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.
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