Exploring the genomic epidemiology of important Gram-positive pathogens and the potential of novel diagnostic- and virulence-based approaches against **Staphylococcus aureus** infections

Infections caused by Gram-positive bacteria such as Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecium represent an enormous health burden in the community as well as in hospitals. While S. aureus and S. pyogenes are known to be highly virulent pathogens causing severe infections, associated with high morbidity and mortality, the past decades have also seen remarkable increases in antibiotic resistance in S. aureus (methicillin-resistant S. aureus, MRSA) and in E. faecium (vancomycin-resistant E. faecium, VRE) that have severely restricted therapeutic options against these pathogens. With the antibiotic pipeline yet to be rejuvenated, these outstanding issues have necessitated the development of alternate solutions, such as the development of rapid diagnostic tests and of virulence/antibodybased preventive or therapeutic approaches. Remarkably, in each of these three pathogens, there are a few ‘pandemic’ clones that have spread worldwide and are recognized as the ‘disease-causing’ clones. However, the advent of next-generation sequencing has allowed to differentiate and dissect the microevolution among these pathogenic, and mostly multi-drug resistant clones. In this thesis, we first address the epidemiology of the three major Gram-positive pathogens utilizing whole-genome sequencing. We studied CC239 MRSA, one of the most widely disseminated hospital-associated MRSA causing multiple epidemics around the world in recent decades, in two European (Serbia and Denmark) and in an Indian hospital to understand population structure differences in these three geographically distinct regions. These studies helped us to highlight the dynamic evolution of ST239 in India, the role of international travel in introducing several ST239 clades in Denmark, and the within-patient microevolutionary changes in the ST239 genome upon the switch from a colonizing to an infecting strain. Furthermore, studying the genomic evolution of invasive and non-invasive S. pyogenes and of VRE in Belgian hospitals showed high genomic heterogeneity among CC17 E. faecium, in contrast to a remarkable genomic stability observed among emm1 S. pyogenes strains collected over 19 years. Further focusing on S. aureus in the clinical context, we studied S. aureus as an important causative agent of ventilator-associated pneumonia (VAP). 8 These studies were primarily focused on the comparison of novel, rapid diagnostics with the currently-used culture-based approaches to accurately detect respiratory tract colonization with S. aureus in mechanically ventilated patients, allowing for early and targeted antibiotic treatment or even an initiation of a novel alpha-toxin-targeting, antibody-based eradication strategy. We performed a literature review to understand the role of alpha-toxin in S. aureus pneumonia pathogenesis. This leads to the observational trial studying the occurrence of S. aureus, and a Phase II study investigating antibody treatment against S. aureus among ICU pneumonia in Europe.

Jaar van publicatie:2019

Trefwoorden:Doctoral thesis

Toegankelijkheid:Closed