CONCORD - CONtrol of COmmunity-acquired MRSA: Rationale and Development of counteractions

Summary:

Until recently, methicillin-resistant Staphylococcus aureus (MRSA) were confined to hospitals (HA-MRSA). However, community- and farm-associated MRSA (CA-and FA-MRSA) have developed as an important cause of infections. At present no effective strategies exist to combat these epidemiologically distinct types of MRSA.

CONCORD aim to explain the ecological success in the community and the farm environment of CA- and FA-MRSA in contrast to HA-MRSA in order to provide knowledge for the development of effective strategies to control the spread of these pathogens.

Epidemiology of CA- and FA-MRSA is complex and incompletely understood. To gain insight into the epidemiology of CA- and FA-MRSA and obtain contemporary isolates, small scale surveillance studies will be performed among patients in the 20 most populous EU countries, pigs from farms in major pig-exporting countries and among calves in important veal-calve raising countries.

Genomics data for CA-MRSA is limited and non-existent for FA-MRSA. Successful adaptation of MRSA to a new environment supposes either the acquisition of novel genetic determinants or the differential expression of native genes. Only two CA-MRSA isolates have been fully sequenced and the UMCU has sequenced a FA-MRSA isolate. Whole genome sequencing, comparative genome hybridization and transcriptomics will be used to understand the genetic adaptations of MRSA in the community environment.

The contribution of putative virulence factors to pathogenicity will be studied by the construction of knock-out mutants and complementation experiments. The mutantstrains will be tested in relevant in vitro and ex vivo models to establish the precise physiological role of the putative virulence determniants.

Nowadays, mathematical modelling is an important tool to manage infection control. A few models exist that evaluate measures to reduce transmission of HA-MRSA or CA-MRSA in jails. Hwoever, no models are available for FA-MRSA. Modelling will provide both fundamental insights into MRSA epidemiology as well as specific recommendations or testable hypotheses for human and veterinary clinical practice.

The potential of intervention strategies to combat CA- and FA-MRSA will be determined.

Problem:

Until recently, methicillin-resistant Staphylococcus aureus (MRSA) were confined to the hospitals and specific infection control measures have proven useful to detain MRSA spread in this particular environment in several European countries. However, MRSA is currently emerging as a community-associated pathogen, which includes the farm environment. The change in epidemiological and microbiological characteristics will provide new challenges to infection control practices in hospitals. Multiresistant and highly epidemic CA-MRSA clones have disseminated in the USA and in several European countries in otherwise healthy individuals. In additon, FA-MRSAhave deleveloped into an important causes of serious infections in animalss. Nevertheless, little information exists on the genetic determinants or metabolic changes responsible for the enhanced epidemicity of the community and farm-associated MRSA strains nor any strategies exist to control the spread of these pathogens.

Aim:

CONCORD aim to explain the ecological success in the community and the farm environment of CA- and FA-MRSA in contrast to hospital-associated MRSA (HA-MRSA) in order to provide the critical knowledge for the development of effective strategies to control both CA- and FA-MRSA.

Expected results:

• a collection of epidemiologically relevant CA- and FA-MRSA isolates.
• identification and characterziation of the most important epidemic clones.
• insights into the evolution of CA- and FA-MRSA in the context of the whole population of S. aureus.
• identification of novel mobile genetic elements and virulence factors.
• identification of proteins that may be used for vaccination.
• identification of the relevant genetic differences between CA- and FA-MRSA compared to HA-MRSA.
• identification of regulatory pathways involved in adaptation to the community environment
• development of an ex vivo porcine skin model in particular for the study of FA-MRSA.
• mathematical models that describe the epidemiology of CA- and FA-MRSA and that can be used to predict the outcome of interventions.
• validated protocols for phage-mediated treatment of animals, which in the future may be extended to humans.

Potential applications:

The results obtained in this project can be applied to various aspects of the problem of CA- and FA-MRSA.

• Typing studies will enable the identification of the important CA-MRSA and FA-MRSA strains. This will allow the development of specific diagnostic assays for these strains. Also, scarce intervention resources for intervention can thus be focused on the most epidemic strains.
• Expression and virulence studies will provide information for the development of vaccines. The major advantage of vaccines is that they prevent disease instead of treating it avoiding the use of antibiotics and thereby does not contribute to the rise in antibiotic resistance.
• Mathematical modelling will be used to make specific recommendations for intervention strategies with regard to human and veterinary medicine to prevent spread and thereby disease.
• Phage-mediated intervention will lead to a reduction in the number of MRSA bacteria carried by either humans or animals, which will significantly decrease spread and thereby disease caused by these newly adapted strains. Together with intervention recommendations predicted by the mathematical modelling, phage-mediated treatment may lead to even higher levels of reduction of carriers and disease.

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