Abstract:
Chronic rhinosinusitis (CRS) represents a spectrum of disorders that result from a variety of immunopathological mechanisms which lead to persistent inflammation of the paranasal sinus mucosa. CRS has a prevalence of approximately 12% and accounts for a high burden of antibiotic use worldwide. Although the role of oral antibiotics remains uncertain, they are currently recommended as part of medical therapy along with sinonasal lavage and systemic or topical corticosteroids. The role of microbes in the pathogenesis of CRS is still being defined, but bacteria likely contribute to the persistence and severity of the disease. However, the required antibiotic concentration at the target site of infection remains unclear. To date, this has been approximated by in vitro microorganism susceptibility testing, which can be misleading, since many of the bacteria in the sinonasal mucosa live in biofilms that have a substantially higher resistance to antibiotics than planktonic organisms.
The first half of this thesis presents novel findings on the pharmacokinetics of oral antibiotics used in the treatment of CRS and the short-term effects of these agents on the microbiota in the sinuses. Changes in the gastrointestinal microbiome are studied in parallel, to provide a better understanding of the off-target effects of antibiotics.
In patients who fail to respond to medical therapy, functional endoscopic sinus surgery (FESS) is warranted. The goal of this operation is to open the obstructed sinus openings (ostia), to improve sinus ventilation and restore mucociliary clearance. However, sompe forms of CRS are driven by self-perpetuating immune-mediated processes, and without long-term topical post-operative medical management, these cases have a higher risk of requiring revision surgery. Topical corticosteroids are the mainstay of postoperative therapy, but it remains unclear how efficiently these are delivered to the sinonasal mucosa. The second half of the thesis presents objective analyses, primarily utilizing computational fluid dynamic techniques to evaluate airflow and particle deposition in the postoperative sinonasal cavity. The effect of surgery on sinonasal interaction evaluated through detailed airflow simulations may have significant consequences for pre- or postoperative assessment and planning, and the design of intranasal devices for optimal topical drug delivery.