A field guide to pandemic, epidemic and sporadic clones of methicillin-resistant Staphylococcus aureus
Dresden University of Technology1, Royal Perth Hospital2, Trinity College, Dublin3, University of the West Indies4, Mater Dei Hospital5, The Chinese University of Hong Kong6, Friedrich Loeffler Institute7, Health Protection Agency8, University of Lyon9, Curtin University10, Shaikh Khalifa Medical City11
TL;DR: A high level of biodiversity among MRSA, especially among strains harbouring SCCmec IV and V elements is shown, and the data indicate a high rate of genetic recombination in MRSA involving SCC elements, bacteriophages or other mobile genetic elements and large-scale chromosomal replacements.
Abstract: In recent years, methicillin-resistant Staphylococcus aureus (MRSA) have become a truly global challenge. In addition to the long-known healthcare-associated clones, novel strains have also emerged outside of the hospital settings, in the community as well as in livestock. The emergence and spread of virulent clones expressing Panton-Valentine leukocidin (PVL) is an additional cause for concern. In order to provide an overview of pandemic, epidemic and sporadic strains, more than 3,000 clinical and veterinary isolates of MRSA mainly from Germany, the United Kingdom, Ireland, France, Malta, Abu Dhabi, Hong Kong, Australia, Trinidad & Tobago as well as some reference strains from the United States have been genotyped by DNA microarray analysis. This technique allowed the assignment of the MRSA isolates to 34 distinct lineages which can be clearly defined based on non-mobile genes. The results were in accordance with data from multilocus sequence typing. More than 100 different strains were distinguished based on affiliation to these lineages, SCCmec type and the presence or absence of PVL. These strains are described here mainly with regard to clinically relevant antimicrobial resistance- and virulence-associated markers, but also in relation to epidemiology and geographic distribution. The findings of the study show a high level of biodiversity among MRSA, especially among strains harbouring SCCmec IV and V elements. The data also indicate a high rate of genetic recombination in MRSA involving SCC elements, bacteriophages or other mobile genetic elements and large-scale chromosomal replacements.
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TL;DR: The origin of MRSA is described, with emphasis on the diverse nature of staphylococcal cassette chromosome mec (SCCmec).
Abstract: SUMMARY Staphylococcus aureus, a major human pathogen, has a collection of virulence factors and the ability to acquire resistance to most antibiotics. This ability is further augmented by constant emergence of new clones, making S. aureus a “superbug.” Clinical use of methicillin has led to the appearance of methicillin-resistant S. aureus (MRSA). The past few decades have witnessed the existence of new MRSA clones. Unlike traditional MRSA residing in hospitals, the new clones can invade community settings and infect people without predisposing risk factors. This evolution continues with the buildup of the MRSA reservoir in companion and food animals. This review focuses on imparting a better understanding of MRSA evolution and its molecular characterization and epidemiology. We first describe the origin of MRSA, with emphasis on the diverse nature of staphylococcal cassette chromosome mec (SCCmec). mecA and its new homologues (mecB, mecC, and mecD), SCCmec types (13 SCCmec types have been discovered to date), and their classification criteria are discussed. The review then describes various typing methods applied to study the molecular epidemiology and evolutionary nature of MRSA. Starting with the historical methods and continuing to the advanced whole-genome approaches, typing of collections of MRSA has shed light on the origin, spread, and evolutionary pathways of MRSA clones.
776 citations
31 May 2018
TL;DR: The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes as discussed by the authors.
Abstract: Since the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) has emerged, disseminated globally and become a leading cause of bacterial infections in both health-care and community settings. However, there is marked geographical variation in MRSA burden owing to several factors, including differences in local infection control practices and pathogen-specific characteristics of the circulating clones. Different MRSA clones have resulted from the independent acquisition of staphylococcal cassette chromosome mec (SCCmec), which contains genes encoding proteins that render the bacterium resistant to most β-lactam antibiotics (such as methicillin), by several S. aureus clones. The success of MRSA is a consequence of the extensive arsenal of virulence factors produced by S. aureus combined with β-lactam resistance and, for most clones, resistance to other antibiotic classes. Clinical manifestations of MRSA range from asymptomatic colonization of the nasal mucosa to mild skin and soft tissue infections to fulminant invasive disease with high mortality. Although treatment options for MRSA are limited, several new antimicrobials are under development. An understanding of colonization dynamics, routes of transmission, risk factors for progression to infection and conditions that promote the emergence of resistance will enable optimization of strategies to effectively control MRSA. Vaccine candidates are also under development and could become an effective prevention measure.
650 citations
TL;DR: The group consensus was to recommend spa and staphylococcal cassette chromosome mec (SCCmec) typing as the preferred methods for MRSA, which are informative in defining particular strain characteristics and utilise standardised nomenclatures, making them applicable globally.
539 citations
Cites background from "A field guide to pandemic, epidemic..."
...Resistance to meticillin primarily derives from acquisition of the mecA gene, not native in this species, which codes a modified penicillin-binding protein (PBP2a) with low affinity for -lactams [3,5]....
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...CA-MRSA clones such as ST8 (USA300), ST30, ST59 nd ST80 have been spreading rapidly in the community and also nfiltrating health care in many regions worldwide....
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...ecently, inexpensive microarray-based analysis of over 3000 RSA isolates from many countries around the world showed otential for assigning isolates to lineages [3] as well as allowing imple analysis of the presence or absence of virulence and resisance genes encoded on MGEs....
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...Transatlantic spread of the USA300 clone of MRSA....
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...Most f these traits are located on mobile genetic elements (MGEs) on he genome [3,4]....
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TL;DR: Current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice are reviewed to give an overview of their specific advantages and disadvantages.
Abstract: Typing methods for discriminating different bacterial isolates of the same species are essential epidemiological tools in infection prevention and control. Traditional typing systems based on phenotypes, such as serotype, biotype, phage-type, or antibiogram, have been used for many years. However, more recent methods that examine the relatedness of isolates at a molecular level have revolutionised our ability to differentiate among bacterial types and subtypes. Importantly, the development of molecular methods has provided new tools for enhanced surveillance and outbreak detection. This has resulted in better implementation of rational infection control programmes and efficient allocation of resources across Europe. The emergence of benchtop sequencers using next generation sequencing technology makes bacterial whole genome sequencing (WGS) feasible even in small research and clinical laboratories. WGS has already been used for the characterisation of bacterial isolates in several large outbreaks in Europe and, in the near future, is likely to replace currently used typing methodologies due to its ultimate resolution. However, WGS is still too laborious and time-consuming to obtain useful data in routine surveillance. Also, a largely unresolved question is how genome sequences must be examined for epidemiological characterisation. In the coming years, the lessons learnt from currently used molecular methods will allow us to condense the WGS data into epidemiologically useful information. On this basis, we have reviewed current and new molecular typing methods for outbreak detection and epidemiological surveillance of bacterial pathogens in clinical practice, aiming to give an overview of their specific advantages and disadvantages.
490 citations
Cites background from "A field guide to pandemic, epidemic..."
...aureus covers 334 target sequences, including approximately 170 distinct genes and their allelic variants [77]....
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TL;DR: There is a detectable bacterial community within human lung tissue that changes in patients with very severe COPD.
Abstract: Rationale: Based on surface brushings and bronchoalveolar lavage fluid, Hilty and coworkers demonstrated microbiomes in the human lung characteristic of asthma and chronic obstructive pulmonary disease (COPD), which have now been confirmed by others. Objectives: To extend these findings to human lung tissue samples. Methods: DNA from lung tissue samples was obtained from nonsmokers (n ¼ 8); smokers without COPD (n ¼ 8); patients with very severe COPD (Global Initiative for COPD [GOLD] 4) (n ¼ 8); and patientswithcysticfibrosis(CF)(n¼8).Thelatterservedasapositive control, with sterile water as a negative control. All bacterial community analyses were based on polymerase chain reaction amplifying16SrRNAgenefragments.Totalbacterialpopulationsweremeasured by quantitative polymerase chain reaction and bacterial community composition was assessed by terminal restriction fragment length polymorphism analysis and pyrotag sequencing. MeasurementandMainResults:Totalbacterialpopulationswithinlung tissue were small (20‐1,252 bacterial cells per 1,000 human cells) but greater in all four sample groups versus the negative control group (P,0.001).Terminalrestrictionfragmentlengthpolymorphismanalysis and sequencing distinguished three distinct bacterial community compositions: one common to the nonsmoker and smoker groups, asecondtotheGOLD4group,andthethirdtotheCF-positivecontrol group. Pyrotag sequencing identified greater than 1,400 unique bacterial sequences and showed an increase in the Firmicutes phylum in GOLD4patientsversusall othergroups (P,0.003) attributable to an increase in the Lactobacillus genus (P , 0.0007).
465 citations
References
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TL;DR: This research presents a novel, scalable and scalable approach that allows for real-time assessment of the severity of the infection and its impact on patients’ health.
Abstract: FRED C. TENOVER,* ROBERT D. ARBEIT, RICHARD V. GOERING, PATRICIA A. MICKELSEN, BARBARA E. MURRAY, DAVID H. PERSING, AND BALA SWAMINATHAN National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333; Veterans Affairs Medical Center, Boston, Massachusetts 02130; Creighton University, Omaha, Nebraska 68178; Stanford University Medical Center, Stanford, California 94305; University of Texas Medical School, Houston, Texas 77030; and Mayo Clinic, Rochester, Minnesota 55905
7,784 citations
"A field guide to pandemic, epidemic..." refers background in this paper
...Traditionally a strain has been defined as ‘‘an isolate or group of isolates that can be distinguished from other isolates of the same genus and species by phenotypic characteristics or genotypic characteristics or both’’ [221;222], which is essentially the same as a clone which is defined as a group of ‘‘isolates that are indistinguishable from each other by a variety of genetic tests’’ [221;222]....
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TL;DR: This article reviews the terminology used for phylogenetic networks and covers both split networks and reticulate networks, how they are defined, and how they can be interpreted and outlines the beginnings of a comprehensive statistical framework for applying split network methods.
Abstract: The evolutionary history of a set of taxa is usually represented by a phylogenetic tree, and this model has greatly facilitated the discussion and testing of hypotheses. However, it is well known that more complex evolutionary scenarios are poorly described by such models. Further, even when evolution proceeds in a tree-like manner, analysis of the data may not be best served by using methods that enforce a tree structure but rather by a richer visualization of the data to evaluate its properties, at least as an essential first step. Thus, phylogenetic networks should be employed when reticulate events such as hybridization, horizontal gene transfer, recombination, or gene duplication and loss are believed to be involved, and, even in the absence of such events, phylogenetic networks have a useful role to play. This article reviews the terminology used for phylogenetic networks and covers both split networks and reticulate networks, how they are defined, and how they can be interpreted. Additionally, the article outlines the beginnings of a comprehensive statistical framework for applying split network methods. We show how split networks can represent confidence sets of trees and introduce a conservative statistical test for whether the conflicting signal in a network is treelike. Finally, this article describes a new program, SplitsTree4, an interactive and comprehensive tool for inferring different types of phylogenetic networks from sequences, distances, and trees.
7,273 citations
"A field guide to pandemic, epidemic..." refers methods in this paper
...In order to visualise similarities between hybridisation profiles, a network tree using SplitsTree software [248] was constructed....
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TL;DR: Invasive MRSA infection affects certain populations disproportionately and is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
Abstract: ContextAs the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed.ObjectivesTo describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005.Design and SettingActive, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care–associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA).Main Outcome MeasuresIncidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains.ResultsThere were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care–associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100 000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100 000; interval estimate, 92.6-156.9), blacks (66.5 per 100 000; interval estimate, 43.5-63.1), and males (37.5 per 100 000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100 000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care–associated infections in all surveillance areas.ConclusionsInvasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
3,803 citations
TL;DR: The causes and effect of cause and effect, and the prerequisites of Selforganization, are explained in more detail in the I.IA.
Abstract: IA. Cause and Effect . . . . . . . . . . . . . . 465 1.2. Prerequisites of Selforganization . . . . . . . 467 1.2.3. Evolut ion Must S ta r t f rom R andom Even ts 467 1.2.2. Ins t ruc t ion Requires In format ion . . . . 467 1.2.3. In format ion Originates or Gains Value by S e l e c t i o n . . . . . . . . . . . . . . . 469 1.2.4. Selection Occurs wi th Special Substances under Special Conditions . . . . . . . . 470
3,347 citations
"A field guide to pandemic, epidemic..." refers background in this paper
...Thus, the concept of ‘‘quasispecies’’ [223-227] could be applied in which the genome ‘‘cannot be described as a defined structure, but rather as a weighted average of a large number of individual sequences’’ [228]....
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TL;DR: A multilocus sequence typing (MLST) scheme has been developed for Staphylococcus aureus and provides an unambiguous method for assigning MRSA and MSSA isolates to known clones or assigning them as novel clones via the Internet.
Abstract: A multilocus sequence typing (MLST) scheme has been developed for Staphylococcus aureus. The sequences of internal fragments of seven housekeeping genes were obtained for 155 S. aureus isolates from patients with community-acquired and hospital-acquired invasive disease in the Oxford, United Kingdom, area. Fifty-three different allelic profiles were identified, and 17 of these were represented by at least two isolates. The MLST scheme was highly discriminatory and was validated by showing that pairs of isolates with the same allelic profile produced very similar SmaI restriction fragment patterns by pulsed-field gel electrophoresis. All 22 isolates with the most prevalent allelic profile were methicillin-resistant S. aureus (MRSA) isolates and had allelic profiles identical to that of a reference strain of the epidemic MRSA clone 16 (EMRSA-16). Four MRSA isolates that were identical in allelic profile to the other major epidemic MRSA clone prevalent in British hospitals (clone EMRSA-15) were also identified. The majority of isolates (81%) were methicillin-susceptible S. aureus (MSSA) isolates, and seven MSSA clones included five or more isolates. Three of the MSSA clones included at least five isolates from patients with community-acquired invasive disease and may represent virulent clones with an increased ability to cause disease in otherwise healthy individuals. The most prevalent MSSA clone (17 isolates) was very closely related to EMRSA-16, and the success of the latter clone at causing disease in hospitals may be due to its emergence from a virulent MSSA clone that was already a major cause of invasive disease in both the community and hospital settings. MLST provides an unambiguous method for assigning MRSA and MSSA isolates to known clones or assigning them as novel clones via the Internet.
2,809 citations
Additional excerpts
.... The sequence types (ST, as defined by multilocus sequence typing, or MLST,...
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