This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This protocol is designed to study the development of fluconazole resistance in patients with advanced immunodeficiency, to correlate that resistance with clinical response and to test the effectiveness of using high doses of fluconazole to treat oropharyngeal infections. OBJECTIVES: Fluconazole resistance has become an important clinical problem in the management of HIV-infected patients with recurrent oropharyngeal candidiasis. 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 multi-drug pumps, and changes in plasma membrane sterols. The prevalence of these mechanisms and the correlation between mechanisms of resistance and antifungal management strategies has not been determined. The use of highly active antiretroviral therapy (HAART) 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 to: 1. 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. Determine the epidemiology of the 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. Characterize molecular resistance mechanisms in selected clinical isolates without known resistance mechanisms. These studies will increase understanding of the epidemiology of resistance mechanisms, assess the correlation between treatment strategies and resistance mechanisms, and ultimately result in improved management of patients with oropharyngeal candidiasis. METHODS: The clinical goals of this study are to longitudinally evaluate a cohort of patients with recurrent oropharyngeal candidiasis treated with fluconazole therapy for the development of fluconazole resistance, to correlate that resistance with clinical response to therapy, and to assess the efficacy of higher doses of fluconazole therapy in eliminating resistant yeast. A total of 64 adult patients over 18 years of age with HIV infection or AIDS and the diagnosis of oropharyngeal candidiasis will be recruited to participate in this study. Patients with oropharyngeal candidiasis will be randomized to receive daily fluconazole therapy or intermittent therapy with development of infection. Patients with recurrent thrush will be treated with a standard dose regimen of fluconazole (100 mg/d for 7 days) that is increased as indicated in order to achieve a clinical response. Patients will undergo serial oropharyngeal culture for yeast. The yeast isolates will be identified and tested for antifungal susceptibility, mechanisms of resistance and molecular typing. Patients with resistant isolates will be randomized to receive either continuation of fluconazole at standard doses or fluconazole at high doses (400-800 mg/d for 7 days) based on susceptibility results. Patients will continue to receive clinical care at the facility where their usual care is given and will also be followed for study visits on an outpatient basis at the GCRC located at the VA hospital.
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