title: An in vivo safety and efficacy demonstration of a topical liposomal nitric oxide donor treatment for Staphylococcus aureus biofilm-associated rhinosinusitis.
abstract: The burden of drug resistance emerges in the wake of chronic and repeated antibiotic use. This underpins the importance of discovering alternatives to current antibiotic regimens. In chronic rhinosinusitis (CRS), topical therapy such as nasal douches and steroid sprays is the mainstay of treatment. However, bacterial sinusitis such as those with Staphylococcus aureus biofilm infection point to more recalcitrant CRS subtypes, focusing research efforts into topical antimicrobial therapies. In the sinuses, both local mucosal and systemic effects must be considered in designing any new topical medication. Nitric oxide (NO), an endogenous antimicrobial agent, is found at extremely low levels in CRS sinuses and high levels in healthy sinuses. As a novel treatment modality, we have designed a liposomal formulation of an NO donor (LFNO) using isosorbide mononitrate, as a topical sinus wash in a sheep model of S. aureus biofilm rhinosinusitis. Heart rate (HR), blood pressure, mean arterial pressure (MAP), and histologic and ciliary analyses were assessed in the safety component. Efficacy was assessed by quantifying biofilm biomass post-treatment. LFNO-treated sheep had lesser inflammation (P = 0.02), and comparable ciliary preservation (P = 0.86) than the control group. A transient increase in HR and decrease in MAP were observed in the LFNO group (P < 0.05), but this was not accompanied by observable side effects. LFNO sheep had significantly lower biofilm biomass vs controls (P = 0.044). Our findings demonstrate the localized and systemic safety of LFNO in an animal model despite using high NO concentrations, thus warranting further investigation for its possible therapeutic role in CRS.
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia. Electronic address: cjardelezamd@yahoo.com.
authors.forename: Camille
authors.initials: C
authors.lastname: Jardeleza
authors.affiliation: Division of Information Technology, Engineering and the Environment, The Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thierry
authors.affiliation: Division of Information Technology, Engineering and the Environment, The Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, Australia.
authors.forename: Shasha
authors.initials: S
authors.lastname: Rao
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sukanya
authors.initials: S
authors.lastname: Rajiv
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Drilling
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Dijana
authors.initials: D
authors.lastname: Miljkovic
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sathish
authors.initials: S
authors.lastname: Paramasivan
authors.affiliation: Adelaide Pathology Partners, Adelaide, South Australia, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: James
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Dong
authors.initials: D
authors.lastname: Dong
authors.affiliation: Division of Information Technology, Engineering and the Environment, The Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, Australia.
authors.forename: Nicky
authors.initials: N
authors.lastname: Thomas
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vreugde
authors.affiliation: Division of Information Technology, Engineering and the Environment, The Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, Australia.
authors.forename: Clive A
authors.initials: CA
authors.lastname: Prestidge
authors.affiliation: Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Peter-John
authors.initials: PJ
authors.lastname: Wormald
mesh_terms: D000287:Administration, Topical; D018441:Biofilms; D006801:Humans; D008081:Liposomes; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000627:therapeutic use; D012852:Sinusitis / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000472:pathogenicity*
chemical_list: D008081:Liposomes; D020030:Nitric Oxide Donors