Klebsiella pneumoniae: a major worldwide source and shuttle for antibiotic resistance
TL;DR: The data highlight the complex evolution of MDR and XDR K. pneumoniae, involving transfer and spread of ARGs, and epidemic plasmids in highly disseminating successful clones, and a need for future genomic and translational studies to decipher specific targets in HiR clones to design targeted prevention and treatment.
Abstract: Klebsiella pneumoniae is an important multidrug-resistant (MDR) pathogen affecting humans and a major source for hospital infections associated with high morbidity and mortality due to limited treatment options We summarize the wide resistome of this pathogen, which encompasses plentiful chromosomal and plasmid-encoded antibiotic resistance genes (ARGs) Under antibiotic selective pressure, K pneumoniae continuously accumulates ARGs, by de novo mutations, and via acquisition of plasmids and transferable genetic elements, leading to extremely drug resistant (XDR) strains harboring a 'super resistome' In the last two decades, numerous high-risk (HiR) MDR and XDR K pneumoniae sequence types have emerged showing superior ability to cause multicontinent outbreaks, and continuous global dissemination The data highlight the complex evolution of MDR and XDR K pneumoniae, involving transfer and spread of ARGs, and epidemic plasmids in highly disseminating successful clones With the worldwide catastrophe of antibiotic resistance and the urgent need to identify the main pathogens that pose a threat on the future of infectious diseases, further studies are warranted to determine the epidemic traits and plasmid acquisition in K pneumoniae There is a need for future genomic and translational studies to decipher specific targets in HiR clones to design targeted prevention and treatment
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TL;DR: The acquisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treatment options for serious infections, increased the burden of disease, and increased death rates due to treatment failure and requires a coordinated global response for antim antibiotic resistance surveillance.
Abstract: Antimicrobial-resistant ESKAPE ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens represent a global threat to human health. The acquisition of antimicrobial resistance genes by ESKAPE pathogens has reduced the treatment options for serious infections, increased the burden of disease, and increased death rates due to treatment failure and requires a coordinated global response for antimicrobial resistance surveillance. This looming health threat has restimulated interest in the development of new antimicrobial therapies, has demanded the need for better patient care, and has facilitated heightened governance over stewardship practices.
674 citations
TL;DR: How genomics approaches have advanced the understanding of K. pneumoniae taxonomy, ecology and evolution as well as the diversity and distribution of clinically relevant determinants of pathogenicity and antimicrobial resistance is discussed.
Abstract: Klebsiella pneumoniae is a common cause of antimicrobial-resistant opportunistic infections in hospitalized patients. The species is naturally resistant to penicillins, and members of the population often carry acquired resistance to multiple antimicrobials. However, knowledge of K. pneumoniae ecology, population structure or pathogenicity is relatively limited. Over the past decade, K. pneumoniae has emerged as a major clinical and public health threat owing to increasing prevalence of healthcare-associated infections caused by multidrug-resistant strains producing extended-spectrum β-lactamases and/or carbapenemases. A parallel phenomenon of severe community-acquired infections caused by 'hypervirulent' K. pneumoniae has also emerged, associated with strains expressing acquired virulence factors. These distinct clinical concerns have stimulated renewed interest in K. pneumoniae research and particularly the application of genomics. In this Review, we discuss how genomics approaches have advanced our understanding of K. pneumoniae taxonomy, ecology and evolution as well as the diversity and distribution of clinically relevant determinants of pathogenicity and antimicrobial resistance. A deeper understanding of K. pneumoniae population structure and diversity will be important for the proper design and interpretation of experimental studies, for interpreting clinical and public health surveillance data and for the design and implementation of novel control strategies against this important pathogen.
399 citations
TL;DR: In this paper, a review aimed at reporting recent strategies to develop innovative organic photosensitizers for enhanced photodynamic therapy, with each example described in detail instead of providing only a general overview, to provide intuitive, vivid, and specific insights to the readers.
Abstract: This review presents a robust strategy to design photosensitizers (PSs) for various species. Photodynamic therapy (PDT) is a photochemical-based treatment approach that involves the use of light combined with a light-activated chemical, referred to as a PS. Attractively, PDT is one of the alternatives to conventional cancer treatment due to its noninvasive nature, high cure rates, and low side effects. PSs play an important factor in photoinduced reactive oxygen species (ROS) generation. Although the concept of photosensitizer-based photodynamic therapy has been widely adopted for clinical trials and bioimaging, until now, to our surprise, there has been no relevant review article on rational designs of organic PSs for PDT. Furthermore, most of published review articles in PDT focused on nanomaterials and nanotechnology based on traditional PSs. Therefore, this review aimed at reporting recent strategies to develop innovative organic photosensitizers for enhanced photodynamic therapy, with each example described in detail instead of providing only a general overview, as is typically done in previous reviews of PDT, to provide intuitive, vivid, and specific insights to the readers.
391 citations
TL;DR: This work proposes K. pneumoniae plays a key role in disseminating AMR genes from environmental microbes to clinically important pathogens and has a wider ecological distribution, significantly more varied DNA composition, greater AMR gene diversity and a higher plasmid burden than other Gram negative opportunists.
281 citations
TL;DR: A better understanding of Klebsiella immune evasion strategies in the context of the host–pathogen interactions is pivotal to develop new therapeutics, which can be based on antagonising the anti-immune strategies of this pathogen.
Abstract: Klebsiella species cause a wide range of diseases including pneumonia, urinary tract infections (UTIs), bloodstream infections and sepsis. These infections are particularly a problem among neonates, elderly and immunocompromised individuals. Klebsiella is also responsible for a significant number of community-acquired infections. A defining feature of these infections is their morbidity and mortality, and the Klebsiella strains associated with them are considered hypervirulent. The increasing isolation of multidrug-resistant strains has significantly narrowed, or in some settings completely removed, the therapeutic options for the treatment of Klebsiella infections. Not surprisingly, this pathogen has then been singled out as an 'urgent threat to human health' by several organisations. This review summarises the tremendous progress that has been made to uncover the sophisticated immune evasion strategies of K. pneumoniae. The co-evolution of Klebsiella in response to the challenge of an activated immune has made Klebsiella a formidable pathogen exploiting stealth strategies and actively suppressing innate immune defences to overcome host responses to survive in the tissues. A better understanding of Klebsiella immune evasion strategies in the context of the host-pathogen interactions is pivotal to develop new therapeutics, which can be based on antagonising the anti-immune strategies of this pathogen.
273 citations
References
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European Centre for Disease Prevention and Control1, Centers for Disease Control and Prevention2, Tel Aviv Sourasky Medical Center3, Tufts University4, ALFA5, Karolinska University Hospital6, University of Geneva7, University of California, Los Angeles8, Royal Brisbane and Women's Hospital9, Brown University10, Brigham and Women's Hospital11
TL;DR: A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control and the Centers for Disease Control and Prevention, to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp.
8,695 citations
"Klebsiella pneumoniae: a major worl..." refers background in this paper
...This constant evolution over the years has led to the emergence of MDR and XDR Enterobacteriaceae strains (Magiorakos et al. 2012) that exhibit resistance to nearly all antibiotics available, without possible treatment options Received: 5 October 2016; Accepted: 28 February 2017 C© FEMS 2017....
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...This constant evolution over the years has led to the emergence of MDR and XDR Enterobacteriaceae strains (Magiorakos et al. 2012) that exhibit resistance to nearly...
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TL;DR: A review of antibiotic resistance development over the past half-century can be found in this article, with the oft-restated conclusion that it is time to act and to restore the therapeutic applications of antibiotics.
Abstract: Antibiotics have always been considered one of the wonder discoveries of the 20th century. This is true, but the real wonder is the rise of antibiotic resistance in hospitals, communities, and the environment concomitant with their use. The extraordinary genetic capacities of microbes have benefitted from man's overuse of antibiotics to exploit every source of resistance genes and every means of horizontal gene transmission to develop multiple mechanisms of resistance for each and every antibiotic introduced into practice clinically, agriculturally, or otherwise. This review presents the salient aspects of antibiotic resistance development over the past half-century, with the oft-restated conclusion that it is time to act. To achieve complete restitution of therapeutic applications of antibiotics, there is a need for more information on the role of environmental microbiomes in the rise of antibiotic resistance. In particular, creative approaches to the discovery of novel antibiotics and their expedited and controlled introduction to therapy are obligatory.
4,364 citations
Tufts Medical Center1, Boston Children's Hospital2, University of California, San Diego3, University of California, Los Angeles4, Los Angeles Biomedical Research Institute5, Providence Portland Medical Center6, Case Western Reserve University7, United States Department of Veterans Affairs8, University of Virginia9, Johns Hopkins University School of Medicine10
TL;DR: An update on potentially effective antibacterial drugs in the late-stage development pipeline is provided, in the hope of encouraging collaboration between industry, academia, the National Institutes of Health, the Food and Drug Administration, and the Centers for Disease Control and Prevention work productively together.
Abstract: The Infectious Diseases Society of America (IDSA) continues to view with concern the lean pipeline for novel therapeutics to treat drug-resistant infections, especially those caused by gram-negative pathogens. Infections now occur that are resistant to all current antibacterial options. Although the IDSA is encouraged by the prospect of success for some agents currently in preclinical development, there is an urgent, immediate need for new agents with activity against these panresistant organisms. There is no evidence that this need will be met in the foreseeable future. Furthermore, we remain concerned that the infrastructure for discovering and developing new antibacterials continues to stagnate, thereby risking the future pipeline of antibacterial drugs. The IDSA proposed solutions in its 2004 policy report, “Bad Bugs, No Drugs: As Antibiotic R&D Stagnates, a Public Health Crisis Brews,” and recently issued a “Call to Action” to provide an update on the scope of the problem and the proposed solutions. A primary objective of these periodic reports is to encourage a community and legislative response to establish greater financial parity between the antimicrobial development and the development of other drugs. Although recent actions of the Food and Drug Administration and the 110th US Congress present a glimmer of hope, significant uncertainly remains. Now, more than ever, it is essential to create a robust and sustainable antibacterial research and development infrastructure—one that can respond to current antibacterial resistance now and anticipate evolving resistance. This challenge requires that industry, academia, the National Institutes of Health, the Food and Drug Administration, the Centers for Disease Control and Prevention, the US Department of Defense, and the new Biomedical Advanced Research and Development Authority at the Department of Health and Human Services work productively together. This report provides an update on potentially effective antibacterial drugs in the late-stage development pipeline, in the hope of encouraging such collaborative action.
4,256 citations
TL;DR: The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance, in Enterobacteriaceae and emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria.
Abstract: Summary Background Until now, polymyxin resistance has involved chromosomal mutations but has never been reported via horizontal gene transfer. During a routine surveillance project on antimicrobial resistance in commensal Escherichia coli from food animals in China, a major increase of colistin resistance was observed. When an E coli strain, SHP45, possessing colistin resistance that could be transferred to another strain, was isolated from a pig, we conducted further analysis of possible plasmid-mediated polymyxin resistance. Herein, we report the emergence of the first plasmid-mediated polymyxin resistance mechanism, MCR-1, in Enterobacteriaceae. Methods The mcr-1 gene in E coli strain SHP45 was identified by whole plasmid sequencing and subcloning. MCR-1 mechanistic studies were done with sequence comparisons, homology modelling, and electrospray ionisation mass spectrometry. The prevalence of mcr-1 was investigated in E coli and Klebsiella pneumoniae strains collected from five provinces between April, 2011, and November, 2014. The ability of MCR-1 to confer polymyxin resistance in vivo was examined in a murine thigh model. Findings Polymyxin resistance was shown to be singularly due to the plasmid-mediated mcr-1 gene. The plasmid carrying mcr-1 was mobilised to an E coli recipient at a frequency of 10 −1 to 10 −3 cells per recipient cell by conjugation, and maintained in K pneumoniae and Pseudomonas aeruginosa . In an in-vivo model, production of MCR-1 negated the efficacy of colistin. MCR-1 is a member of the phosphoethanolamine transferase enzyme family, with expression in E coli resulting in the addition of phosphoethanolamine to lipid A. We observed mcr-1 carriage in E coli isolates collected from 78 (15%) of 523 samples of raw meat and 166 (21%) of 804 animals during 2011–14, and 16 (1%) of 1322 samples from inpatients with infection. Interpretation The emergence of MCR-1 heralds the breach of the last group of antibiotics, polymyxins, by plasmid-mediated resistance. Although currently confined to China, MCR-1 is likely to emulate other global resistance mechanisms such as NDM-1. Our findings emphasise the urgent need for coordinated global action in the fight against pan-drug-resistant Gram-negative bacteria. Funding Ministry of Science and Technology of China, National Natural Science Foundation of China.
3,647 citations
"Klebsiella pneumoniae: a major worl..." refers background in this paper
...For example, pKF3-70 carrying the blaCTX-M-14 gene from China had a conserved FII backbone but acquired an iron transport system, and several open reading frames of unknown function (Yi et al. 2010)....
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...For instance, FIIK-R multireplicon plasmids carrying blaKPC-2 have been identified in Italy, USA, China, Russia and Taiwan, suggesting a successful international spread of these plasmids (Table 1; Frasson et al. 2012)....
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...A ventilatorassociated outbreak in China is a dramatic example of successful transmission of KPC-2 ST11 K. pneumoniae bypassing patient-to-patient contact (Hu et al. 2016)....
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...Nr7∗ KM406491 blaOXA-48 L Switzerland, Ireland, Australia, France, Netherlands 32 pNL194∗ GU585907 blaVIM-1 N1 (R) Greece, Norway, Switzerland 33 pIMP-HZ1 JX457479 blaIMP N1 Hong Kong 34 p801-IMP KT345947 blaIMP N3 China 35 pIMP-PH114 KF250428 blaIMP A/C2 China 36 pKP-M1144 KF745070 blaIMP-8, blaGES-5 ColE Portugal 37 pGES-GZ KT070138 blaGES-5 N China 38 pKF3-70 FJ494913 blaCTX-M-14 FII China 39 pKP09085∗ KF719970 blaCTX-M-15 FIIK, FIBpKpN3 China, Sweden, Korea, Norway 40 pKDO1 JX424423 blaCTX-M-15 FIIK, Rep3 Czech Republic 41 pKPX-2 AP012056 blaCTX-M-15 HI1, FII Taiwan, Germany 42 p628-CTXM KP987217 blaCTX-M-55 I1 China 43 pK29 EF382672 blaCTX-M-3 HI2 Taiwan 44 pCTX-M-360 EU938349 blaCTX-M-3 M China 45 pKP12226 KP453775 blaCTX-M-15 Y, FII, FIA South Korea 46 pJIE137 EF219134 blaCTX-M-62 N3 Australia 47 pIP843 AY033516 blaCTX-M-17 ColE Vietnam 48 pLJ1 EU880929 blaSHV-12 N1 Australia 49 pKPS77 KF954150 blaSHV-12 N1, R France 50 pKPN-068 CP007733 blaSHV-12 L USA 51 pCAV1193-166 CP013324 blaSHV-7 A/C2 UK, Japan 52 pH11 CP013215 blaSHV-12 HI2 China, USA, Brazil, UK Plasmids that are schematically presented in Fig....
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...Plasmid-mediated polymyxin resistance was reported only recently, with the identification of the mcr-1 gene in China (Liu et al. 2016)....
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TL;DR: Two easy-to-use Web tools for in silico detection and characterization of whole-genome sequence (WGS) and whole-plasmid sequence data from members of the family Enterobacteriaceae are designed and developed.
Abstract: In the work presented here, we designed and developed two easy-to-use Web tools for in silico detection and characterization of whole-genome sequence (WGS) and whole-plasmid sequence data from members of the family Enterobacteriaceae. These tools will facilitate bacterial typing based on draft genomes of multidrug-resistant Enterobacteriaceae species by the rapid detection of known plasmid types. Replicon sequences from 559 fully sequenced plasmids associated with the family Enterobacteriaceae in the NCBI nucleotide database were collected to build a consensus database for integration into a Web tool called PlasmidFinder that can be used for replicon sequence analysis of raw, contig group, or completely assembled and closed plasmid sequencing data. The PlasmidFinder database currently consists of 116 replicon sequences that match with at least at 80% nucleotide identity all replicon sequences identified in the 559 fully sequenced plasmids. For plasmid multilocus sequence typing (pMLST) analysis, a database that is updated weekly was generated from www.pubmlst.org and integrated into a Web tool called pMLST. Both databases were evaluated using draft genomes from a collection of Salmonella enterica serovar Typhimurium isolates. PlasmidFinder identified a total of 103 replicons and between zero and five different plasmid replicons within each of 49 S . Typhimurium draft genomes tested. The pMLST Web tool was able to subtype genomic sequencing data of plasmids, revealing both known plasmid sequence types (STs) and new alleles and ST variants. In conclusion, testing of the two Web tools using both fully assembled plasmid sequences and WGS-generated draft genomes showed them to be able to detect a broad variety of plasmids that are often associated with antimicrobial resistance in clinically relevant bacterial pathogens.
2,834 citations
"Klebsiella pneumoniae: a major worl..." refers methods in this paper
...We identified the replicons on these plasmids using the PlasmidFinder database (https://cge.cbs.dtu.dk/services/PlasmidFinder/) (Carattoli et al. 2014)....
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