FLUCONAZOLE RESISTANCE IN OROPHARYNGEAL CANDIDIASIS

描述：(改编自申请者摘要)对氟康唑耐药 成为HIV感染者管理中的一个重要问题 复发性口咽念珠菌病(OPC)。可能会对氟康唑产生耐药性 在一个持久的菌株中或从一个新的抗药性菌株的出现中。 对其他抗真菌药物的交叉耐药性很常见。其分子机制研究进展 对氟康唑的耐药性包括靶酶的改变，增加 两种多药泵介导的药物外排及血浆变化 膜甾醇。这些机制的普遍存在及其相互关系 在抗性机制和抗真菌管理策略之间还没有 已经确定了。高效逆转录病毒疗法的使用减少了 口咽念珠菌病在一些患者中的发病率，但对 抗感染复发的抗逆转录病毒治疗及其具体机制 耐药性尚不清楚。因此，这项提案的目标是 沙眼衣原体对真菌耐药性的分子流行病学调查 口咽念珠菌病与抗真菌治疗疗效的相关性 抗性机制。这些目标将通过独特的 有机会在4500多个样本中分析耐药性的机制 从地区291余起鹅口疮中前瞻性采集酵母菌 对患者进行连续评估。这项建议的具体目的是：1) 评价高效抗逆转录病毒治疗对口咽部的影响 大剂量氟康唑治疗念珠菌病的疗效观察 酵母菌致口咽念珠菌病的敏感性依次降低 确定治疗策略对耐药性发展的影响； 2)确定猪瘟病毒耐药分子机制的流行病学 口咽念珠菌感染与耐药性的相关性评估 机制、抗真菌管理策略和治疗反应；以及 3)研究临床分离株耐药的分子机制 在没有已知耐药机制的情况下，评估治疗之间的相关性 战略和抵抗机制，并最终导致改善 口咽部念珠菌病患者的处理。

DESCRIPTION: (Adapted from Applicant's Abstract) Fluconazole resistance has become an important problem in the management of HIV-infected patients with recurrent oropharyngeal candidiasis (OPC). Fluconazole resistance can develop in a persistent strain or from emergence of a new resistant strain. Cross-resistance to other antifungals is common. Molecular mechanisms of fluconazole resistance include alterations in the target enzyme, increased efflux of drug mediated by two types of multidrug pumps, and changes in plasma membrane sterols. The prevalance of these mechanisms and the correlation between mechanisms of resistance and antifungal management strategies has not been determined. The use of highly active retroviral therapy has reduced the incidence of oropharyngeal candidiasis in some patients, but the impact of antiretroviral therapy on recurrence of infection and specific mechanisms of resistance is not known. Thus, the objectives of this proposal are to investigate the molecular epidemiology of antifungal resistance in oropharyngeal candidiasis and to correlate efficacy of antifungal therapy with mechanisms of resistance. These objectives will be achieved through the unique opportunity to analyze mechanisms of resistance in a collection of over 4,500 yeast isolates collected prospectively from over 291 episodes of thrush in 64 patients serially evaluated. The specific aims of this proposal are: 1) to evaluate the impact of highly active antiretroviral therapy on oropharyngeal candidiasis and to determine the efficacy of high dose fluconazole in oropharyngeal candidiasis due to yeasts with decreased susceptibility in order to establish the effect of therapeutic strategies on development of resistance; 2) to determine the epidemiology of molecular mechanisms of resistance in oropharyngeal candidiasis and to assess the correlation between resistance mechanisms and antifungal management strategies and response to treatment; and 3) to characterize molecular resistance mechanisms in selected clinical isolate without known resistance mechanisms, assess the correlation between treatment strategies and resistance mechanisms, and ultimately result in improved management of patients with oropharyngeal candidiasis.