Predicting and Improving Clinical Outcomes for Bacterial Keratitis

产品描述：我寻求K23职业发展奖的目标有两个方面：1）使用NEI赞助的类固醇角膜溃疡试验（SCUT）的基础设施，以检查添加局部类固醇是否改善细菌性角膜溃疡亚组的临床结果; 2）通过实践研究经验，教学和指导，发展我作为眼部感染和炎症独立研究者的职业生涯。关于使用类固醇治疗细菌性角膜溃疡一直存在争议。需要额外的数据，包括特定亚组的结果，以帮助临床医生了解风险与受益。类固醇用于角膜溃疡治疗（SCUT）是一项由NEI资助的试验，在加州大学旧金山分校的普罗克特基金会、印度南部的Arvind眼科医院和达特茅斯-希区柯克医疗中心招募患者。SCUT的主要目的是研究局部类固醇对细菌性角膜溃疡的影响，通过3个月时的最佳矫正视力和瘢痕大小等结局进行测量。研究者建议进行辅助研究，按微生物（铜绿假单胞菌与所有其他微生物）、遗传差异（通过细胞毒性铜绿假单胞菌的侵袭性）和抗生素敏感性比较基线特征和临床结局。将讨论三个具体目标：目标1：确定连续局部类固醇治疗对铜绿假单胞菌角膜炎与其他微生物引起的细菌性角膜炎的临床结局的影响。目标二：确定铜绿假单胞菌的侵袭性和细胞毒性亚型在入组时是否具有不同的临床体征，或对治疗的反应是否不同。目的3：确定细菌性角膜炎的抗生素敏感性与临床结果之间是否存在相关性。作为SCUT试验的一部分，已经收集了这些目标所需的数据和样本。作为本研究提案的一部分，将对铜绿假单胞菌分离株进行目标2的亚型分型，并将测定目标3中每种细菌分离株对研究抗生素利多卡因的最小抑菌浓度。将使用回归模型确定各种因素（包括类固醇治疗、细菌分离株类型、铜绿假单胞菌毒力因子和最小抑菌浓度）对细菌性角膜炎基线特征和临床结局的影响。细菌性角膜炎是世界范围内视力损害的主要原因，影响患者的生活质量和功能状态。我们的目标是提供数据，使临床医生能够以循证方式对细菌性角膜溃疡患者进行风险分层。

Description: My objectives in seeking a K23 career development award are two-fold: 1) to use the infrastructure of the NEI-sponsored Steroid for Corneal Ulcers Trial (SCUT) to examine whether adding topical steroids improves clinical outcomes of subgroups of bacterial corneal ulcers; 2) to develop my career as an independent investigator in ocular infection and inflammation by hands-on research experience, didactics and mentorship. There is ongoing controversy regarding the use of steroids in treating bacterial corneal ulcers. Additional data, including results in specific subgroups, are needed to help clinicians understand the risks vs benefits. Steroid for Corneal Ulcer Treatment (SCUT) is an NEI-funded, trial enrolling patients at the Proctor Foundation at UCSF, Arvind Eye Hospital in South India, and Dartmouth-Hitchcock Medical Center. The main objective of SCUT is to study the effect of topical steroids on bacterial corneal ulcers, as measured by outcomes including best corrected visual acuity and scar size at 3 months. The investigator proposes to perform ancillary studies comparing baseline characteristics and clinical outcome by organisms (Pseudomonas aeruginosa vs. all others) by genetic difference (Invasive via cytotoxic P. aeruginosa) and by antibiotic susceptibility. Three specific aims will be addressed: Aim 1: to determine the effect of adjunctive topical steroid therapy on clinical outcomes in P. aeruginosa keratitis compared to bacterial keratitis due to the other organisms. Aim 2: To determine whether the invasive and cytotoxic subtypes of P. aeruginosa have different clinical signs at enrollment, or have a different response to treatment. Aim 3: To determine whether there is a correlation between antibiotic susceptibility and the clinical outcome in bacterial keratitis. The data and samples necessary for these aims are already being collected as part of the SCUT trial. As part of this research proposal, P.aeruginosa isolates will be subtyped for Aim 2 and the minimum inhibitory concentration of each bacterial isolate to the study antibiotic moxifloxacin will be determined for Aim 3. Regression models will be utilized to determine the impact of various factors, including treatment with steroids, bacterial isolate type, P.aeruginosa virulence factors, and minimum inhibitory concentration, on baseline characteristics and clinical outcomes in bacterial keratitis. Bacterial keratitis is a major cause of visual impairment worldwide, affecting both patients' quality of life and functional status. Our goal is to provide data to allow clinicians to risk-stratify patients with bacterial corneal ulcers in an evidence-based manner.