Antifungal Drug Susceptibility of Cryptococcus neoformans

描述(申请人提供)：新生隐球菌在免疫系统完整的人中很少致病，但在宿主免疫力受损的人中是一个非常常见的问题--特别是艾滋病患者。在发展中国家，隐球菌性脑膜炎和肺结核是两种最常见的机会性感染。目前，抗真菌药物的选择(两性霉素B、氟康唑或两者合用)、剂量和疗程都是通过综合已报道的临床试验来指导临床判断。与细菌病原体不同，在细菌病原体中，抗菌素敏感性模式被用来选择最有效的抗生素方案，而新生葡萄球菌对抗真菌药物的敏感性并未被用来指导治疗。我们的长期目标是建立一种简单的实验室抗真菌敏感性测试方法，以预测治疗的生物学反应。因此，我们打算在治疗和生物反应之间建立关联。我们将使用临床信息和从NIH赞助的两个预期临床试验中收集的分离株来支持这一申请。1.氟康唑治疗艾滋病相关隐球菌性脑膜炎的第二阶段剂量发现研究(坦桑尼亚的国际艾滋病相关并发症研究(SASAC)研究)2.两性霉素B单独或与氟康唑联合治疗艾滋病相关隐球菌性脑膜炎的第二阶段随机试验：(细菌和真菌研究组：BAMSG 3-01)。这些临床试验为评估治疗的定量生物学反应提供了一个独特的机会。这两项临床试验都包含了对微生物反应的定量评估，方法是在治疗两周后计数脑脊液中的新生葡萄球菌数量。拥有一种能够可靠地预测治疗后反应的体外测量方法，将使医生能够选择活性最大的治疗方案，预测何时需要延长强化治疗，或者何时使用联合药物治疗可能有用。

DESCRIPTION (provided by applicant): Cryptococcus neoformans rarely causes disease among those with an intact immune system but is a very common problem among those with impaired host immunity - particularly those with AIDS. In the developing world cryptococcal meningitis and pulmonary tuberculosis are the two most common opportunistic infections. Presently selection of which anti-fungal agent (amphotericin B, fluconazole or the two combined), the dose and the duration of therapy are guided by clinical judgment from the synthesis of reported clinical trials. Unlike bacterial pathogens wherein the antimicrobial susceptibility pattern is used to select the most active antibiotic regimen, the susceptibility of C. neoformans to antifungal drugs has not been used to guide therapy. Our long-term goal is to establish a simple laboratory method of antifungal susceptibility testing which predicts the biological response to treatment. As such, we intend to establish a correlative association between treatment and biologic response. We will use the clinical information and the collection of isolates from two prospective clinical trials sponsored by the NIH in support of this application. 1. A phase II dose finding study of fluconazole treatment in AIDS-associated cryptococcal meningitis (International Studies of Aids Associated Complications (ISAAC) study in Tanzania) 2. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of AIDS-associated cryptococcal meningitis: (Bacterial and Mycoses Study Group: BAMSG 3-01). These clinical trials offer a unique opportunity to assess the quantitative biological response to treatment. Both clinical trials incorporate a quantitative assessment of microbial response by enumerating the number of C. neoformans in the cerebrospinal fluid following two weeks of treatment. Having an in vitro measure that can reliably predict response following treatment would permit physicians to select the treatment regimen with the greatest activity, predict when it would be necessary to extend intensive treatments or when it may be useful to employ combination drug therapy.