treat patients (7). Unfortunately, resistance to colistin and tigecycline has also been reported, with a 17% resistance rate of CRKP to colistin in Taiwan (8). A surveillance study also revealed that 43% of carbapenemase-producing K. pneumoniae isolates were resistant to colistin in Italy (9).Colistin, also called polymyxin E, is a cationic antimicrobial peptide that targets bacterial lipopolysaccharide (LPS), causing cell membrane leakage (10). Previous studies have demonstrated that the modification of lipid A with 4-amino-4-deoxy-L-arabinose (Ara4N) and phosphoethanolamine neutralizes the negative charge and reduces susceptibility to colistin in Enterobacteriaceae (11)(12)(13)(14)(15). Modification of Ara4N is achieved by the pmrHFIJKLM operon (13), and the two-component systems PhoPQ and PmrAB with connector PmrD are involved in the regulation of the pmrHFIJKLM operon (16,17). Moreover, MgrB is a negative regulator that influences PhoQ-PhoP phosphorylation (18)(19)(20). In this study, we analyzed capsular type and multilocus sequence type (MLST) distribution of colistin-resistant K. pneumoniae in Taiwan and attempted to define the mechanisms of resistance to colistin.Colistin-resistant K. pneumoniae strains were retrospectively collected from patients in the Taipei Veterans General Hospital (VGH) from February to August 2013. All 26 strains were clinical isolates and were isolated from different patients. Among the 26 clinical isolates, the Col14 and Col40 strains were CRKP, and only the Col14 strain harbored the carbapenemase KPC. Colistin was used to treat infections in 16 of the 26 patients prior to the isolation of strains, and the other patients did not receive colistin in the VGH (Table 1). However, we could not trace the colistin usage of these patients in other hospitals. Previous studies also showed that some colistin-resistant strains are isolated from healthy individuals (21). Resistance to colistin in strains that were not exposed to colistin might be due to spontaneous...

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supporting

confidence: 71%

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Cheng

Lin

Pan

et al. 2015

Antimicrob Agents Chemother

140

103

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“…Clinically, AMR phenotypes are monitored routinely in most hospital laboratories; however, our study indicates that it also will be crucial to perform active surveillance for key virulence genes and to determine clonal background. Genomic surveillance is being used increasingly to monitor KPC-producing K. pneumoniae, especially ST258, and the emergence of NDM-1 and colistin-resistant (XDR) isolates (27,28,(65)(66)(67). Crucially, our study shows that we can augment these surveillance efforts by using key virulence genes as strong predictors of invasive disease in humans, and by determining clonal background, so that we can identify and track XDR hypervirulent clones as they emerge.…”

Section: Resultsmentioning

confidence: 99%

“…Several recent genomic analyses indicate that sequence type (ST) 258 is a recombinant strain that has undergone capsular exchange since its emergence as a cause of KPC outbreaks (28)(29)(30). However, little attention has been paid to other MDR clones, which also are common and can spread carbapenem resistance (31).…”

Section: Significancementioning

confidence: 99%

Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae , an urgent threat to public health

Holt

Wertheim

Zadoks

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

1,004

1,123

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Klebsiella pneumoniae is now recognized as an urgent threat to human health because of the emergence of multidrug-resistant strains associated with hospital outbreaks and hypervirulent strains associated with severe community-acquired infections. K. pneumoniae is ubiquitous in the environment and can colonize and infect both plants and animals. However, little is known about the population structure of K. pneumoniae, so it is difficult to recognize or understand the emergence of clinically important clones within this highly genetically diverse species. Here we present a detailed genomic framework for K. pneumoniae based on whole-genome sequencing of more than 300 human and animal isolates spanning four continents. Our data provide genome-wide support for the splitting of K. pneumoniae into three distinct species, KpI (K. pneumoniae), KpII (K. quasipneumoniae), and KpIII (K. variicola). Further, for K. pneumoniae (KpI), the entity most frequently associated with human infection, we show the existence of >150 deeply branching lineages including numerous multidrug-resistant or hypervirulent clones. We show K. pneumoniae has a large accessory genome approaching 30,000 protein-coding genes, including a number of virulence functions that are significantly associated with invasive community-acquired disease in humans. In our dataset, antimicrobial resistance genes were common among human carriage isolates and hospital-acquired infections, which generally lacked the genes associated with invasive disease. The convergence of virulence and resistance genes potentially could lead to the emergence of untreatable invasive K. pneumoniae infections; our data provide the whole-genome framework against which to track the emergence of such threats.

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“…Strains originated from a collection of KPC-producing K. pneumoniae isolates obtained from a consortium of tertiary-care hospitals previously described (16,17). Colistin MICs were determined with a Sensititre system (17) and confirmed by Etest strips (bioMérieux). Genome sequencing was previously described (17) and consisted of Illumina HiSeq reads assembled with Newbler and annotated using the Comprehensive Microbial Resource annotation pipeline (18).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genomic and Transcriptomic Analyses of Colistin-Resistant Clinical Isolates of Klebsiella pneumoniae Reveal Multiple Pathways of Resistance

Wright

Suzuki

Jones

et al. 2015

Antimicrob Agents Chemother

Self Cite

187

158

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fThe emergence of multidrug-resistant (MDR) Klebsiella pneumoniae has resulted in a more frequent reliance on treatment using colistin. However, resistance to colistin (Col r ) is increasingly reported from clinical settings. The genetic mechanisms that lead to Col r in K. pneumoniae are not fully characterized. Using a combination of genome sequencing and transcriptional profiling by RNA sequencing (RNA-Seq) analysis, distinct genetic mechanisms were found among nine Col r clinical isolates. Col r was related to mutations in three different genes in K. pneumoniae strains, with distinct impacts on gene expression. Upregulation of the pmrH operon encoding 4-amino-4-deoxy-L-arabinose (Ara4N) modification of lipid A was found in all Col r strains. Alteration of the mgrB gene was observed in six strains. One strain had a mutation in phoQ. Common among these seven strains was elevated expression of phoPQ and unaltered expression of pmrCAB, which is involved in phosphoethanolamine addition to lipopolysaccharide (LPS). In two strains, separate mutations were found in a previously uncharacterized histidine kinase gene that is part of a two-component regulatory system (TCRS) now designated crrAB. In these strains, expression of pmrCAB, crrAB, and an adjacent glycosyltransferase gene, but not that of phoPQ, was elevated. Complementation with the wild-type allele restored colistin susceptibility in both strains. The crrAB genes are present in most K. pneumoniae genomes, but not in Escherichia coli. Additional upregulated genes in all strains include those involved in cation transport and maintenance of membrane integrity. Because the crrAB genes are present in only some strains, Col r mechanisms may be dependent on the genetic background.T he increasing occurrence of multidrug-resistant (MDR) Klebsiella pneumoniae has expanded reliance on last-line therapies like colistin, a cationic antimicrobial peptide, for effective treatment (1). Of concern is the growing recovery of colistin-resistant (Col r ) strains from clinical settings (2-4). Colistin disrupts membrane integrity through displacement of cations like Mg 2ϩ and Ca 2ϩ in the outer membrane, leading to cell lysis (5). Resistance mechanisms described to date involve lipopolysaccharide (LPS) modification, particularly through derivatization of lipid A phosphate moieties with a sugar or ethanolamine. These modifications reduce the electrostatic affinity between the cationic colistin and anionic LPS. Mutations in the transcriptional regulatory systems controlling these LPS modifications are a common genetic mechanism leading to colistin resistance. For example, the PhoPQ and PmrAB two-component regulatory systems (TCRS) regulate expression of the gene (pmrC) that codes for the addition of phosphoethanolamine (pETN) and genes encoding biosynthesis and lipid A transfer of 4-amino-4-deoxy-L-arabinose (Ara4N) (pmrHFIJKLM) (Fig. 1A). Other regulatory components in this pathway include PmrD and MgrB, two connector proteins that convey feedback between the PmrAB and PhoPQ TCRS ...

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Population Structure of KPC-Producing Klebsiella pneumoniae Isolates from Midwestern U.S. Hospitals

Cited by 65 publications

References 30 publications

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Colistin Resistance Mechanisms in Klebsiella pneumoniae Strains from Taiwan

Genomic analysis of diversity, population structure, virulence, and antimicrobial resistance in Klebsiella pneumoniae , an urgent threat to public health

Genomic and Transcriptomic Analyses of Colistin-Resistant Clinical Isolates of Klebsiella pneumoniae Reveal Multiple Pathways of Resistance

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