Blue light for drug resistant skin and soft tissue infections

蓝光治疗耐药性皮肤和软组织感染

• 批准号: 8856131
• 负责人: Tianhong Dai
• 金额: $ 21.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8856131
• 关键词: Acinetobacter baumannii; Address; Adverse effects; Affect; Alkaline Single-Cell Gel Electrophoresis Assay; Animals; Antibiotics; Antimicrobial Effect; Attention; Bacteria; Bacterial Infections; Bioluminescence; Biopsy; Burn injury; Cells; Colony-forming units; Comet Assay; Development; Dose; Drug resistance; Endothelial Cells; Enterobacter cloacae; Enterococcus faecium; Enzymes; Event; Exhibits; Fiber; Fibroblasts; Foundations; Genetic Engineering; Imaging Techniques; Immunocompetent; Immunocompromised Host; Impetigo; In Vitro; Individual; Infection; Klebsiella pneumonia bacterium; Laboratories; Lactamase; Lasers; Life; Light; Modeling; Monitor; Multi-Drug Resistance; Mus; Operative Surgical Procedures; Photosensitizing Agents; Physicians; Porphyrins; Predisposition; Production; Prophylactic treatment; Protocols documentation; Pseudomonas aeruginosa; Publishing; Rattus; Reactive Oxygen Species; Reporting; Research; Resistance development; Rodent; Site; Skin; Skin Tissue; Smooth Muscle Myocytes; Soft Tissue Infections; Staging; Staphylococcus aureus; Testing; Therapeutic; Time; Tissues; United States; antimicrobial; bacterial resistance; base; bioluminescence imaging; blue light therapy; clinical practice; cytotoxic; in vivo; infected vector rodent; irradiation; keratinocyte; luminescence; macrophage; methicillin resistant Staphylococcus aureus; new technology; novel; novel strategies; novel therapeutic intervention; pathogen; pathogenic bacteria; public health relevance; research study

DESCRIPTION (provided by applicant): Skin and soft tissue infections (SSTI) are one of the most common problems encountered in clinical practice and affect millions of individuals annually in the United States. These infections may range from uncomplicated superficial SSTI to life-threatening complicated deep SSTI. Treatment of SSTI has been significantly complicated by the increasing emergence of multidrug-resistant pathogenic bacteria. As a result, there is a pressing need for the development of new therapeutic approaches. The objective of this proposal is to investigate the utility of a non-antibiotic approach, antimicrobial blue light theray, for multidrug-resistant SSTI. Specifically, we propose to: Aim 1: Demonstrate the efficacy of antimicrobial blue light therapy for superficial or deep SSTI in rodents infected with Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) or Gram-negative multidrug-resistant Pseudomonas aeruginosa. We will use superficial impetigo in mice and deep incisional surgical site infections in rats as the representative models of superficial and deep SSTI, respectively. Both immunocompetent and immunocompromised mice/rats will be tested. Bacterial inocula of 3x105 and 3x107 colony-forming units/rodent will be used to represent the infections caused by a low and a high inoculum, respectively. We will use the in vivo bioluminescence imaging technique to quantitatively and noninvasively monitor in real time the extent of infections in living animals. Blue light (405-415 nm wavelength) will be initiated at 30 min, 24 h, and 48 h after bacterial inoculation, respectively. The efficacy found with blue light therapy will be compared with that of clinically used antibiotics for SSTI. Aim 2: Determine the potential side effects of antimicrobial blue light therapy for SSTI. We will first compare the susceptibilities to blue light inactivation in vitro between pathogenic bacteria and host cells. We will also determine whether the pathogenic bacteria can develop resistance to blue light inactivation. The experiment will be implemented by carrying out repeated cycles of sub-lethal blue light inactivation of bacteria in vitro followed by bacterial regrowth. Finally, wewill investigate whether blue light is genotoxic to host cells by using the alkaline comet assay after irradiation of host cells in vitro and in vivo. Successful completion of these specific aims will provide the foundation required to assess the efficacy (Aim 1) as well as the potential side effects (Aim 2) of antimicrobial blue light therapy for SSTI, and will help establish protocols for the use of this prophylaxis/therapeutic option. Given the significant drawbacks in current management of multidrug-resistant SSTI, this new technology using blue light exhibits great potential.

描述（由申请人提供）：皮肤和软组织感染（SSTI）是临床实践中最常见的问题之一，每年影响美国数百万人。这些感染的范围可能从简单的浅表 SSTI 到危及生命的复杂深部 SSTI。由于多重耐药病原菌的不断出现，SSTI 的治疗变得非常复杂。因此，迫切需要开发新的治疗方法。本提案的目的是研究非抗生素方法（抗菌蓝光疗法）治疗多重耐药性 SSTI 的效用。具体来说，我们建议： 目标 1：证明抗菌蓝光疗法对浅表或深部 SSTI 的疗效 感染革兰氏阳性耐甲氧西林金黄色葡萄球菌 (MRSA) 或革兰氏阴性多重耐药铜绿假单胞菌的啮齿动物。我们将分别使用小鼠浅表脓疱病和大鼠深部切口手术部位感染作为浅表和深部 SSTI 的代表模型。免疫功能健全和免疫功能低下的小鼠/大鼠都将接受测试。 3x105 和 3x107 菌落形成单位/啮齿动物的细菌接种物将分别用于代表低接种量和高接种量引起的感染。我们将利用体内生物发光成像技术来定量、无创地实时监测活体动物的感染程度。蓝光（405-415 nm 波长）将分别在细菌接种后 30 分钟、24 小时和 48 小时启动。蓝光疗法的疗效将与临床上使用的抗生素治疗 SSTI 的疗效进行比较。 目标 2：确定抗菌蓝光疗法对 SSTI 的潜在副作用。我们将首先比较病原菌和宿主细胞对体外蓝光灭活的敏感性。我们还将确定致病菌是否能够对蓝光灭活产生抵抗力。该实验将通过在体外重复进行亚致死蓝光灭活细菌然后细菌再生的循环来实施。最后，我们将在体内和体外照射宿主细胞后，通过碱性彗星实验来研究蓝光是否对宿主细胞具有遗传毒性。成功完成这些具体目标将为评估 SSTI 抗菌蓝光疗法的功效（目标 1）和潜在副作用（目标 2）提供所需的基础，并将有助于制定治疗方案 使用这种预防/治疗方案。鉴于当前多重耐药 SSTI 管理的显着缺陷，这种使用蓝光的新技术展现出巨大的潜力。

项目成果

Antimicrobial Blue Light Inactivation of Gram-Negative Pathogens in Biofilms: In Vitro and In Vivo Studies.

生物膜中革兰氏阴性病原体的抗菌蓝光灭活：体外和体内研究。

• DOI: 10.1093/infdis/jiw070
• 发表时间: 2016-05-01
• 期刊: The Journal of infectious diseases
• 作者: Yucheng Wang;Ximing Wu;Jia Chen;Rehab Amin;Min Lu;Brijesh Bhayana;Jie Zhao;C. Murray;Michael R Hamblin;D. Hooper;T. Dai
• 通讯作者: T. Dai

Antimicrobial blue light inactivation of Candida albicans: In vitro and in vivo studies.

白色念珠菌的抗菌蓝光灭活：体外和体内研究。

• 发表时间: 2016-07-03
• 影响因子: 5.2
• 作者: Zhang, Yunsong;Zhu, Yingbo;Chen, Jia;Wang, Yucheng;Sherwood, Margaret E;Murray, Clinton K;Vrahas, Mark S;Hooper, David C;Hamblin, Michael R;Dai, Tianhong
• 通讯作者: Dai, Tianhong

Antimicrobial Blue Light Therapy for Infectious Keratitis: Ex Vivo and In Vivo Studies.

传染性角膜炎的抗菌蓝光疗法：体外和体内研究。

• 发表时间: 2017-01-01
• 影响因子: 4.4
• 作者: Zhu, Hong;Kochevar, Irene E;Behlau, Irmgard;Zhao, Jie;Wang, Fenghua;Wang, Yucheng;Sun, Xiaodong;Hamblin, Michael R;Dai, Tianhong
• 通讯作者: Dai, Tianhong