Relationship between in vitro antifungal resistance and in vivo response in coccidioidomycosis

球孢子菌病体外抗真菌耐药性与体内反应的关系

• 批准号: 10541236
• 负责人: THOMAS F. PATTERSON
• 金额: $ 28.01万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10541236
• 关键词: African; Amphotericin B; Antifungal Agents; Area; Arizona; Azole resistance; Azoles; California; Central Nervous System; Central Nervous System Diseases; Clinical; Coccidioides; Coccidioides immitis; Coccidioides posadasii; Coccidioidomycosis; Data; Databases; Disease; Dose; Drug Kinetics; Drug Screening; Effectiveness; Ethnic Origin; Evaluation; Filipino; Fluconazole; Fungal Drug Resistance; Goals; HIV/AIDS; Immunity; Immunocompromised Host; In Vitro; Incidence; Infection; Inhalation; Integration Host Factors; Link; Lung; Lung infections; Measures; Medical History; Military Personnel; Modeling; Mycoses; Nevada; New Mexico; Organ Transplantation; Outcome; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Predisposition; Pregnancy; Progressive Disease; Recommendation; Research; Resistance; Respiratory Signs and Symptoms; Risk; Testing; Texas; Therapeutic; Time; Treatment Efficacy; Utah; Vaccines; Virulent; Visit; Work; acute infection; candidate identification; clinically relevant; clinically significant; desert fever; efficacy evaluation; fungus; high risk; improved outcome; in vitro activity; in vivo; mouse model; novel; response; therapeutic development; treatment response; vaccine strategy

Coccidioidomycosis is an invasive fungal infection that is caused by Coccidioides species and is increasing in the US. Fluconazole is the drug most frequently used for mild to moderate infection. Decreased susceptibility of Coccidioides isolates to fluconazole was documented in >37% of isolates in a large in vitro study by our group. This raises the question of whether fluconazole, a drug frequently used against these infections, or other azoles should be utilized in those situations. The objective of Project 2 is to evaluate the in vivo and clinical significance of in vitro resistance to the azole antifungals and evaluate the efficacy of alternative therapeutic strategies to treat CNS and pulmonary coccidioidomycosis. The ultimate goal of these studies is to provide data that may help guide clinical therapy and improve the outcomes of patients with coccidioidomycosis. To achieve this objective, we will determine the in vivo significance of decreased Coccidioides susceptibility to azole antifungals using murine models of CNS and pulmonary coccidioidomycosis (Aim 1). Both Coccidioides immitis and C. posadasii isolates with different in vitro fluconazole susceptibilities will be used in established murine models of CNS and pulmonary infections. Treatment efficacy with azoles will be compared for azole-susceptible and azole-resistant clinical isolates in order to determine the significance of in vitro resistance on in vivo response. We will also determine the in vivo effectiveness of novel compounds against CNS and pulmonary coccidioidomycosis caused by azole-resistant isolates (Aim 2). Azole-resistant C. immitis and C. posadasii isolates will be used to evaluate different therapeutic approaches in the CNS and pulmonary models of coccidioidomycosis. This will include the evaluation of novel compounds identified in Project 1 and the Drug Screening Core with in vitro or in vivo activity against wild-type Coccidioides isolates. Promising candidates will be tested in combination with promising vaccine strategies in Project 3. Finally, we assess the correlation between in vitro susceptibility to fluconazole and other azoles and clinical outcomes over time in patients with coccidioidomycosis (Aim 3). Patients infected with fluconazole susceptible (MIC <8 g/ml) and resistant (MIC >32 g/ml) Coccidioides isolates will be identified from a clinical susceptibility database. Retrospective reviews of medical histories will be conducted to determine responses to fluconazole and other azole therapy and these will be correlated with in vitro susceptibility results. Other variables that will be assessed will include host factors, extent of disease, and other factors that may influence clinical outcomes. Changes in azole MIC patterns over time will also be measured to determine whether reduced susceptibility is a continuing problem. The results of Project 2 will further our understanding of the relationship between in vitro antifungal resistance of Coccidioides isolates to antifungals and in vivo responses and clinical outcomes in coccidioidomycosis.

球虫菌病是由球虫剂引起的一种侵入性真菌感染，正在增加 美国。氟康唑是最常用于轻度至中度感染的药物。敏感性降低 在我们的大型体外研究中，在> 37％的分离株中记录了与氟康唑分离株与氟康唑的分离株的。 团体。这就提出了一个问题，即氟康唑，一种经常用于这些感染的药物还是 在这些情况下应使用其他azoles。项目2的目的是评估体内和 体外抵抗对偶氮抗真菌的临床意义，并评估替代性的有效性 治疗中枢神经系统和肺球菌病的治疗策略。这些研究的最终目标是 提供可能有助于指导临床疗法并改善患者的结果的数据 球菌病。为了实现这一目标，我们将确定减少的体内意义 使用中枢神经系统和肺的鼠模型，球球菌对偶氮抗真菌的敏感性 球菌病（AIM 1）。球虫毒剂免疫炎和c. posadasii分离株与不同的体外 氟康唑的敏感性将用于CNS和肺部感染的已建立鼠模型。 将偶氮对氮唑的治疗效率进行比较 为了确定体外耐药性对体内反应的重要性。我们还将确定体内 针对中枢神经系统的新化合物和由抗硫唑耐药引起的肺球菌病的有效性 分离物（目标2）。抗硫杆菌的侵入性炎和c。posadasii分离株将用于评估不同的 Coccidioycomisois的中枢神经系统和肺模型的治疗方法。这将包括 评估项目1中鉴定出的新型化合物以及体外或体内的药物筛选核心 针对野生型球虫分离株的活性。有希望的候选人将与 项目3中有希望的疫苗策略。最后，我们评估了体外敏感性与 氟康唑和其他硫唑体随着时间的流逝而在球虫病的患者中会随着时间的流逝而随着时间的流逝（AIM 3）。 感染了氟康唑易感的患者（MIC <8G/mL）和抗性（MIC> 32G/ml）球球菌 分离株将从临床易感性数据库中识别。对医学历史的回顾性评论将 进行以确定对氟康唑和其他唑局治疗的反应，这些将与 体外敏感性结果。将评估的其他变量将包括宿主因素，疾病程度， 以及可能影响临床结果的其他因素。随着时间的推移，Azole MIC模式的变化也将是 测量以确定降低的敏感性是否是一个持续问题。项目2的结果将 进一步，我们了解了球虫分离株与 抗真菌剂，体内反应和球菌病的临床结果。