title: Long-Term Safety of Topical Bacteriophage Application to the Frontal Sinus Region.
abstract: Background:Staphylococcus aureusbiofilms contribute negatively to a number of chronic conditions, including chronic rhinosinusitis (CRS). With the inherent tolerance of biofilm-bound bacteria to antibiotics and the global problem of bacterial antibiotic resistance, the need to develop novel therapeutics is paramount. Phage therapy has previously shown promise in treating sinonasalS. aureusbiofilms.Methods:This study investigates the long term (20 days) safety of topical sinonasal flushes with bacteriophage suspensions. The bacteriophage cocktail NOV012 againstS. aureusselected for this work contains two highly characterized and different phages, P68 and K710. Host range was assessed againstS. aureusstrains isolated from CRS patients using agar spot tests. NOV012 was applied topically to the frontal sinus region of sheep, twice daily for 20 days. General sheep wellbeing, mucosal structural changes and inflammatory load were assessed to determine safety of NOV012 application.Results:NOV012 could lyse 52/61 (85%) of a panel of locally derived CRS clinical isolates. Application of NOV012 to the frontal sinuses of sheep for 20 days was found to be safe, with no observed inflammatory infiltration or tissue damage within the sinus mucosa.Conclusion:NOV012 cocktail appears safe to apply for extended periods to sheep sinuses and it could infect and lyse a wide range ofS. aureusCRS clinical isolates. This indicates that phage therapy has strong potential as a treatment for chronic bacterial rhinosinusitis.
authors.affiliation: Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Drilling
authors.affiliation: Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Mian L
authors.initials: ML
authors.lastname: Ooi
authors.affiliation: Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Dijana
authors.initials: D
authors.lastname: Miljkovic
authors.affiliation: Adelaide Pathology Partners Adelaide, SA, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: James
authors.affiliation: School of Biological Sciences, Flinders University Bedford Park, SA, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Speck
authors.affiliation: Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vreugde
authors.affiliation: Fixed Phage Limited Glasgow, UK.
authors.forename: Jason
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Surgery-Otolaryngology Head and Neck Surgery, The University of Adelaide Adelaide, SA, Australia.
authors.forename: Peter-John
authors.initials: PJ
authors.lastname: Wormald
mesh_terms: D000287:Administration, Topical; D000818:Animals; D004195:Disease Models, Animal; D005626:Frontal Sinus / Q000382:microbiology*; D058507:Host Specificity; D009297:Nasal Mucosa / Q000473:pathology; D000071059:Phage Therapy / Q000009:adverse effects* / Q000379:methods*; D012756:Sheep; D012852:Sinusitis / Q000628:therapy*; D013204:Staphylococcus Phages / Q000502:physiology; D013211:Staphylococcus aureus / Q000821:virology
keywords: Staphylococcus aureus; bacteriophage; cilia; inflammation; therapeutic safety; topical