Jardeleza Camille, Thierry Benjamin, Rao Shasha, Rajiv Sukanya, Drilling Amanda, Miljkovic Dijana, Paramasivan Sathish, James Craig, Dong Dong, Thomas Nicky, Vreugde Sarah, Prestidge Clive A, Wormald Peter-John
Department of Surgery-Otorhinolaryngology Head and Neck Surgery, The Queen Elizabeth Hospital, The University of Adelaide, Adelaide, South Australia, Australia.
Division of Information Technology, Engineering and the Environment, The Ian Wark Research Institute, University of South Australia, Mawson Lakes, South Australia, Australia.
Transl Res. 2015 Dec;166(6):683-92. doi: 10.1016/j.trsl.2015.06.009. Epub 2015 Jun 24.
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.
耐药负担在长期和反复使用抗生素后出现。这凸显了发现当前抗生素治疗方案替代方法的重要性。在慢性鼻窦炎（CRS）中，局部治疗如鼻腔冲洗和类固醇喷雾是主要治疗方法。然而，诸如金黄色葡萄球菌生物膜感染导致的细菌性鼻窦炎指向了更难治疗的CRS亚型，促使研究工作聚焦于局部抗菌治疗。在鼻窦中，设计任何新的局部用药时都必须考虑局部黏膜和全身效应。一氧化氮（NO）是一种内源性抗菌剂，在CRS鼻窦中含量极低，而在健康鼻窦中含量很高。作为一种新型治疗方式，我们使用单硝酸异山梨酯设计了一种NO供体的脂质体制剂（LFNO），作为金黄色葡萄球菌生物膜性鼻窦炎绵羊模型的局部鼻窦冲洗剂。在安全性部分评估了心率（HR）、血压、平均动脉压（MAP）以及组织学和纤毛分析。通过量化治疗后生物膜生物量评估疗效。与对照组相比，LFNO治疗的绵羊炎症较轻（P = 0.02），纤毛保存情况相当（P = 0.86）。在LFNO组观察到HR短暂升高和MAP降低（P < 0.05），但未伴有明显副作用。与对照组相比，LFNO组绵羊的生物膜生物量显著更低（P = 0.044）。我们的研究结果表明，尽管使用了高浓度的NO，但LFNO在动物模型中具有局部和全身安全性，因此有必要进一步研究其在CRS中可能的治疗作用。
