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"Bentley, Matthew A"
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Routine Use of Microbial Whole Genome Sequencing in Diagnostic and Public Health Microbiology
According to the current diagnostic paradigm for Mycobacterium tuberculosis complex (MTBC), clinical samples (usually sputum) are first analysed using smear microscopy to detect high numbers of acid-fast bacilli. Most prominently, only some but not all strains of M. canettii, which are intrinsically resistant against pyrazinamide, and potentially the novel agent PA-824 can be identified [113]-[115]. [...]phenotypic testing is still required.
Journal Article
Whole-genome sequencing for analysis of an outbreak of meticillin-resistant Staphylococcus aureus: a descriptive study
The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of whole-genome sequencing to enhance detection of MRSA transmission between these settings.
We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used whole-genome sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain.
The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With whole-genome sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-genome sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean.
Whole-genome sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs.
UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.
Journal Article
Methicillin-resistant Staphylococcus aureus emerged long before the introduction of methicillin into clinical practice
Background
The spread of drug-resistant bacterial pathogens poses a major threat to global health. It is widely recognised that the widespread use of antibiotics has generated selective pressures that have driven the emergence of resistant strains. Methicillin-resistant
Staphylococcus aureus
(MRSA) was first observed in 1960, less than one year after the introduction of this second generation beta-lactam antibiotic into clinical practice. Epidemiological evidence has always suggested that resistance arose around this period, when the
mecA
gene encoding methicillin resistance carried on an SCC
mec
element, was horizontally transferred to an intrinsically sensitive strain of
S. aureus
.
Results
Whole genome sequencing a collection of the first MRSA isolates allows us to reconstruct the evolutionary history of the archetypal MRSA. We apply Bayesian phylogenetic reconstruction to infer the time point at which this early MRSA lineage arose and when SCC
mec
was acquired. MRSA emerged in the mid-1940s, following the acquisition of an ancestral type I SCC
mec
element, some 14 years before the first therapeutic use of methicillin.
Conclusions
Methicillin use was not the original driving factor in the evolution of MRSA as previously thought. Rather it was the widespread use of first generation beta-lactams such as penicillin in the years prior to the introduction of methicillin, which selected for
S. aureus
strains carrying the
mecA
determinant. Crucially this highlights how new drugs, introduced to circumvent known resistance mechanisms, can be rendered ineffective by unrecognised adaptations in the bacterial population due to the historic selective landscape created by the widespread use of other antibiotics.
Journal Article
Evolution of MRSA During Hospital Transmission and Intercontinental Spread
Current methods for differentiating isolates of predominant lineages of pathogenic bacteria often do not provide sufficient resolution to define precise relationships. Here, we describe a high-throughput genomics approach that provides a high-resolution view of the epidemiology and microevolution of a dominant strain of methicillin-resistant Staphylococcus aureus (MRSA). This approach reveals the global geographic structure within the lineage, its intercontinental transmission through four decades, and the potential to trace person-to-person transmission within a hospital environment. The ability to interrogate and resolve bacterial populations is applicable to a range of infectious diseases, as well as microbial ecology.
Journal Article
Engineered probiotic Escherichia coli can eliminate and prevent Pseudomonas aeruginosa gut infection in animal models
Bacteria can be genetically engineered to kill specific pathogens or inhibit their virulence. We previously developed a synthetic genetic system that allows a laboratory strain of
Escherichia coli
to sense and kill
Pseudomonas aeruginosa in vitro
. Here, we generate a modified version of the system, including a gene encoding an anti-biofilm enzyme, and use the probiotic strain
Escherichia coli
Nissle 1917 as host. The engineered probiotic shows
in vivo
prophylactic and therapeutic activity against
P. aeruginosa
during gut infection in two animal models (
Caenorhabditis elegans
and mice). These findings support the further development of engineered microorganisms with potential prophylactic and therapeutic activities against gut infections.
Bacteria can be engineered to kill specific pathogens. Here, the authors modify and optimize a synthetic genetic system in a probiotic strain of
Escherichia coli
, and show that the engineered probiotic can sense and kill the pathogen
Pseudomonas aeruginosa
in two animal models of gut infection.
Journal Article
Response of the East Antarctic Ice Sheet to Past and Future Climate Change
The East Antarctic Ice Sheet (EAIS) contains the vast majority of Earth’s glacier ice (~52 metres sea-level equivalent), but is often viewed as less vulnerable to global warming than the West Antarctic or Greenland ice sheets. However, some regions of the EAIS have lost mass over recent decades, prompting the need to re-evaluate its sensitivity to climate change. Here we review the EAIS’s response to past warm periods, synthesise current observations of change, and evaluate future projections. Some marine-based catchments that underwent significant mass loss during past warm periods are currently losing mass, but most projections indicate increased accumulation across the EAIS over the 21st Century, keeping the ice sheet broadly in balance. Beyond 2100, high emissions scenarios generate increased ice discharge and potentially several metres of sea-level rise within just a few centuries, but substantial mass loss could be averted if the Paris Agreement to limit warming below 2°C is satisfied.
Journal Article
How social learning shapes the efficacy of preventative health behaviors in an outbreak
The global pandemic of COVID-19 revealed the dynamic heterogeneity in how individuals respond to infection risks, government orders, and community-specific social norms. Here we demonstrate how both individual observation and social learning are likely to shape behavioral, and therefore epidemiological, dynamics over time. Efforts to delay and reduce infections can compromise their own success, especially when disease risk and social learning interact within sub-populations, as when people observe others who are (a) infected and/or (b) socially distancing to protect themselves from infection. Simulating socially-learning agents who observe effects of a contagious virus, our modelling results are consistent with with 2020 data on mask-wearing in the U.S. and also concur with general observations of cohort induced differences in reactions to public health recommendations. We show how shifting reliance on types of learning affect the course of an outbreak, and could therefore factor into policy-based interventions incorporating age-based cohort differences in response behavior.
Journal Article
OpenABM-Covid19—An agent-based model for non-pharmaceutical interventions against COVID-19 including contact tracing
SARS-CoV-2 has spread across the world, causing high mortality and unprecedented restrictions on social and economic activity. Policymakers are assessing how best to navigate through the ongoing epidemic, with computational models being used to predict the spread of infection and assess the impact of public health measures. Here, we present OpenABM-Covid19: an agent-based simulation of the epidemic including detailed age-stratification and realistic social networks. By default the model is parameterised to UK demographics and calibrated to the UK epidemic, however, it can easily be re-parameterised for other countries. OpenABM-Covid19 can evaluate non-pharmaceutical interventions, including both manual and digital contact tracing, and vaccination programmes. It can simulate a population of 1 million people in seconds per day, allowing parameter sweeps and formal statistical model-based inference. The code is open-source and has been developed by teams both inside and outside academia, with an emphasis on formal testing, documentation, modularity and transparency. A key feature of OpenABM-Covid19 are its Python and R interfaces, which has allowed scientists and policymakers to simulate dynamic packages of interventions and help compare options to suppress the COVID-19 epidemic.
Journal Article
Rapid Whole-Genome Sequencing for Investigation of a Neonatal MRSA Outbreak
Rapid whole-genome sequencing of microorganisms can identify relationships among clusters of infections. In this investigation of an outbreak of methicillin-resistant Staphylococcus aureus (MRSA), genomic sequencing helped to ascertain which cases were related.
Microbial whole-genome sequencing is poised to enhance diagnostic and public health microbiology.
1
–
3
Its discriminatory power has already been shown in a number of recent outbreaks, including cholera,
4
tuberculosis,
5
and
Escherichia coli
O104:H4.
6
,
7
The next step is to translate this technology from a research tool into one with clinical utility in the routine diagnostic setting. A compelling target is invasive methicillin-resistant
Staphylococcus aureus
(MRSA) infection, a major public health problem related primarily to health care.
8
In 2005, an estimated 94,360 invasive MRSA infections (including 18,900 hospital-acquired cases of bacteremia) occurred in the United States, associated with 18,650 deaths.
9
On . . .
Journal Article