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，由球孢子菌属物种引起， 美方氟康唑是最常用于轻度至中度感染的药物。敏感性降低 在我们的一项大型体外研究中， 组这就提出了一个问题，是否氟康唑，一种经常用于治疗这些感染的药物， 在这些情况下应使用其它唑类。项目2的目的是评价体内和 唑类抗真菌药体外耐药的临床意义及替代药物的疗效评价 治疗CNS和肺球孢子菌病的治疗策略。这些研究的最终目的是 提供可能有助于指导临床治疗和改善患者结局的数据， 球孢子菌病为了实现这一目标，我们将确定在体内的意义， 使用CNS和肺的小鼠模型的球孢子菌对唑类抗真菌剂的敏感性 球孢子菌病（Aim 1）。粗球孢子菌（Coccidioides immitis）和粗球孢子菌（C.不同体外培养条件下的Posadasii菌株 氟康唑药敏性将用于已建立的CNS和肺部感染的鼠模型。 将比较唑类药物对唑类敏感和唑类耐药临床分离株的治疗效果， 以确定体外耐药性对体内反应的重要性。我们还将确定体内 新化合物对耐唑类药物引起的CNS和肺球孢子菌病的有效性 分离株（目的2）。抗唑C. immitis和C. Posadasii分离株将用于评价不同的 在球孢子菌病的CNS和肺模型中的治疗方法。这将包括 在项目1和药物筛选核心中鉴定的新化合物的体外或体内评价 抗野生型球孢子菌分离株的活性。有希望的候选人将结合测试， 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推移的临床结局（目的3）。 感染氟康唑敏感（MIC <8 μ g/ml）和耐药（MIC >32 μ g/ml）球孢子菌的患者 将从临床敏感性数据库中鉴定分离株。对病史的回顾性审查将 以确定对氟康唑和其他唑类药物治疗的反应，这些反应将与 体外敏感性结果。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。还将研究唑类药物MIC模式随时间的变化。 测量以确定敏感性降低是否是一个持续的问题。项目2的成果将 进一步加深了我们对球孢子菌属分离株体外抗真菌耐药性与 抗真菌药和球孢子菌病的体内反应和临床结果。

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.