Novel Topical Anti-biofilm Agents in the Treatment of Recalcitrant Chronic Rhinosinusitis

Abstract

Chapter 1 of this thesis reviews the current literature on Chronic Rhinosinusitis (CRS) including its aetiology and the role of bacterial biofilms in CRS. It also presents an updated review on all current and emerging topical anti-biofilm options in the management of CRS. Chapter 2 describes the optimisation of an in vivo model using Chitogel (CG) as a drug delivery vehicle for anti-biofilm agents to treat Staphylococcus aureus biofilms. Budesonide and Mupirocin were incorporated as they have some efficacy in the management of recalcitrant CRS in the form of topical irrigations. This study showed that Chitogel- Budesonide-Mupirocin gel significantly reduces S. aureus biofilms in vivo and is the first study to suggest an alternative mode of topical drug delivery to the sinuses. Chapter 3 furthers the study of topical anti-biofilm gel by incorporating novel antimicrobial agents Deferiprone and Gallium Protoporphyrin (DG) into Chitogel. DG has a synergistic anti-biofilm effect against S. aureus and Methicillin Resistant S. aureus (MRSA) biofilms by targeting the iron metabolism pathway that is crucial for bacterial growth and survival. This study has shown that Chitogel- Deferiprone- Gallium Protoporphyrin is safe and effective in eradicating S. aureus biofilms in vivo. Chapter 4 explores the potential wound healing properties of Deferiprone in vitro. In this study Deferiprone was shown to delay primary nasal fibroblast migration without affecting epithelial migration, decrease collagen and reactive oxygen species (ROS) production and reduce interleukin 6 (IL-6) production. This anti-inflammatory potential and ability to limit scar tissue formation has wide prospective applications in the field of sinus surgery. Chapter 5 explores the long-term safety of S. aureus bacteriophage (NOV012) in vivo as a novel treatment option in CRS. Bacteriophage (Phage) therapy was first proposed as an antibacterial treatment in the 1910s and has been recently revived in the face of a global antibiotic resistance crisis. In this study we have shown that S. aureus phage are safe as a topical sinus irrigation in vivo for up to 3 weeks. Chapter 6 furthers the study of Pseudomonas aeruginosa phage (CT-PA) in vivo. Topical sinus irrigation of CT-PA was safe and effective in reducing P. aeruginosa biofilms in vivo over 3 weeks. Chapter 7 explores the translation of our in vivo studies into the first phase-1 clinical trial investigating the safety and preliminary efficacy of phage in S. aureus CRS. It was safe and well tolerated up to 3×109 PFU twice daily for 14 days with no dose-limiting side effects. Preliminary efficacy indicated favourable outcomes across all cohorts with 2 out of 9 patients achieving eradication of infection. Chapter 8 presents a pilot study investigating the evidence behind alternative treatments like colloidal silver (CS) in recalcitrant CRS. This is the first clinical study looking at the safety and efficacy of CS as a topical sinus irrigation in the management of CRS despite it being widely available for purchase over-the-counter. Twice daily CS sinonasal rinses for 10 days is safe but not superior to culture-directed oral antibiotics. We believe that a larger study and further optimisation of treatment duration could further the potential of this therapy. Chapter 9 investigates the role of manuka honey (MH) sinus irrigations with augmented methylglyoxal (MGO) in recalcitrant CRS. Twice daily MH rinses for 14 days have not been shown to be superior to culture-directed oral antibiotics and saline rinses in bacterial eradication but have shown significant improvement in endoscopic scores comparable to control. In the face of a global antibiotic resistance crisis, now more than ever, clinicians are practising more judicious use of systemic oral antibiotics. With an eye to the future, we hope that this thesis on novel topical anti-biofilm therapies would spur further research and someday offer clinicians viable alternatives to systemic oral antibiotics in the management of recalcitrant CRS.