Combating MRSA; combining and increasing our understanding on colonisation, transmission and reservoirs will lead to control of infections by MRSA
Lead Research Organisation:
St George's, University of London
Department Name: Institute of Infection & Immunity
Abstract
The underlying reasons for the epidemiological dynamics of MRSA clones in the hospital and the community are debated intensely and different explanations can be controversial. Most studies focus either on the genetic basis of the ability of MRSA to spread and be sustained, like the presence of PVL, SCCmec type IV etc. or on the epidemiological features, like risk groups, selection due to antibiotic use, or prevention measures in health care centres.
After introduction of new strains, antibiotic or disinfectant use is an important driving force, prevention should be focused on that point. When selected strains are more able to spread due to their genetic profile, measures should be developed targeted on prevention of transmission of these particular strains. However, a combination of driving forces will be often present. In short, this study will create more insight into the success and failure of MRSA, and together with the mathematical model, will target specific and realistic tools to prevent further spreading and thus disease. This accounts both for hospitalized patients and in otherwise healthy individuals, as present in the large uncontrolled epidemic by USA300. MACOTRA will join approaches on understanding the epidemiology of MRSA together, will add the host-factor and herewith aims to explain the epidemiological behaviour of MRSA in its rise, maintenance or disappearance. We believe that only by combining all these aspects, we can understand the epidemiology and thus design optimal and focused prevention measures.
After introduction of new strains, antibiotic or disinfectant use is an important driving force, prevention should be focused on that point. When selected strains are more able to spread due to their genetic profile, measures should be developed targeted on prevention of transmission of these particular strains. However, a combination of driving forces will be often present. In short, this study will create more insight into the success and failure of MRSA, and together with the mathematical model, will target specific and realistic tools to prevent further spreading and thus disease. This accounts both for hospitalized patients and in otherwise healthy individuals, as present in the large uncontrolled epidemic by USA300. MACOTRA will join approaches on understanding the epidemiology of MRSA together, will add the host-factor and herewith aims to explain the epidemiological behaviour of MRSA in its rise, maintenance or disappearance. We believe that only by combining all these aspects, we can understand the epidemiology and thus design optimal and focused prevention measures.
Technical Summary
MACOTRA will, for the first time, bring together a range of relevant information on MRSA across three countries, including -
- Phenotypic and genotypic characteristics for transmission and resistance
- The epidemiology of these strains, including incidence and reservoirs.
- Antibiotic and antiseptic usage policies, protocols and real-world evidence
- Relative fitness of different clones, in models relevant to their niche in the host, and pressures such as microbiome competition and antibiotic/antiseptic exposure
- Potential host-specific interactions impacting on survival.
The collection of all of this data will then be incorporated into mathematical models to understand why different countries have different clones and epidemiology, and to predict the impact of changes in antibiotic/antiseptic on MRSA incidence and reservoir
In the epidemiology of MRSA, the clone, the host and the environment, including selection and prevention measures all need to be studied for it to be understand. We believe that by combining, the understanding of the epidemiology will be better, and thus prevention measures can be developed more focused. The project is well feasible as 1. Reference laboratories are included of all countries, 2. all participating centres have many years of experience in this field and are proven successful in MRSA research 3. The mathematical modellers are well experienced in their field and have proven to successfully publish their work on different infectious disease topics. The partners and their colleagues have known each other for several years in the field of MRSA research.
- Phenotypic and genotypic characteristics for transmission and resistance
- The epidemiology of these strains, including incidence and reservoirs.
- Antibiotic and antiseptic usage policies, protocols and real-world evidence
- Relative fitness of different clones, in models relevant to their niche in the host, and pressures such as microbiome competition and antibiotic/antiseptic exposure
- Potential host-specific interactions impacting on survival.
The collection of all of this data will then be incorporated into mathematical models to understand why different countries have different clones and epidemiology, and to predict the impact of changes in antibiotic/antiseptic on MRSA incidence and reservoir
In the epidemiology of MRSA, the clone, the host and the environment, including selection and prevention measures all need to be studied for it to be understand. We believe that by combining, the understanding of the epidemiology will be better, and thus prevention measures can be developed more focused. The project is well feasible as 1. Reference laboratories are included of all countries, 2. all participating centres have many years of experience in this field and are proven successful in MRSA research 3. The mathematical modellers are well experienced in their field and have proven to successfully publish their work on different infectious disease topics. The partners and their colleagues have known each other for several years in the field of MRSA research.
Planned Impact
MRSA first emerged as a major cause of infection in the health care centers, and later on in the community with significant morbidity and mortality. Currently, MRSA epidemiology varies by country. The Netherlands has a lower incidence of healthcare MRSA compared to the UK and France and each country has different clones. CA-MRSA is rare in the UK, proportionally more prevalent in the Netherlands and higher in France due to USA300 and CC80 clones. LA-MRSA is prevalent in the Netherlands, lower in France and rare in the UK. Furthermore, clones, reservoirs, host-range and incidence change. For example, the relatively emergence of CA-MRSA infections in healthy people over the last 15 years and their rapid epidemic and pandemic spread in the USA, South America and Asia shows that some MRSA strains do not require healthcare exposure, representing an even more severe danger for public health.
The questions; We do not understand why success of clonal complexes is geographically different, e.g. the severe epidemic by USA300 is virtually restricted to North America, despite frequent global travel and introduction in Europe. However, this did not lead to an epidemic as encountered in USA. It is, however, clear that presence of particular genes is associated with the success of some of the clonal complexes in certain locations. Examples are the superantigen encoding gene tstH in CC30 in France and sasX in ST239 encoding a surface bound protein that modulates host interaction in China.
The solutions; Critical success factors for expanding clones will be studied and results in;
- First comparison of decolonisation, antibiotic use and associated MRSA clones, comprehensive resistant profiles and epidemiology across more than one country. Knowledge will be obtained on strain characteristics influencing successful carriage or even epidemic behaviour and on the influence of the host response, including microbiome.
-Identification that particular antimicrobials/antiseptics usage is selecting for particular clones, which could have a public health benefit by supporting a reduction in their use (e.g. UK fluoroquinolones usage decline associated with 50% reduction HA-MRSA incidence).
-Identification of bacterial markers associated with successful spread in different clones or different countries leading to novel diagnostic tools, and better interpretation of epidemiological data.
Disinfection of the environment has been studied, but never in relation to epidemiological characteristics, as we will do. We aim to elucidate whether the difference in epidemic behaviour are solely strain related, e.g. resistance to drying or disinfectants or the affinity to the human nose, skin or wounds or just due to antibiotic resistance differences.
-Identification of different microbiome compositions or responses to antibiotics/antimicrobials in carriers vs non-carriers or between countries - potential for change of use of antibiotics/antimicrobials or probiotics
- Identification of antibody responses that may be associated with survival or fitness of particular clones or resistances - potential impact on vaccine development.
Results of MACOTRA come together in mathematical models to predict (future) epidemiology and to predict potential interventions for control. We aim for 1.Improved interventions that reduce colonization potential, 2.Diagnostic targets for epidemic behaviour 3.Novel interventions designed and informed by mathematical modelling. 4.Input for guidelines on prevention, disinfectants and antibiotics. Results will be disseminated by publications and in ESCMID Study Groups for Nosocomial Infections and for Staphylococci and Staph. Diseases and nationally to ensure knowledge will be transferred into practice.
The questions; We do not understand why success of clonal complexes is geographically different, e.g. the severe epidemic by USA300 is virtually restricted to North America, despite frequent global travel and introduction in Europe. However, this did not lead to an epidemic as encountered in USA. It is, however, clear that presence of particular genes is associated with the success of some of the clonal complexes in certain locations. Examples are the superantigen encoding gene tstH in CC30 in France and sasX in ST239 encoding a surface bound protein that modulates host interaction in China.
The solutions; Critical success factors for expanding clones will be studied and results in;
- First comparison of decolonisation, antibiotic use and associated MRSA clones, comprehensive resistant profiles and epidemiology across more than one country. Knowledge will be obtained on strain characteristics influencing successful carriage or even epidemic behaviour and on the influence of the host response, including microbiome.
-Identification that particular antimicrobials/antiseptics usage is selecting for particular clones, which could have a public health benefit by supporting a reduction in their use (e.g. UK fluoroquinolones usage decline associated with 50% reduction HA-MRSA incidence).
-Identification of bacterial markers associated with successful spread in different clones or different countries leading to novel diagnostic tools, and better interpretation of epidemiological data.
Disinfection of the environment has been studied, but never in relation to epidemiological characteristics, as we will do. We aim to elucidate whether the difference in epidemic behaviour are solely strain related, e.g. resistance to drying or disinfectants or the affinity to the human nose, skin or wounds or just due to antibiotic resistance differences.
-Identification of different microbiome compositions or responses to antibiotics/antimicrobials in carriers vs non-carriers or between countries - potential for change of use of antibiotics/antimicrobials or probiotics
- Identification of antibody responses that may be associated with survival or fitness of particular clones or resistances - potential impact on vaccine development.
Results of MACOTRA come together in mathematical models to predict (future) epidemiology and to predict potential interventions for control. We aim for 1.Improved interventions that reduce colonization potential, 2.Diagnostic targets for epidemic behaviour 3.Novel interventions designed and informed by mathematical modelling. 4.Input for guidelines on prevention, disinfectants and antibiotics. Results will be disseminated by publications and in ESCMID Study Groups for Nosocomial Infections and for Staphylococci and Staph. Diseases and nationally to ensure knowledge will be transferred into practice.
Organisations
- St George's, University of London (Lead Research Organisation)
- National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) (Collaboration)
- National Institute for Public Health and Environment (RIVM) (Collaboration)
- Erasmus MC (Collaboration)
- London School of Hygiene and Tropical Medicine (LSHTM) (Collaboration)
- ST GEORGE'S UNIVERSITY OF LONDON (Collaboration)
Publications
Moller AG
(2019)
Determinants of Phage Host Range in Staphylococcus Species.
in Applied and environmental microbiology
Lindsay JA
(2019)
Staphylococci: Evolving Genomes.
in Microbiology spectrum
Leclerc QJ
(2022)
Growth-Dependent Predation and Generalized Transduction of Antimicrobial Resistance by Bacteriophage.
in mSystems
Leclerc QJ
(2022)
Modelling the synergistic effect of bacteriophage and antibiotics on bacteria: Killers and drivers of resistance evolution.
in PLoS computational biology
Leclerc QJ
(2019)
Mathematical modelling to study the horizontal transfer of antimicrobial resistance genes in bacteria: current state of the field and recommendations.
in Journal of the Royal Society, Interface
Knight G
(2018)
The importance of cross-disciplinary research to combat antimicrobial resistance: introducing a new pop-up journal, X-AMR.
in Microbiology (Reading, England)
Knight G
(2019)
Mathematical modelling for antibiotic resistance control policy: do we know enough?
in BMC Infectious Diseases
Description | MRC DTP LSHTM-SGUL, Studentship awarded to Jacob Wildfire |
Amount | £2,090,490 (GBP) |
Funding ID | MR/N013638/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2020 |
End | 03/2024 |
Description | MRC DTP LSHTM-SGUL, Studentship awarded to Quentin Leclerc |
Amount | £2,090,490 (GBP) |
Funding ID | MR/N013638/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2018 |
End | 03/2022 |
Description | MRC LID |
Amount | £2,090,490 (GBP) |
Funding ID | MR/N013638/1 - MRC DTP LSHTM-SGUL, Studentship awarded to Alastair Clements |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2021 |
End | 03/2025 |
Description | Medical Research Council (MRC) MRC DTP LSHTM-SGUL: MR/N013638/1 - MRC DTP LSHTM-SGUL, Studentship awarded to Max Wallat - MRC LID (£ 2090490; 2021 - 2025) |
Amount | £2,090,490 (GBP) |
Funding ID | MR/N013638/1 |
Organisation | London School of Hygiene and Tropical Medicine (LSHTM) |
Sector | Academic/University |
Country | United Kingdom |
Start | 09/2022 |
End | 03/2026 |
Title | MRSA infection incidence and antibiotic use |
Description | Dataset and methods to compare and correlate across 27 European countries in 2015 - MRSA incidence: ECDC data from Cassini et al., 2019 https://doi.org/10.1016/S1473-3099(18)30605-4 Antibiotic usage : ECDC data from : https://www.ecdc.europa.eu/en/antimicrobial-consumption/surveillance-and-disease-data/database Full analysis and description in Baede et al., 2023 : DOI: 10.1016/j.cmi.2023.05.015 |
Type Of Material | Computer model/algorithm |
Year Produced | 2023 |
Provided To Others? | Yes |
Impact | Publication in Baede et al., 2013. Presented at conferences. |
URL | https://github.com/gwenknight/mrsa_inf_abx |
Title | Whole genome sequence of strain collection |
Description | European Nucleotide Archive database accession number PRJEB47238. 157 successful and 221 sporadic MRSA from UK, Netherlands and France. Described in Baede et al., 2023 https://doi.org/10.1016/j.cmi.2023.05.015. The data shows that MRSA spread between countries but different isolates dominate in different countries. This is partly related to carriage of antimicrobial resistance genes. |
Type Of Material | Database/Collection of data |
Year Produced | 2023 |
Provided To Others? | Yes |
Impact | MRSA spread between countries but different isolates dominate in different countries. This is partly related to antimicrobial resistance genes. |
URL | https://www.ncbi.nlm.nih.gov/bioproject/?term=PRJEB47238 |
Description | MACOTRA |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Expertise, intellectual input. |
Collaborator Contribution | Expertise, intellectual input. |
Impact | Two papers, 10.1186/s12879-019-4630-y and doi.org/10.1098/rsif.2019.0260 Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling. |
Start Year | 2017 |
Description | MACOTRA |
Organisation | London School of Hygiene and Tropical Medicine (LSHTM) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Expertise, intellectual input. |
Collaborator Contribution | Expertise, intellectual input. |
Impact | Two papers, 10.1186/s12879-019-4630-y and doi.org/10.1098/rsif.2019.0260 Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling. |
Start Year | 2017 |
Description | MACOTRA |
Organisation | National Center for Scientific Research (Centre National de la Recherche Scientifique CNRS) |
Department | International Center for Infectiology Research |
Country | France |
Sector | Academic/University |
PI Contribution | Expertise, intellectual input. |
Collaborator Contribution | Expertise, intellectual input. |
Impact | Two papers, 10.1186/s12879-019-4630-y and doi.org/10.1098/rsif.2019.0260 Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling. |
Start Year | 2017 |
Description | MACOTRA |
Organisation | National Institute for Public Health and Environment (RIVM) |
Department | Centre for Control of Infectious Diseases |
Country | Netherlands |
Sector | Public |
PI Contribution | Expertise, intellectual input. |
Collaborator Contribution | Expertise, intellectual input. |
Impact | Two papers, 10.1186/s12879-019-4630-y and doi.org/10.1098/rsif.2019.0260 Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling. |
Start Year | 2017 |
Description | MRSA resistance dynamics |
Organisation | St George's University of London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of multidisciplinary PhD students |
Collaborator Contribution | Co-supervision of multidisciplinary PhD students |
Impact | MACOTRA grant 3 MRC-LID studentships thru LSHTM/St George's grant Multi-discplinary: mathematical modelling and microbiology |
Start Year | 2018 |
Description | Utrecht data analysis |
Organisation | Erasmus MC |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | I work to extract parameters from their data to infer the underlying bacterial growth. Together we work to understand the impact of dehydration on MRSA strain growth, variation between strains and the link to epidemic success. |
Collaborator Contribution | They provide bacterial strain growth and survival data for me to analyse. Together we work to understand the impact of dehydration on MRSA strain growth, variation between strains and the link to epidemic success. |
Impact | Multi-discplinary - microbiology and mathematical modelling One paper under review, another in progress. |
Start Year | 2020 |
Description | Presentation at Parliament |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Presentation of empirical prescribing modelling work at a Parliamentary Office for Science and Technology (POST) event at Portcullis House. Good networking with other academics including the global sewage surveillance project which may lead to a future collaboration. |
Year(s) Of Engagement Activity | 2020 |
URL | https://twitter.com/i/events/1232714747763724288 |