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.

球孢子菌病是一种由球孢子菌属物种引起的侵袭性真菌感染，并且其发病率正在增加 在美国，氟康唑是最常用于降低易感性的药物。 在我们的一项大型体外研究中，>37% 的分离株记录了球孢子菌分离株对氟康唑的耐药性 这就提出了一个问题：氟康唑（一种经常用于治疗这些感染的药物）是否有效？ 在这些情况下应使用其他唑类药物。项目 2 的目的是评估体内和体外的效果。 唑类抗真菌药物体外耐药性的临床意义及替代药物的疗效评价 治疗中枢神经系统和肺球孢子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治疗并改善患者预后的数据 为了实现这一目标，我们将确定球孢子菌病减少的体内意义。 使用中枢神经系统和肺部小鼠模型研究球孢子菌对唑类抗真菌药的敏感性 球孢子菌病（目标 1）：Coccidioides immitis 和 C. posadasii 具有不同的体外分离株。 氟康唑敏感性将用于已建立的中枢神经系统和肺部感染小鼠模型。 将比较唑类敏感和唑类耐药临床分离株的治疗效果 为了确定体外耐药性对体内反应的重要性，我们还将确定体内反应。 新型化合物对抗唑类耐药引起的中枢神经系统和肺球孢子菌病的有效性 抗唑类 C. immitis 和 C. posadasii 分离株将用于评估不同的菌株。 球孢子菌病的中枢神经系统和肺部模型的治疗方法这将包括 项目 1 和药物筛选核心中鉴定的新化合物的体外或体内评价 将结合测试针对野生型球孢子菌分离株的活性。 项目 3 中有前途的疫苗策略。最后，我们评估了体外易感性之间的相关性 氟康唑和其他唑类药物以及球孢子菌病患者随时间的临床结果（目标 3）。 感染氟康唑敏感（MIC <8 µg/ml）和耐药（MIC >32 µg/ml）球孢子菌的患者 将从临床敏感性数据库中鉴定分离株。 进行以确定对氟康唑和其他唑类治疗的反应，这些将与 将评估的其他变量包括宿主因素、疾病程度、 以及其他可能影响临床结果的因素也会随着时间的推移而改变。 项目 2 的结果将进行测量以确定敏感性降低是否是一个持续存在的问题。 进一步了解球孢子菌分离株的体外抗真菌耐药性与 球孢子菌病的抗真菌药物和体内反应以及临床结果。