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

球孢子菌病是一种侵袭性真菌感染，由球孢子虫引起，并在 美国。氟康唑是最常用于轻到中度感染的药物。敏感度降低 在我们的一项大型体外研究中，37%的球孢子虫分离株对氟康唑的耐药性被记录在案 一群人。这就提出了一个问题：经常用于治疗这些感染的药物氟康唑，或者 在这些情况下，应使用其他唑类药物。项目2的目标是评估体内和 唑类抗真菌药物体外耐药的临床意义及替代方案的疗效评价 治疗中枢神经系统和肺部球孢子菌病的治疗策略。这些研究的最终目标是 提供有助于指导临床治疗和改善患者预后的数据 球孢子菌病。为了实现这一目标，我们将确定降低的体内意义 用小鼠中枢神经系统和肺脏模型研究球虫对唑类抗真菌药物的敏感性 球孢子菌病(目标1)。免疫球虫和波斯达西球虫在体外的不同分离株 氟康唑的敏感性将用于已建立的中枢神经系统和肺部感染的小鼠模型。 在#年，将比较使用唑类药物治疗敏感和耐药临床分离株的疗效。 以确定体外耐药对体内反应的意义。我们还将测定体内的 新化合物抗唑耐药所致中枢神经系统和肺部球孢子菌病的疗效 分离株(目标2)。耐氮唑的金黄色葡萄球菌和波斯达西葡萄球菌分离株将被用来评估不同的 球孢子菌病的中枢和肺模型的治疗方法。这将包括 项目1中确定的新化合物和药物筛选核心的体内外评价 对野生型球孢子虫分离株的活性。有前途的候选人将接受联合测试 在项目3中有希望的疫苗策略。最后，我们评估了体外易感性与 氟康唑和其他唑类药物与球孢子菌病患者随时间变化的临床结果(目标3)。 感染氟康唑的患者对球虫敏感(MIC&lt；8g/ml)和耐药(MIC&Gt；32g/ml) 分离株将从临床药敏数据库中鉴定。对病历的回顾将 以确定对氟康唑和其他唑类治疗的反应，这些将与 体外药敏结果。其他将被评估的变量将包括宿主因素、疾病程度、 以及其他可能影响临床结果的因素。随着时间的推移，唑类MIC模式的变化也将是 测量以确定敏感性降低是否是一个持续存在的问题。项目2的结果将 进一步了解球孢子菌对真菌的体外耐药性与抗药性的关系 球孢子菌病的抗真菌药物和体内反应及临床结果。

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.