Nitric Oxide-Releasing Intranasal Gel To Decolonize Biofilm-embedded S. Aureus

释放一氧化氮的鼻内凝胶可去除嵌入生物膜的金黄色葡萄球菌

• 批准号: 8324559
• 负责人: Susanne Bauman
• 金额: $ 29.3万
• 依托单位: NOVAN, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-25 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8324559
• 关键词: Accounting; Bacteria; Bactroban; Belief; Breathing; Breeding; Cell membrane; Cessation of life; Clinical; Clinical Research; Contracts; Development; Diffuse; Dose; Drug Formulations; Drug resistance; FDA approved; Free Radicals; Gases; Gel; Goals; Growth; Hospital Costs; Hospitalization; Hospitals; Human body; In Vitro; Infection; Inpatients; Investigational New Drug Application; Lead; Link; Measures; Microbial Biofilms; Modeling; Mupirocin; Mutagenesis; Nitric Oxide; Nitric Oxide Donors; Nose; Operative Surgical Procedures; Patients; Pharmaceutical Preparations; Phase; Plague; Population; Prevalence; Problem Solving; Prodrugs; Rattus; Research; Resistance; Resistance development; Risk; Risk Factors; Safety; Sepsis; Serial Passage; Silicon Dioxide; Small Business Innovation Research Grant; Staphylococcal Infections; Staphylococcus aureus; Symptoms; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicology; Treatment Failure; Vertebral column; Work; antimicrobial; antimicrobial drug; bacterial resistance; bactericide; base; cost; drug development; experience; fighting; in vivo; irritation; killings; manufacturing scale-up; mouse model; particle; pre-clinical; preclinical evaluation; resistant strain; small molecule; success

DESCRIPTION (provided by applicant): Staphylococcus aureus is the second leading cause of hospital-acquired bloodstream infections. In 2003, nearly 300,000 patients in US hospitals acquired an S. aureus infection, which accounted for nearly three million days of hospitalization, $9.5 billion in excess costs, and at least 12,000 inpatient deaths. Additionally, approximately 50% of the US population either persistently or intermittently carries a biofilm of S. aureus in their nose without experiencing any symptoms. Despite the lack of symptoms, nasal carriage of S. aureus is a well-known risk factor for developing a hospital-associated staphylococcal infection. Nasal carriers of S. aureus are three- to six-times more likely to acquire an S. aureus infection in the hospital, and, approximately 80% of the time, that infection is caused by the strain of S. aureus that lives in their nose. Based on infection rates and the prevalence of S. aureus nasal carriers, it has been estimated that eradicating S. aureus from the noses of surgical patients could save $4.5 billion a year in US hospital costs. The only FDA-approved treatment for nasal decolonization of S. aureus is 2% mupirocin. Clinical studies have shown that nasal decolonization decreases the number of infections contracted by S. aureus carriers, but resistance to mupirocin is becoming a concern. In vitro, the concentration of mupirocin required to inhibit growth of S. aureus increases significantly after only one exposure, and there is a growing body of clinical evidence linking mupirocin resistance to unsuccessful nasal decolonization. Nitric oxide, a free radical gas naturally produced by the human body to help fight infection, is a promising alternative to mupirocin for nasal decolonization of S. aureus. In recent years, the use of nitric oxide as an antimicrobial agent has been investigated due to its broad-spectrum antimicrobial activity, ability to diffuse directly through cell membranes, and the belief that it would be very difficult for nitric oxide-resistant strains of bacteria to develop. Additionally, nitric oxide has been shown to be effective against biofilm embedded bacteria. The goal of this SBIR project is to use Novan's proprietary nitric oxide-releasing technology to develop a topical nitric oxide-releasing nasal product capable of eradicating S. aureus biofilms from the noses of carriers without breeding bacterial resistance. In this proposal, Novan aims to: 1) Establish the minimum concentration of nitric oxide-releasing silica (Nitricil(tm)) required for bactericidal activity against 90% of S. aureus clinical isolates under planktonic and biofilm growth conditions in vitro; 2) Determine whether S. aureus can develop stable resistance to nitric oxide; and 3) Evaluate the safety of Nitricil(tm) particles for use in the nose. Upon achieving these aims, Phase II efforts will focus on preclinical evaluation of intranasal Nitricil(tm) formulations, including: 1) testing the lead formulations against a mouse model of S. aureus nasal colonization; 2) full preclinical toxicology; and 3) the quality scale-up manufacturing of both drug substance and drug product required to submit an Investigational New Drug application to the FDA.

描述（由申请人提供）：金黄色葡萄球菌是医院获得性血流感染的第二大原因。 2003年，美国医院有近30万名患者感染金黄色葡萄球菌，造成近300万天的住院时间、95亿美元的超额费用以及至少12,000名住院患者死亡。此外，大约 50% 的美国人鼻子中持续或间歇性携带金黄色葡萄球菌生物膜，但没有出现任何症状。尽管没有症状，但鼻腔携带金黄色葡萄球菌是发生医院相关葡萄球菌感染的一个众所周知的危险因素。金黄色葡萄球菌鼻腔携带者在医院感染金黄色葡萄球菌的可能性高出三到六倍，并且大约 80% 的情况下，这种感染是由生活在其体内的金黄色葡萄球菌菌株引起的。鼻子。根据金黄色葡萄球菌鼻带菌的感染率和流行率，据估计，根除手术患者鼻子中的金黄色葡萄球菌每年可为美国医院节省 45 亿美元的费用。 FDA 批准的唯一用于金黄色葡萄球菌鼻去定植的治疗方法是 2% 莫匹罗星。临床研究表明，鼻去定植可减少金黄色葡萄球菌携带者感染的数量，但对莫匹罗星的耐药性正成为一个问题。在体外，仅接触一次后，抑制金黄色葡萄球菌生长所需的莫匹罗星浓度就显着增加，并且越来越多的临床证据表明莫匹罗星耐药性与不成功的鼻去定植有关。一氧化氮是人体自然产生的一种自由基气体，有助于抵抗感染，是莫匹罗星的一种很有前途的替代品，用于金黄色葡萄球菌的鼻去定植。近年来，人们对一氧化氮作为抗菌剂的使用进行了研究，因为它具有广谱抗菌活性，能够直接通过细胞膜扩散，并且人们相信一氧化氮耐药菌株很难使用它发展。此外，一氧化氮已被证明可以有效对抗生物膜嵌入的细菌。该SBIR项目的目标是利用Novan专有的一氧化氮释放技术来开发一种局部一氧化氮释放鼻用产品，能够根除携带者鼻子中的金黄色葡萄球菌生物膜，而不滋生细菌耐药性。在该提案中，Novan 的目标是： 1) 确定在体外浮游和生物膜生长条件下对 90% 的金黄色葡萄球菌临床分离株具有杀菌活性所需的释放一氧化氮的二氧化硅 (Nitricil(tm)) 的最低浓度； 2) 确定金黄色葡萄球菌是否能够对一氧化氮产生稳定的抗性； 3) 评估 Nitricil(tm) 颗粒在鼻子中使用的安全性。实现这些目标后，第二阶段工作将集中于鼻内 Nitricil(tm) 制剂的临床前评估，包括：1) 针对金黄色葡萄球菌鼻定植小鼠模型测试先导制剂； 2）完整的临床前毒理学； 3) 向 FDA 提交研究性新药申请所需的原料药和制剂的质量放大生产。