Antifungal Drug Susceptibility of Cryptococcus neoformans

描述（由申请人提供）：新生隐球菌很少在免疫系统完整的人群中引起疾病，但在宿主免疫功能受损的人群中非常常见，尤其是艾滋病患者。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。目前选用哪种抗真菌药物（两性霉素B、氟康唑或两者合用）、剂量和治疗时间由临床试验报告综合判断来指导。与细菌性病原体的抗菌药物敏感性模式用于选择最有效的抗生素方案不同，新生梭状芽孢杆菌对抗真菌药物的敏感性尚未用于指导治疗。我们的长期目标是建立一种简单的实验室抗真菌药敏试验方法，预测对治疗的生物反应。因此，我们打算建立治疗和生物反应之间的相关关系。我们将使用由NIH赞助的两项前瞻性临床试验的临床信息和分离物收集来支持这一申请。1. 氟康唑治疗艾滋病相关隐球菌性脑膜炎的II期剂量发现研究（坦桑尼亚艾滋病相关并发症国际研究（ISAAC）研究）两性霉素B单独或联合氟康唑治疗艾滋病相关隐球菌性脑膜炎的II期随机试验：（细菌和真菌病研究组：BAMSG 3-01）。这些临床试验提供了一个独特的机会来评估对治疗的定量生物学反应。这两项临床试验都纳入了微生物反应的定量评估，方法是在治疗两周后，计算脑脊液中新生梭形菌的数量。拥有一种能够可靠地预测治疗后反应的体外测量方法，将允许医生选择最有效的治疗方案，预测何时需要延长强化治疗，或者何时可能有用使用联合药物治疗。

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.