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.

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.

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.

Publications

10 25 50
 
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 Academic/University
Country United Kingdom
Start 09/2018 
End 03/2022
 
Description MACOTRA 
Organisation Erasmus University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Expertise, intellectual input.
Collaborator Contribution Expertise, intellectual input.
Impact None yet. Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling.
Start Year 2017
 
Description MACOTRA 
Organisation International Center for Research in Infectiology
PI Contribution Expertise, intellectual input.
Collaborator Contribution Expertise, intellectual input.
Impact None yet. 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 None yet. 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 None yet. Multidisciplinary and includes microbiology, bioinformatics, public health, mathematical modelling.
Start Year 2017