Biocompatibility and Safety Assessment of Combined Topical Ozone and Antibiotics for Treatment of Infected Wounds.
Biocompatibility and Safety Assessment of Combined Topical Ozone and Antibiotics for Treatment of Infected Wounds.
复制标题
局部臭氧和抗生素联合治疗感染伤口的生物相容性和安全性评估。
DOI：
10.1021/acsbiomaterials.2c01548
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发表时间：
2023
影响因子：
5.8
通讯作者：
Rahimi,Rahim
中科院分区：
文献类型：
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作者：
Roth,Alexander;Krishnakumar,Akshay;McCain,RobynR;Maruthamuthu,MuraliKanaan;McIntosh,MacKenzie;Chen,YueXiang;Cox,AbigailD;HopfJannasch,AmberS;Nguyen,Juliane;Seleem,MohamedN;Rahimi,Rahim
伤口感染的耐药性细菌，特别是革兰氏阴性菌株，对患者造成了巨大的健康风险，治疗选择有限。最近，通过便携式系统局部施用气态臭氧及其与抗生素的组合已被证明是根除伤口感染中常见的革兰氏阴性细菌菌株的有前途的方法。然而，尽管臭氧在治疗越来越多的耐药性感染方面具有重大影响，但不受控制的高浓度臭氧可能会对周围组织造成损害。因此，在这种治疗可以推进到临床使用之前，最重要的是确定在治疗细菌感染中有效并且在局部施用中安全使用的适当水平的局部臭氧。为了解决这一问题，我们进行了一系列体内研究，以评估便携式和可穿戴的辅助臭氧和抗生素伤口治疗系统的有效性和安全性。臭氧和抗生素通过伤口界面透气敷料应用，该敷料涂覆有含有万古霉素和利奈唑胺（传统上用于治疗革兰氏阳性菌感染）的水溶性纳米纤维，并连接到便携式臭氧输送系统。在感染铜绿假单胞菌的离体伤口模型上评价了联合治疗的杀菌特性，铜绿假单胞菌是一种常见的革兰氏阴性细菌菌株，在许多皮肤感染中发现，对目前可用的多种抗生素具有高耐药性。结果表明，臭氧（4 mg h-1）和局部抗生素（200 μg cm-2）的最佳组合递送在治疗6 h后提供了完全的细菌根除，同时对人成纤维细胞具有最小的细胞毒性。此外，体内局部和全身毒性研究（例如，皮肤监测、皮肤组织病理学和血液分析）显示，即使在连续给药5天后，臭氧和抗生素联合治疗也没有副作用的迹象。辅助臭氧和抗生素治疗的确认疗效和生物安全性特征使其成为治疗耐抗生素细菌伤口感染和进一步进行人体临床试验的强有力候选者。
Wound infections with antibiotic-resistant bacteria, particularly the Gram-negative strains, pose a substantial health risk for patients with limited treatment options. Recently topical administration of gaseous ozone and its combination with antibiotics through portable systems has been demonstrated to be a promising approach to eradicate commonly found Gram-negative strains of bacteria in wound infections. However, despite the significant impact of ozone in treating the growing number of antibiotic-resistant infections, uncontrolled and high concentrations of ozone can cause damage to the surrounding tissue. Hence, before such treatments could advance into clinical usage, it is paramount to identify appropriate levels of topical ozone that are effective in treating bacterial infections and safe for use in topical administration. To address this concern, we have conducted a series of in vivo studies to evaluate the efficacy and safety of a portable and wearable adjunct ozone and antibiotic wound therapy system. The concurrent ozone and antibiotics are applied through a wound interfaced gas permeable dressing coated with water-soluble nanofibers containing vancomycin and linezolid (traditionally used to treat Gram-positive infections) and connected to a portable ozone delivery system. The bactericidal properties of the combination therapy were evaluated on an ex vivo wound model infected withPseudomonas aeruginosa, a common Gram-negative strain of bacteria found in many skin infections with high resistance to a wide range of currently available antibiotics. The results indicated that the optimized combination delivery of ozone (4 mg h–1) and topical antibiotic (200 μg cm–2) provided complete bacteria eradication after 6 h of treatment while having minimum cytotoxicity to human fibroblast cells. Furthermore, in vivo local and systemic toxicity studies (e.g., skin monitoring, skin histopathology, and blood analysis) on pig models showed no signs of adverse effects of ozone and antibiotic combination therapy even after 5 days of continuous administration. The confirmed efficacy and biosafety profile of the adjunct ozone and antibiotic therapy places it as a strong candidate for treating wound infection with antimicrobial-resistant bacteria and further pursuing human clinical trials.