Publications by authors named "David M Aanensen"

88 Publications

Overcoming Data Bottlenecks in Genomic Pathogen Surveillance.

Clin Infect Dis 2021 Dec;73(Supplement_4):S267-S274

Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.

Performing whole genome sequencing (WGS) for the surveillance of antimicrobial resistance offers the ability to determine not only the antimicrobials to which rates of resistance are increasing, but also the evolutionary mechanisms and transmission routes responsible for the increase at local, national, and global scales. To derive WGS-based outputs, a series of processes are required, beginning with sample and metadata collection, followed by nucleic acid extraction, library preparation, sequencing, and analysis. Throughout this pathway there are many data-related operations required (informatics) combined with more biologically focused procedures (bioinformatics). For a laboratory aiming to implement pathogen genomics, the informatics and bioinformatics activities can be a barrier to starting on the journey; for a laboratory that has already started, these activities may become overwhelming. Here we describe these data bottlenecks and how they have been addressed in laboratories in India, Colombia, Nigeria, and the Philippines, as part of the National Institute for Health Research Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance. The approaches taken include the use of reproducible data parsing pipelines and genome sequence analysis workflows, using technologies such as Data-flo, the Nextflow workflow manager, and containerization of software dependencies. By overcoming barriers to WGS implementation in countries where genome sampling for some species may be underrepresented, a body of evidence can be built to determine the concordance of antimicrobial sensitivity testing and genome-derived resistance, and novel high-risk clones and unknown mechanisms of resistance can be discovered.
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http://dx.doi.org/10.1093/cid/ciab785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634317PMC
December 2021

Rapid Genomic Characterization and Global Surveillance of Klebsiella Using Pathogenwatch.

Clin Infect Dis 2021 Dec;73(Supplement_4):S325-S335

Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.

Background: Klebsiella species, including the notable pathogen K. pneumoniae, are increasingly associated with antimicrobial resistance (AMR). Genome-based surveillance can inform interventions aimed at controlling AMR. However, its widespread implementation requires tools to streamline bioinformatic analyses and public health reporting.

Methods: We developed the web application Pathogenwatch, which implements analytics tailored to Klebsiella species for integration and visualization of genomic and epidemiological data. We populated Pathogenwatch with 16 537 public Klebsiella genomes to enable contextualization of user genomes. We demonstrated its features with 1636 genomes from 4 low- and middle-income countries (LMICs) participating in the NIHR Global Health Research Unit (GHRU) on AMR.

Results: Using Pathogenwatch, we found that GHRU genomes were dominated by a small number of epidemic drug-resistant clones of K. pneumoniae. However, differences in their distribution were observed (eg, ST258/512 dominated in Colombia, ST231 in India, ST307 in Nigeria, ST147 in the Philippines). Phylogenetic analyses including public genomes for contextualization enabled retrospective monitoring of their spread. In particular, we identified hospital outbreaks, detected introductions from abroad, and uncovered clonal expansions associated with resistance and virulence genes. Assessment of loci encoding O-antigens and capsule in K. pneumoniae, which represent possible vaccine candidates, showed that 3 O-types (O1-O3) represented 88.9% of all genomes, whereas capsule types were much more diverse.

Conclusions: Pathogenwatch provides a free, accessible platform for real-time analysis of Klebsiella genomes to aid surveillance at local, national, and global levels. We have improved representation of genomes from GHRU participant countries, further facilitating ongoing surveillance.
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http://dx.doi.org/10.1093/cid/ciab784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634497PMC
December 2021

Clones and Clusters of Antimicrobial-Resistant Klebsiella From Southwestern Nigeria.

Clin Infect Dis 2021 Dec;73(Supplement_4):S308-S315

Global Health Research  Unit on Genomic Surveillance of Antimicrobial Resistance, Department of Pharmaceutical Microbiology, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria.

Background: Klebsiella pneumoniae is a World Health Organization high-priority antibiotic-resistant pathogen. However, little is known about Klebsiella lineages circulating in Nigeria.

Methods: We performed whole-genome sequencing (WGS) of 141 Klebsiella isolated between 2016 and 2018 from clinical specimens at 3 antimicrobial-resistance (AMR) sentinel surveillance tertiary hospitals in southwestern Nigeria. We conducted in silico multilocus sequence typing; AMR gene, virulence gene, plasmid, and K and O loci profiling; as well as phylogenetic analyses, using publicly available tools and Nextflow pipelines.

Results: Phylogenetic analysis revealed that the majority of the 134 K. pneumoniae and 5 K. quasipneumoniae isolates from Nigeria characterized are closely related to globally disseminated multidrug-resistant clones. Of the 39 K. pneumoniae sequence types (STs) identified, the most common were ST307 (15%), ST5241 (12%), ST15 (~9%), and ST25 (~6%). ST5241, 1 of 10 novel STs detected, is a single locus variant of ST636 carrying dfrA14, tetD, qnrS, and oqxAB resistance genes. The extended-spectrum β-lactamase (ESBL) gene blaCTX_M-15 was seen in 72% of K. pneumoniae genomes, while 8% encoded a carbapenemase. No isolate carried a combination of carbapenemase-producing genes. Four likely outbreak clusters from 1 facility, within STs 17, 25, 307, and 5241, were ESBL but not carbapenemase-bearing clones.

Conclusions: This study uncovered known and novel K. pneumoniae lineages circulating in 3 hospitals in Southwest Nigeria that include multidrug-resistant ESBL producers. Carbapenemase-producing isolates remain uncommon. WGS retrospectively identified outbreak clusters, pointing to the value of genomic approaches in AMR surveillance for improving infection prevention and control in Nigerian hospitals.
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http://dx.doi.org/10.1093/cid/ciab769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634535PMC
December 2021

Integrating Scalable Genome Sequencing Into Microbiology Laboratories for Routine Antimicrobial Resistance Surveillance.

Clin Infect Dis 2021 Dec;73(Supplement_4):S258-S266

Centre for Genomic Pathogen Surveillance, Big Data Institute, University of Oxford, Old Road Campus, Oxford, United Kingdom.

Antimicrobial resistance (AMR) is considered a global threat, and novel drug discovery needs to be complemented with systematic and standardized epidemiological surveillance. Surveillance data are currently generated using phenotypic characterization. However, due to poor scalability, this approach does little for true epidemiological investigations. There is a strong case for whole-genome sequencing (WGS) to enhance the phenotypic data. To establish global AMR surveillance using WGS, we developed a laboratory implementation approach that we applied within the NIHR Global Health Research Unit (GHRU) on Genomic Surveillance of Antimicrobial Resistance. In this paper, we outline the laboratory implementation at 4 units: Colombia, India, Nigeria, and the Philippines. The journey to embedding WGS capacity was split into 4 phases: Assessment, Assembly, Optimization, and Reassessment. We show that on-boarding WGS capabilities can greatly enhance the real-time processing power within regional and national AMR surveillance initiatives, despite the high initial investment in laboratory infrastructure and maintenance. Countries looking to introduce WGS as a surveillance tool could begin by sequencing select Global Antimicrobial Resistance Surveillance System (GLASS) priority pathogens that can demonstrate the standardization and impact genome sequencing has in tackling AMR.
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http://dx.doi.org/10.1093/cid/ciab796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634525PMC
December 2021

Complexity of Genomic Epidemiology of Carbapenem-Resistant Klebsiella pneumoniae Isolates in Colombia Urges the Reinforcement of Whole Genome Sequencing-Based Surveillance Programs.

Clin Infect Dis 2021 Dec;73(Supplement_4):S290-S299

Colombian Integrated Program for Antimicrobial Resistance Surveillance (COIPARS), CI Tibaitatá, Corporación Colombiana de Investigación Agropecuaria (AGROSAVIA), Tibaitatá - Mosquera, Cundinamarca, Colombia.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an emerging public health problem. This study explores the specifics of CRKP epidemiology in Colombia based on whole genome sequencing (WGS) of the National Reference Laboratory at Instituto Nacional de Salud (INS)'s 2013-2017 sample collection.

Methods: A total of 425 CRKP isolates from 21 departments were analyzed by HiSeq-X10®Illumina high-throughput sequencing. Bioinformatic analysis was performed, primarily using the pipelines developed collaboratively by the National Institute for Health Research Global Health Research Unit (GHRU) on Genomic Surveillance of Antimicrobial Resistance (AMR), and AGROSAVIA.

Results: Of the 425 CRKP isolates, 91.5% were carbapenemase-producing strains. The data support a recent expansion and the endemicity of CRKP in Colombia with the circulation of 7 high-risk clones, the most frequent being CG258 (48.39% of isolates). We identified genes encoding carbapenemases blaKPC-3, blaKPC-2, blaNDM-1, blaNDM-9, blaVIM-2, blaVIM-4, and blaVIM-24, and various mobile genetic elements (MGE). The virulence of CRKP isolates was low, but colibactin (clb3) was present in 25.2% of isolates, and a hypervirulent CRKP clone (CG380) was reported for the first time in Colombia. ST258, ST512, and ST4851 were characterized by low levels of diversity in the core genome (ANI > 99.9%).

Conclusions: The study outlines complex CRKP epidemiology in Colombia. CG258 expanded clonally and carries specific carbapenemases in specific MGEs, while the other high-risk clones (CG147, CG307, and CG152) present a more diverse complement of carbapenemases. The specifics of the Colombian situation stress the importance of WGS-based surveillance to monitor evolutionary trends of sequence types (STs), MGE, and resistance and virulence genes.
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http://dx.doi.org/10.1093/cid/ciab777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634422PMC
December 2021

Genome Sequencing Identifies Previously Unrecognized Klebsiella pneumoniae Outbreaks in Neonatal Intensive Care Units in the Philippines.

Clin Infect Dis 2021 Dec;73(Supplement_4):S316-S324

Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridge, UK.

Background: Klebsiella pneumoniae is a critically important pathogen in the Philippines. Isolates are commonly resistant to at least 2 classes of antibiotics, yet mechanisms and spread of its resistance are not well studied.

Methods: A retrospective sequencing survey was performed on carbapenem-, extended spectrum beta-lactam-, and cephalosporin-resistant Klebsiella pneumoniae isolated at 20 antimicrobial resistance (AMR) surveillance sentinel sites from 2015 through 2017. We characterized 259 isolates using biochemical methods, antimicrobial susceptibility testing, and whole-genome sequencing (WGS). Known AMR mechanisms were identified. Potential outbreaks were investigated by detecting clusters from epidemiologic, phenotypic, and genome-derived data.

Results: Prevalent AMR mechanisms detected include blaCTX-M-15 (76.8%) and blaNDM-1 (37.5%). An epidemic IncFII(Yp) plasmid carrying blaNDM-1 was also detected in 46 isolates from 6 sentinel sites and 14 different sequence types (STs). This plasmid was also identified as the main vehicle of carbapenem resistance in 2 previously unrecognized local outbreaks of ST348 and ST283 at 2 different sentinel sites. A third local outbreak of ST397 was also identified but without the IncFII(Yp) plasmid. Isolates in each outbreak site showed identical STs and K- and O-loci, and similar resistance profiles and AMR genes. All outbreak isolates were collected from blood of children aged < 1 year.

Conclusion: WGS provided a better understanding of the epidemiology of multidrug resistant Klebsiella in the Philippines, which was not possible with only phenotypic and epidemiologic data. The identification of 3 previously unrecognized Klebsiella outbreaks highlights the utility of WGS in outbreak detection, as well as its importance in public health and in implementing infection control programs.
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http://dx.doi.org/10.1093/cid/ciab776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634409PMC
December 2021

Good Financial Grant Practice: A Tool for Developing and Demonstrating Institutional Financial and Grant Management Capacity in Global Health.

Clin Infect Dis 2021 Dec;73(Supplement_4):S275-S282

Oxford Big Data Institute, University of Oxford, Oxford, United Kingdom; Wellcome Genome Campus, Hinxton, United Kingdom.

The administration and governance of grant funding across global health organizations presents enormous challenges. Meeting these challenges is crucial to ensuring that funds are used in the most effective way to improve health outcomes, in line with the United Nations' Sustainable Development Goal 3, "Ensure healthy lives and promote well-being for all at all ages." The Good Financial Grant Practice (GFGP) Standard (ARS 1651) is the world's first and, currently, only international standard for the financial governance and management of grant funding. Through consensus building and global harmonization between both low- and middle-income and high-income country players, the GFGP Standard has achieved a leveling impact: GFGP applies equally to, and can be implemented by, all types of organization, regardless of location, size, or whether they predominantly give or receive funding. GFGP can be used as a tool for addressing some of the challenges of the current funding model. Here, we describe our experiences and lessons learned from implementing GFGP across 4 diverse research institutions in India, Nigeria, Colombia, and the Philippines as part of our National Institute for Health Research Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance.
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http://dx.doi.org/10.1093/cid/ciab768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634540PMC
December 2021

High-Resolution Genomic Profiling of Carbapenem-Resistant Klebsiella pneumoniae Isolates: A Multicentric Retrospective Indian Study.

Clin Infect Dis 2021 Dec;73(Supplement_4):S300-S307

Central Research Laboratory, Kempegowda Institute of Medical Sciences, Bengaluru, India.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a threat to public health in India because of its high dissemination, mortality, and limited treatment options. Its genomic variability is reflected in the diversity of sequence types, virulence factors, and antimicrobial resistance (AMR) mechanisms. This study aims to characterize the clonal relationships and genetic mechanisms of resistance and virulence in CRKP isolates in India.

Materials And Methods: We characterized 344 retrospective K. pneumoniae clinical isolates collected from 8 centers across India collected in 2013-2019. Susceptibility to antibiotics was tested with VITEK 2. Capsular types, multilocus sequence type, virulence genes, AMR determinants, plasmid replicon types, and a single-nucleotide polymorphism phylogeny were inferred from their whole genome sequences.

Results: Phylogenetic analysis of the 325 Klebsiella isolates that passed quality control revealed 3 groups: K. pneumoniae sensu stricto (n = 307), K. quasipneumoniae (n = 17), and K. variicola (n = 1). Sequencing and capsular diversity analysis of the 307 K. pneumoniae sensu stricto isolates revealed 28 sequence types, 26 K-locus types, and 11 O-locus types, with ST231, KL51, and O1V2 being predominant. blaOXA-48-like and blaNDM-1/5 were present in 73.2% and 24.4% of isolates, respectively. The major plasmid replicon types associated with carbapenase genes were IncF (51.0%) and Col group (35.0%).

Conclusion: Our study documents for the first time the genetic diversity of K and O antigens circulating in India. The results demonstrate the practical applicability of genomic surveillance and its utility in tracking the population dynamics of CRKP. It alerts us to the urgency for longitudinal surveillance of these transmissible lineages.
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http://dx.doi.org/10.1093/cid/ciab767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634558PMC
December 2021

Train-the-Trainer as an Effective Approach to Building Global Networks of Experts in Genomic Surveillance of Antimicrobial Resistance (AMR).

Clin Infect Dis 2021 Dec;73(Supplement_4):S283-S289

Centre for Genomic Pathogen Surveillance, Big Data Institute, University of Oxford, Oxford, UK, and Wellcome Genome Campus, Hinxton, UK.

Advanced genomics and sequencing technologies are increasingly becoming critical for global health applications such as pathogen and antimicrobial resistance (AMR) surveillance. Limited resources challenge capacity development in low- and middle-income countries (LMICs), with few countries having genomics facilities and adequately trained staff. Training research and public health experts who are directly involved in the establishment of such facilities offers an effective, but limited, solution to a growing need. Instead, training them to impart their knowledge and skills to others provides a sustainable model for scaling up the much needed capacity and capability for genomic sequencing and analysis locally with global impact. We designed and developed a Train-the-Trainer course integrating pedagogical aspects with genomic and bioinformatics activities. The course was delivered to 18 participants from 12 countries in Africa, Asia, and Latin America. A combination of teaching strategies culminating in a group project created a foundation for continued development at home institutions. Upon follow-up after 6 months, at least 40% of trainees had initiated training programs and collaborations to build capacity at local, national, and regional level. This work provides a framework for implementing a training and capacity building program for the application of genomics tools and resources in AMR surveillance.
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http://dx.doi.org/10.1093/cid/ciab770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634536PMC
December 2021

Implementing Whole-Genome Sequencing for Ongoing Surveillance of Antimicrobial Resistance: Exemplifying Insights Into Klebsiella pneumoniae.

Clin Infect Dis 2021 Dec;73(Supplement_4):S255-S257

Central Research Laboratory, Kempegowda Institute of Medical Sciences, Bengaluru, India.

In this Supplement, we detail outputs of the National Institute for Health Research Global Health Research Unit on Genomic Surveillance of Antimicrobial Resistance project, covering practical implementation of whole-genome sequencing across our consortium, which consists of laboratories in Colombia, India, Nigeria, and the Philippines.
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http://dx.doi.org/10.1093/cid/ciab795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634455PMC
December 2021

High-resolution sweep metagenomics using fast probabilistic inference.

Wellcome Open Res 2020 8;5:14. Epub 2021 Oct 8.

Helsinki Institute for Information Technology HIIT, Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland.

Determining the composition of bacterial communities beyond the level of a genus or species is challenging because of the considerable overlap between genomes representing close relatives. Here, we present the mSWEEP pipeline for identifying and estimating the relative sequence abundances of bacterial lineages from plate sweeps of enrichment cultures. mSWEEP leverages biologically grouped sequence assembly databases, applying probabilistic modelling, and provides controls for false positive results. Using sequencing data from major pathogens, we demonstrate significant improvements in lineage quantification and detection accuracy. Our pipeline facilitates investigating cultures comprising mixtures of bacteria, and opens up a new field of plate sweep metagenomics.
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http://dx.doi.org/10.12688/wellcomeopenres.15639.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543175PMC
October 2021

Circulation of third-generation cephalosporin resistant Salmonella Typhi in Mumbai, India.

Clin Infect Dis 2021 Oct 9. Epub 2021 Oct 9.

Central Research Laboratory, Kempegowda Institute of Medical Sciences, Bengaluru, India.

We report the persistent circulation of third-generation cephalosporin resistant Salmonella Typhi in Mumbai, linked to the acquisition and maintenance of a previously characterized IncX3 plasmid carrying the ESBL gene blaSHV-12 and the fluoroquinolone resistance gene qnrB7 in the genetic context of a triple mutant also associated with fluoroquinolone resistance.
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http://dx.doi.org/10.1093/cid/ciab897DOI Listing
October 2021

Genomic surveillance of in the Philippines, 2013-2014.

Western Pac Surveill Response J 2021 Apr-Jun;12(2):4-18. Epub 2021 Apr 28.

Antimicrobial Resistance Surveillance Reference Laboratory, Research Institute for Tropical Medicine, Muntinlupa, Philippines.

is an opportunistic pathogen that often causes nosocomial infections resistant to treatment. Rates of antimicrobial resistance (AMR) are increasing, as are rates of multidrug-resistant (MDR) and possible extensively drug-resistant (XDR) infections. Our objective was to characterize the molecular epidemiology and AMR mechanisms of this pathogen. We sequenced the whole genome for each of 176 isolates collected in the Philippines in 2013-2014; derived the multilocus sequence type (MLST), presence of AMR determinants and relatedness between isolates; and determined concordance between phenotypic and genotypic resistance. Carbapenem resistance was associated with loss of function of the OprD porin and acquisition of the metallo-β-lactamase (MBL) gene . Concordance between phenotypic and genotypic resistance was 93.27% overall for six antibiotics in three classes, but varied among aminoglycosides. The population of was diverse, with clonal expansions of XDR genomes belonging to MLSTs ST235, ST244, ST309 and ST773. We found evidence of persistence or reintroduction of the predominant clone ST235 in one hospital, and of transfer between hospitals. Most of the ST235 genomes formed a distinct lineage from global genomes, thus raising the possibility that they may be unique to the Philippines. In addition, long-read sequencing of one representative XDR ST235 isolate identified an integron carrying multiple resistance genes (including ), with differences in gene composition and synteny from the class 1 integrons described previously. The survey bridges the gap in genomic data from the Western Pacific Region and will be useful for ongoing surveillance; it also highlights the importance of curtailing the spread of ST235 within the Philippines.
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http://dx.doi.org/10.5365/wpsar.2020.11.1.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421739PMC
October 2021

Assignment of epidemiological lineages in an emerging pandemic using the pangolin tool.

Virus Evol 2021 30;7(2):veab064. Epub 2021 Jul 30.

Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH93FL, UK.

The response of the global virus genomics community to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been unprecedented, with significant advances made towards the 'real-time' generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude of more genomes than previously available. Here, we present and describe Phylogenetic Assignment of Named Global Outbreak Lineages (pangolin), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic lineage nomenclature scheme. To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic's transmission lineages.
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http://dx.doi.org/10.1093/ve/veab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344591PMC
July 2021

Spatiotemporal invasion dynamics of SARS-CoV-2 lineage B.1.1.7 emergence.

Science 2021 08 22;373(6557):889-895. Epub 2021 Jul 22.

Instituto de Medicina Tropical, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil.

Understanding the causes and consequences of the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern is crucial to pandemic control yet difficult to achieve because they arise in the context of variable human behavior and immunity. We investigated the spatial invasion dynamics of lineage B.1.1.7 by jointly analyzing UK human mobility, virus genomes, and community-based polymerase chain reaction data. We identified a multistage spatial invasion process in which early B.1.1.7 growth rates were associated with mobility and asymmetric lineage export from a dominant source location, enhancing the effects of B.1.1.7's increased intrinsic transmissibility. We further explored how B.1.1.7 spread was shaped by nonpharmaceutical interventions and spatial variation in previous attack rates. Our findings show that careful accounting of the behavioral and epidemiological context within which variants of concern emerge is necessary to interpret correctly their observed relative growth rates.
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http://dx.doi.org/10.1126/science.abj0113DOI Listing
August 2021

CLIMB-COVID: continuous integration supporting decentralised sequencing for SARS-CoV-2 genomic surveillance.

Genome Biol 2021 07 1;22(1):196. Epub 2021 Jul 1.

Institute of Microbiology and Infection, University of Birmingham, Birmingham, UK.

In response to the ongoing SARS-CoV-2 pandemic in the UK, the COVID-19 Genomics UK (COG-UK) consortium was formed to rapidly sequence SARS-CoV-2 genomes as part of a national-scale genomic surveillance strategy. The network consists of universities, academic institutes, regional sequencing centres and the four UK Public Health Agencies. We describe the development and deployment of CLIMB-COVID, an encompassing digital infrastructure to address the challenge of collecting and integrating both genomic sequencing data and sample-associated metadata produced across the COG-UK network.
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http://dx.doi.org/10.1186/s13059-021-02395-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247108PMC
July 2021

Genomic surveillance of methicillin-resistant in the Philippines, 
2013-2014.

Western Pac Surveill Response J 2021 Jan-Mar;12(1):6-16. Epub 2021 Feb 26.

Antimicrobial Resistance Surveillance Reference Laboratory, Research Institute for Tropical Medicine, Muntinlupa, Philippines.

Methicillin-resistant (MRSA) remains one of the leading causes of both nosocomial and community infections worldwide. In the Philippines, MRSA rates have remained above 50% since 2010, but resistance to other antibiotics, including vancomycin, is low. The MRSA burden can be partially attributed to pathogen-specific characteristics of the circulating clones, but little was known about the clones circulating in the Philippines. We sequenced the whole genomes of 116 isolates collected in 2013-2014 within the Antimicrobial Resistance Surveillance Program. The multilocus sequence type, type, SCC type, presence of antimicrobial resistance (AMR) determinants and virulence genes and relatedness between the isolates were all derived from the sequence data. The concordance between phenotypic and genotypic resistance was also determined. The MRSA population in the Philippines comprised a limited number of genetic clones, including several international epidemic clones, such as CC30--t019-SCC-IV-PVL+, CC5-SCC-typeIV and ST239--t030-SCC-typeIII. The CC30 genomes were related to the South-West Pacific clone but formed a distinct, diverse lineage, with evidence of global dissemination. We showed independent acquisition of resistance to sulfamethoxazole/trimethoprim in various locations and genetic clones but mostly in paediatric patients with invasive infections. The concordance between phenotypic and genotypic resistance was 99.68% overall for eight antibiotics in seven classes. We have made the first comprehensive genomic survey of S. aureus in the Philippines, which bridges the gap in genomic data from the Western Pacific Region and will constitute the genetic background for contextualizing prospective surveillance.
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http://dx.doi.org/10.5365/wpsar.2020.11.1.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143927PMC
August 2021

Protocol for an interdisciplinary cross-sectional study investigating the social, biological and community-level drivers of antimicrobial resistance (AMR): Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA).

BMJ Open 2021 03 8;11(3):e041418. Epub 2021 Mar 8.

School of Medicine, University of St Andrews, St Andrews, UK.

Introduction: Antimicrobial resistance (AMR) is a global health threat that requires urgent research using a multidisciplinary approach. The biological drivers of AMR are well understood, but factors related to treatment seeking and the social contexts of antibiotic (AB) use behaviours are less understood. Here we describe the Holistic Approach to Unravel Antibacterial Resistance in East Africa, a multicentre consortium that investigates the diverse drivers of drug resistance in urinary tract infections (UTIs) in East Africa.

Methods And Analysis: This study will take place in Uganda, Kenya and Tanzania. We will conduct geospatial mapping of AB sellers, and conduct mystery client studies and in-depth interviews (IDIs) with drug sellers to investigate AB provision practices. In parallel, we will conduct IDIs with doctors, alongside community focus groups. Clinically diagnosed patients with UTI will be recruited from healthcare centres, provide urine samples and complete a questionnaire capturing retrospective treatment pathways, sociodemographic characteristics, attitudes and knowledge. Bacterial isolates from urine and stool samples will be subject to culture and antibiotic sensitivity testing. Genomic DNA from bacterial isolates will be extracted with a subset being sequenced. A follow-up household interview will be conducted with 1800 UTI-positive patients, where further environmental samples will be collected. A subsample of patients will be interviewed using qualitative tools. Questionnaire data, microbiological analysis and qualitative data will be linked at the individual level. Quantitative data will be analysed using statistical modelling, including Bayesian network analysis, and all forms of qualitative data analysed through iterative thematic content analysis.

Ethics And Dissemination: Approvals have been obtained from all national and local ethical review bodies in East Africa and the UK. Results will be disseminated in communities, with local and global policy stakeholders, and in academic circles. They will have great potential to inform policy, improve clinical practice and build regional pathogen surveillance capacity.
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http://dx.doi.org/10.1136/bmjopen-2020-041418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942251PMC
March 2021

A global resource for genomic predictions of antimicrobial resistance and surveillance of Salmonella Typhi at pathogenwatch.

Nat Commun 2021 05 17;12(1):2879. Epub 2021 May 17.

Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK.

As whole-genome sequencing capacity becomes increasingly decentralized, there is a growing opportunity for collaboration and the sharing of surveillance data within and between countries to inform typhoid control policies. This vision requires free, community-driven tools that facilitate access to genomic data for public health on a global scale. Here we present the Pathogenwatch scheme for Salmonella enterica serovar Typhi (S. Typhi), a web application enabling the rapid identification of genomic markers of antimicrobial resistance (AMR) and contextualization with public genomic data. We show that the clustering of S. Typhi genomes in Pathogenwatch is comparable to established bioinformatics methods, and that genomic predictions of AMR are highly concordant with phenotypic susceptibility data. We demonstrate the public health utility of Pathogenwatch with examples selected from >4,300 public genomes available in the application. Pathogenwatch provides an intuitive entry point to monitor of the emergence and spread of S. Typhi high risk clones.
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http://dx.doi.org/10.1038/s41467-021-23091-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128892PMC
May 2021

A community-driven resource for genomic epidemiology and antimicrobial resistance prediction of Neisseria gonorrhoeae at Pathogenwatch.

Genome Med 2021 04 19;13(1):61. Epub 2021 Apr 19.

Centre for Genomic Pathogen Surveillance, Big Data Institute, Nuffield Department of Medicine, University of Oxford, Oxford, Oxfordshire, UK.

Background: Antimicrobial-resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last-line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. Whole genome sequencing (WGS) data can be used to identify new AMR clones and transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community-driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance.

Methods: Here we present a public health-focussed scheme for genomic epidemiology of N. gonorrhoeae at Pathogenwatch ( https://pathogen.watch/ngonorrhoeae ). An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to inform on the utility of current and future analytics in the platform. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants linked to a genotypic prediction of resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization.

Results: AMR prediction from genome data revealed specificity values over 99% for azithromycin, ciprofloxacin and ceftriaxone and sensitivity values around 99% for benzylpenicillin and tetracycline. A case study using the Pathogenwatch collection of N. gonorrhoeae public genomes showed the global expansion of an azithromycin-resistant lineage carrying a mosaic mtr over at least the last 10 years, emphasising the power of Pathogenwatch to explore and evaluate genomic epidemiology questions of public health concern.

Conclusions: The N. gonorrhoeae scheme in Pathogenwatch provides customised bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower-resourced settings with internet connection but limited computational infrastructure. The advisory group will assess and identify ongoing public health needs in the field of gonorrhoea, particularly regarding gonococcal AMR, in order to further enhance utility with modified or new analytic methods.
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http://dx.doi.org/10.1186/s13073-021-00858-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054416PMC
April 2021

Population genomics and antimicrobial resistance dynamics of Escherichia coli in wastewater and river environments.

Commun Biol 2021 04 12;4(1):457. Epub 2021 Apr 12.

Antimicrobial Resistance Unit (ARU), Animal Health Department, Faculty of Veterinary Medicine and VISAVET Health Surveillance Centre, Complutense University of Madrid, Madrid, Spain.

Aquatic environments are key niches for the emergence, evolution and dissemination of antimicrobial resistance. However, the population diversity and the genetic elements that drive the dynamics of resistant bacteria in different aquatic environments are still largely unknown. The aim of this study was to understand the population genomics and evolutionary events of Escherichia coli resistant to clinically important antibiotics including aminoglycosides, in anthropogenic and natural water ecosystems. Here we show that less different E. coli sequence types (STs) are identified in wastewater than in rivers, albeit more resistant to antibiotics, and with significantly more plasmids/cell (6.36 vs 3.72). However, the genomic diversity within E. coli STs in both aquatic environments is similar. Wastewater environments favor the selection of conserved chromosomal structures associated with diverse flexible plasmids, unraveling promiscuous interplasmidic resistance genes flux. On the contrary, the key driver for river E. coli adaptation is a mutable chromosome along with few plasmid types shared between diverse STs harboring a limited resistance gene content.
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http://dx.doi.org/10.1038/s42003-021-01949-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041779PMC
April 2021

Genomic Epidemiology of CC30 Methicillin-Resistant Staphylococcus aureus Strains from Argentina Reveals Four Major Clades with Distinctive Genetic Features.

mSphere 2021 03 10;6(2). Epub 2021 Mar 10.

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Buenos Aires, Argentina

clonal complex 30 (CC30) has given rise to epidemics worldwide and is one of the most prevalent lineages in Argentina, represented by sequence type 30 methicillin-resistant SCC type IV (ST30-MRSA-IV). ST30-MRSA-IV has displaced previous prevalent clones in the country and demonstrated increased virulence. Despite the burden of infections caused by ST30-MRSA-IV both in hospitals and in communities in Argentina, no detailed genome-based characterization of this clone is available to date. In this study, we used whole-genome sequencing (WGS) to evaluate the genetic diversity, population structure, and genomic characteristics of 190 CC30-MRSA strains circulating in Argentina between 2004 and 2015. Phylogenetic analysis revealed the existence of 4 major clades: ARG-1 (CC30-MRSA-IVc- t012), ARG-2 (ST30-MRSA-IVc- t021 related), ARG-3 (ST30-MRSA-IVh/j- t021 and related), and ARG-4 (CC30-MRSA-IVc- t019 and related). The clades were characterized by different distributions of antimicrobial resistance determinants, virulence genes, and mobile genetic elements (MGEs). While ARG-1 and ARG-4 were related to global epidemic MRSA-16 (EMRSA-16) and South West Pacific (SWP) clones, respectively, ARG-3 was phylogenetically distinct from previously defined CC30 epidemic clones. ARG-4, the most prevalent and geographically disseminated in the collection ( = 164), was characterized by specific MGEs and chromosomal mutations that might have contributed to its virulence and success. To our knowledge, this is the first genomic epidemiology study of CC30-MRSA in Argentina, which will serve as baseline genomic data going forward to inform public health measures for infection prevention and control. The rise in prevalence of community-associated methicillin-resistant (CA-MRSA) is of public health concern. In Argentina, several studies documented a shift in the epidemiology of CA-MRSA since 2009, with clonal complex 30 (CC30) and, in particular, sequence type 30 MRSA SCC type IV (ST30-MRSA-IV) replacing other clones both in communities and in hospitals and possibly displaying increased virulence. By sequencing the whole genomes of 190 CC30 MRSA isolates recovered from Argentina between 2005 and 2015, we showed that they represented a diverse population composed of 4 major clades. The predominant clade evolved from the South West Pacific clone but has acquired a distinct repertoire of mobile genetic elements, virulence genes, and chromosomal mutations that might play a role in its success. Our work is the first extensive genomic study of CC30 in Argentina and will contribute not only to the development of genomic surveillance in the region but also to our understanding of the global epidemiology of this pathogen.
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http://dx.doi.org/10.1128/mSphere.01297-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546718PMC
March 2021

Globetrotting strangles: the unbridled national and international transmission of between horses.

Microb Genom 2021 03 8;7(3). Epub 2021 Mar 8.

Labor Dr Böse GmbH, Harsum, Germany.

The equine disease strangles, which is characterized by the formation of abscesses in the lymph nodes of the head and neck, is one of the most frequently diagnosed infectious diseases of horses around the world. The causal agent, subspecies , establishes a persistent infection in approximately 10 % of animals that recover from the acute disease. Such 'carrier' animals appear healthy and are rarely identified during routine veterinary examinations pre-purchase or transit, but can transmit to naïve animals initiating new episodes of disease. Here, we report the analysis and visualization of phylogenomic and epidemiological data for 670 isolates of recovered from 19 different countries using a new core-genome multilocus sequence typing (cgMLST) web bioresource. Genetic relationships among all 670 S. isolates were determined at high resolution, revealing national and international transmission events that drive this endemic disease in horse populations throughout the world. Our data argue for the recognition of the international importance of strangles by the Office International des Épizooties to highlight the health, welfare and economic cost of this disease. The Pathogenwatch cgMLST web bioresource described herein is available for tailored genomic analysis of populations of and its close relative subspecies that are recovered from horses and other animals, including humans, throughout the world. This article contains data hosted by Microreact.
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http://dx.doi.org/10.1099/mgen.0.000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190609PMC
March 2021

Establishment and lineage dynamics of the SARS-CoV-2 epidemic in the UK.

Science 2021 02 8;371(6530):708-712. Epub 2021 Jan 8.

Department of Zoology, University of Oxford, Oxford, UK.

The United Kingdom's COVID-19 epidemic during early 2020 was one of world's largest and was unusually well represented by virus genomic sampling. We determined the fine-scale genetic lineage structure of this epidemic through analysis of 50,887 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes, including 26,181 from the UK sampled throughout the country's first wave of infection. Using large-scale phylogenetic analyses combined with epidemiological and travel data, we quantified the size, spatiotemporal origins, and persistence of genetically distinct UK transmission lineages. Rapid fluctuations in virus importation rates resulted in >1000 lineages; those introduced prior to national lockdown tended to be larger and more dispersed. Lineage importation and regional lineage diversity declined after lockdown, whereas lineage elimination was size-dependent. We discuss the implications of our genetic perspective on transmission dynamics for COVID-19 epidemiology and control.
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http://dx.doi.org/10.1126/science.abf2946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877493PMC
February 2021

The changing epidemiology of carbapenemase-producing Klebsiella pneumoniae in Italy: toward polyclonal evolution with emergence of high-risk lineages.

J Antimicrob Chemother 2021 01;76(2):355-361

Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.

Background: Previous studies showed that the epidemic of carbapenem-resistant Klebsiella pneumoniae (CR-KP) observed in Italy since 2010 was sustained mostly by strains of clonal group (CG) 258 producing KPC-type carbapenemases. In the framework of the National Antibiotic-Resistance Surveillance (AR-ISS), a countrywide survey was conducted in 2016 to explore the evolution of the phenotypic and genotypic characteristics of CR-KP isolates.

Methods: From March to July 2016, hospital laboratories participating in AR-ISS were requested to provide consecutive, non-duplicated CR-KP (meropenem and/or imipenem MIC >1 mg/L) from invasive infections. Antibiotic susceptibility was determined according to EUCAST recommendations. A WGS approach was adopted to characterize the isolates by investigating phylogeny, resistome and virulome.

Results: Twenty-four laboratories provided 157 CR-KP isolates, of which 156 were confirmed as K. pneumoniae sensu stricto by WGS and found to carry at least one carbapenemase-encoding gene, corresponding in most cases (96.1%) to blaKPC. MLST- and SNP-based phylogeny revealed that 87.8% of the isolates clustered in four major lineages: CG258 (47.4%), with ST512 as the most common clone, CG307 (19.9%), ST101 (15.4%) and ST395 (5.1%). A close association was identified between lineages and antibiotic resistance phenotypes and genotypes, virulence traits and capsular types. Colistin resistance, mainly associated with mgrB mutations, was common in all major lineages except ST395.

Conclusions: This WGS-based survey showed that, although CG258 remained the most common CR-KP lineage in Italy, a polyclonal population has emerged with the spread of the new high-risk lineages CG307, ST101 and ST395, while KPC remained the most common carbapenemase.
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http://dx.doi.org/10.1093/jac/dkaa431DOI Listing
January 2021

Integrated chromosomal and plasmid sequence analyses reveal diverse modes of carbapenemase gene spread among .

Proc Natl Acad Sci U S A 2020 10 23;117(40):25043-25054. Epub 2020 Sep 23.

Centre for Genomic Pathogen Surveillance, Wellcome Genome Campus, Hinxton, CB10 1SA Cambridge, United Kingdom;

Molecular and genomic surveillance systems for bacterial pathogens currently rely on tracking clonally evolving lineages. By contrast, plasmids are usually excluded or analyzed with low-resolution techniques, despite being the primary vectors of antibiotic resistance genes across many key pathogens. Here, we used a combination of long- and short-read sequence data of isolates ( = 1,717) from a European survey to perform an integrated, continent-wide study of chromosomal and plasmid diversity. This revealed three contrasting modes of dissemination used by carbapenemase genes, which confer resistance to last-line carbapenems. First, genes have spread primarily via the single epidemic pOXA-48-like plasmid, which emerged recently in clinical settings and spread rapidly to numerous lineages. Second, and genes have spread via transient associations of many diverse plasmids with numerous lineages. Third, genes have transmitted predominantly by stable association with one successful clonal lineage (ST258/512) yet have been mobilized among diverse plasmids within this lineage. We show that these plasmids, which include pKpQIL-like and IncX3 plasmids, have a long association (and are coevolving) with the lineage, although frequent recombination and rearrangement events between them have led to a complex array of mosaic plasmids carrying Taken altogether, these results reveal the diverse trajectories of antibiotic resistance genes in clinical settings, summarized as using one plasmid/multiple lineages, multiple plasmids/multiple lineages, and multiple plasmids/one lineage. Our study provides a framework for the much needed incorporation of plasmid data into genomic surveillance systems, an essential step toward a more comprehensive understanding of resistance spread.
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http://dx.doi.org/10.1073/pnas.2003407117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587227PMC
October 2020

Integrating whole-genome sequencing within the National Antimicrobial Resistance Surveillance Program in the Philippines.

Nat Commun 2020 06 1;11(1):2719. Epub 2020 Jun 1.

Antimicrobial Resistance Surveillance Reference Laboratory, Research Institute for Tropical Medicine, Muntinlupa, The Philippines.

National networks of laboratory-based surveillance of antimicrobial resistance (AMR) monitor resistance trends and disseminate these data to AMR stakeholders. Whole-genome sequencing (WGS) can support surveillance by pinpointing resistance mechanisms and uncovering transmission patterns. However, genomic surveillance is rare in low- and middle-income countries. Here, we implement WGS within the established Antimicrobial Resistance Surveillance Program of the Philippines via a binational collaboration. In parallel, we characterize bacterial populations of key bug-drug combinations via a retrospective sequencing survey. By linking the resistance phenotypes to genomic data, we reveal the interplay of genetic lineages (strains), AMR mechanisms, and AMR vehicles underlying the expansion of specific resistance phenotypes that coincide with the growing carbapenem resistance rates observed since 2010. Our results enhance our understanding of the drivers of carbapenem resistance in the Philippines, while also serving as the genetic background to contextualize ongoing local prospective surveillance.
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http://dx.doi.org/10.1038/s41467-020-16322-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264328PMC
June 2020

Visualizing variation within Global Pneumococcal Sequence Clusters (GPSCs) and country population snapshots to contextualize pneumococcal isolates.

Microb Genom 2020 05 29;6(5). Epub 2020 Apr 29.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, and the NIHR Oxford Biomedical Research Centre, Oxford, UK.

Knowledge of pneumococcal lineages, their geographic distribution and antibiotic resistance patterns, can give insights into global pneumococcal disease. We provide interactive bioinformatic outputs to explore such topics, aiming to increase dissemination of genomic insights to the wider community, without the need for specialist training. We prepared 12 country-specific phylogenetic snapshots, and international phylogenetic snapshots of 73 common Global Pneumococcal Sequence Clusters (GPSCs) previously defined using PopPUNK, and present them in Microreact. Gene presence and absence defined using Roary, and recombination profiles derived from Gubbins are presented in Phandango for each GPSC. Temporal phylogenetic signal was assessed for each GPSC using BactDating. We provide examples of how such resources can be used. In our example use of a country-specific phylogenetic snapshot we determined that serotype 14 was observed in nine unrelated genetic backgrounds in South Africa. The international phylogenetic snapshot of GPSC9, in which most serotype 14 isolates from South Africa were observed, highlights that there were three independent sub-clusters represented by South African serotype 14 isolates. We estimated from the GPSC9-dated tree that the sub-clusters were each established in South Africa during the 1980s. We show how recombination plots allowed the identification of a 20 kb recombination spanning the capsular polysaccharide locus within GPSC97. This was consistent with a switch from serotype 6A to 19A estimated to have occured in the 1990s from the GPSC97-dated tree. Plots of gene presence/absence of resistance genes (, , ) across the GPSC23 phylogeny were consistent with acquisition of a composite transposon. We estimated from the GPSC23-dated tree that the acquisition occurred between 1953 and 1975. Finally, we demonstrate the assignment of GPSC31 to 17 externally generated pneumococcal serotype 1 assemblies from Utah via Pathogenwatch. Most of the Utah isolates clustered within GPSC31 in a USA-specific clade with the most recent common ancestor estimated between 1958 and 1981. The resources we have provided can be used to explore to data, test hypothesis and generate new hypotheses. The accessible assignment of GPSCs allows others to contextualize their own collections beyond the data presented here.
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http://dx.doi.org/10.1099/mgen.0.000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371119PMC
May 2020

Epidemic of carbapenem-resistant Klebsiella pneumoniae in Europe is driven by nosocomial spread.

Nat Microbiol 2019 11 29;4(11):1919-1929. Epub 2019 Jul 29.

Institute for Infection Prevention and Hospital Epidemiology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Public health interventions to control the current epidemic of carbapenem-resistant Klebsiella pneumoniae rely on a comprehensive understanding of its emergence and spread over a wide range of geographical scales. We analysed the genome sequences and epidemiological data of >1,700 K. pneumoniae samples isolated from patients in 244 hospitals in 32 countries during the European Survey of Carbapenemase-Producing Enterobacteriaceae. We demonstrate that carbapenemase acquisition is the main cause of carbapenem resistance and that it occurred across diverse phylogenetic backgrounds. However, 477 of 682 (69.9%) carbapenemase-positive isolates are concentrated in four clonal lineages, sequence types 11, 15, 101, 258/512 and their derivatives. Combined analysis of the genetic and geographic distances between isolates with different β-lactam resistance determinants suggests that the propensity of K. pneumoniae to spread in hospital environments correlates with the degree of resistance and that carbapenemase-positive isolates have the highest transmissibility. Indeed, we found that over half of the hospitals that contributed carbapenemase-positive isolates probably experienced within-hospital transmission, and interhospital spread is far more frequent within, rather than between, countries. Finally, we propose a value of 21 for the number of single nucleotide polymorphisms that optimizes the discrimination of hospital clusters and detail the international spread of the successful epidemic lineage, ST258/512.
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http://dx.doi.org/10.1038/s41564-019-0492-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244338PMC
November 2019
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