Corticosteroids and the Sinonasal Microbiome Lisa Mary Cherian MBBS, Masters in Otorhinolaryngology A thesis submitted for the degree of Doctor of Philosophy at the University of Adelaide, Adelaide, Australia Faculty of Health and Medical Sciences, School of Medicine, Discipline of Surgery July 2019 1 Table of contents Abstract …………………………………………………………..6 Thesis declaration................................................................................. 8 Acknowledgements .............................................................................. 9 Publications arising from thesis ......................................................... 11 Presentation arising from thesis ......................................................... 12 Awards arising from thesis................................................................. 13 Abbreviations ..................................................................................... 14 List of tables ....................................................................................... 16 List of figures ..................................................................................... 17 Chapter 1- A systematic review of the literature ............................... 19 1.1 Chronic rhinosinusitis – definition .......................................................................... 20 1.2 Incidence ................................................................................................................. 20 1.3 Etiopathogenesis ..................................................................................................... 20 1.3.1 Anatomical variations ................................................................................................. 21 1.3.2 Physiology and its dysfunction ................................................................................... 22 1.3.3 Immunology ................................................................................................................ 24 1.3.4 Fungus ......................................................................................................................... 28 1.3.5 Bacteria ....................................................................................................................... 29 1.3.6 Other factors ............................................................................................................... 30 1.4 Bacteriology in CRS ............................................................................................... 32 1.4.1 Bacteria isolation and culture techniques .................................................................. 32 1.4.2 Bacteria in health ........................................................................................................ 34 1.4.3 Bacteria in CRS ............................................................................................................ 35 1.4.4 Biofilms in CRS ............................................................................................................ 37 1.4.5 Staphylococcus aureus ............................................................................................... 38 1.4.6 Methicillin resistantstaphylococcus aureus (MRSA) .................................................. 39 2 1.4.7 Staphylococcus epidermidis (Coagulase negative staphylococcus -CNS) .................. 40 1.4.8 Corynebacterium species (sp.).................................................................................... 40 1.4.9 Bacterial co-occurrence .............................................................................................. 40 1.5 Microbiome ............................................................................................................. 41 1.5.1 Microbiome isolation techniques ............................................................................... 42 1.5.2 Comparison of bacteria by traditional isolation techniques and NGS ....................... 45 1.5.3 Microbiome in health ................................................................................................. 46 1.5.4 Microbiome in CRS ...................................................................................................... 47 1.5.5 Significance of the different bacteria in health and disease ...................................... 52 1.6 Medical therapy in CRS .......................................................................................... 53 1.6.1 Saline irrigations ......................................................................................................... 54 1.6.2 Oral antibiotics ............................................................................................................ 55 1.6.3 Topical antibiotics ....................................................................................................... 57 1.6.4 Antifungals .................................................................................................................. 58 1.7 Corticosteroids ........................................................................................................ 58 1.7.1 Oral steroid ................................................................................................................. 61 1.7.2 Topical nasal steroids .................................................................................................. 62 1.8 Types of intranasal steroids ..................................................................................... 65 1.8.1 Hydrocortisone ........................................................................................................... 65 1.8.2 Beclomethasone ......................................................................................................... 65 1.8.3 Fluticasone .................................................................................................................. 65 1.8.4 Mometasone ............................................................................................................... 66 1.8.5 Budesonide ................................................................................................................. 67 1.9 Pulmicort in CRS .................................................................................................... 69 1.10 Influence of therapy on sinonasal bacterial profile ................................................. 70 1.10.1 Invitro studies ............................................................................................................. 71 1.10.2 Animal models ............................................................................................................ 71 1.10.3 Clinical trials ................................................................................................................ 71 1.10.4 Effect of steroids on microbiome or bacteriology of CRS .......................................... 75 1.10.5 Corticosteroids on microbiome outside the sinonasal cavity .................................... 77 1.11 Bacterial and steroid metabolic interactions ........................................................... 78 Chapter 2: Effect of commercial nasal steroid preparation on bacterial growth .................................................................................. 82 2.1 Statement of authorship........................................................................................... 83 3 2.2 Abstract ................................................................................................................... 86 2.3 Introduction ............................................................................................................. 87 2.4 Methods ................................................................................................................... 88 2.5 Results ..................................................................................................................... 93 2.6 Discussion ............................................................................................................. 101 2.7 Conclusion............................................................................................................. 105 2.8 Acknowledgments ................................................................................................. 106 Chapter 3: Staphylococcus aureus metabolises hydrocortisone: effects on anti-inflammatory activity and antimicrobial susceptibility108 3.1 Statement of authorship......................................................................................... 109 3.2 Abstract: ................................................................................................................ 112 3.3 Introduction: .......................................................................................................... 113 3.4 Methods: ................................................................................................................ 114 3.5 Results ................................................................................................................... 122 3.6 Discussion: ............................................................................................................ 132 3.7 Conclusion: ........................................................................................................... 136 3.8 Acknowledgement: ............................................................................................... 136 Chapter 4: The clinical and microbiome outcomes of medical treatments in chronic rhinosinusitis: