Fluconazole is very effective in the treatment of oral thrush, but an increasing number of patients with recurrent oropharyngeal candidiasis have developed fluconazole-resistant yeasts following repeated courses of fluconazole therapy. Fluconazole resistance can develop in a single persistent strain of yeast, but more commonly fluconazole resistance results from emergence of a different Candida albicans strain or another Candida species. Higher doses of fluconazole are more effective against resistant strains in murine candidiasis, but the utility of identifying resistant isolates and treating resistant yeasts with high doses of fluconazole is not established. Thus, the objectives of this proposal are to define prospectively the epidemiology of fluconazole-resistant oropharyngeal candidiasis, to correlate therapeutic response with fluconazole resistance, and to evaluate the role of higher doses of fluconazole in treating resistant yeasts. These objectives will be achieved by longitudinally evaluating patients with HIV infection/AIDS treated with fluconazole for recurrent oropharyngeal candidiasis. The goal of these studies is to improve the treatment of oropharyngeal candidiasis in patients with HIV infection/AIDS.
The specific aims of this proposal are: 1) To longitudinally evaluate a cohort of patients with recurrent oropharyngeal candidiasis for the development of fluconazole resistance and to correlate that resistance with clinical response to therapy; 2) To establish strain identity using molecular characterization of the yeasts in order to establish the epidemiology of fluconazole- resistant oropharyngeal candidiasis; 3) To correlate antifungal susceptibility testing with clinical outcome and to determine the utility of screening susceptibility techniques to detect fluconazole resistant yeasts; 4) To evaluate high doses of fluconazole against resistant yeasts in a murine model of candidiasis; 5) To determine the clinical utility of high doses of fluconazole in treating patients with fluconazole-resistant yeasts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE011381-02
Application #
2132671
Study Section
Special Emphasis Panel (ZDE1-YS (33))
Project Start
1994-09-30
Project End
1997-09-29
Budget Start
1995-09-30
Budget End
1996-09-29
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Texas Health Science Center San Antonio
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Patterson, Thomas F (2005) Advances and challenges in management of invasive mycoses. Lancet 366:1013-25
Redding, Spencer W; Kirkpatrick, William R; Saville, Stephen et al. (2003) Multiple patterns of resistance to fluconazole in Candida glabrata isolates from a patient with oropharyngeal candidiasis receiving head and neck radiation. J Clin Microbiol 41:619-22
Bachmann, Stefano P; Ramage, Gordon; VandeWalle, Kacy et al. (2003) Antifungal combinations against Candida albicans biofilms in vitro. Antimicrob Agents Chemother 47:3657-9
Martinez, Marcos; Lopez-Ribot, Jose L; Kirkpatrick, William R et al. (2002) Replacement of Candida albicans with C. dubliniensis in human immunodeficiency virus-infected patients with oropharyngeal candidiasis treated with fluconazole. J Clin Microbiol 40:3135-9
Bachmann, Stefano P; Patterson, Thomas F; Lopez-Ribot, Jose L (2002) In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J Clin Microbiol 40:2228-30
Perea, Sofia; Lopez-Ribot, Jose L; Wickes, Brian L et al. (2002) Molecular mechanisms of fluconazole resistance in Candida dubliniensis isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 46:1695-703
Martinez, M; Lopez-Ribot, J L; Kirkpatrick, W R et al. (2002) Heterogeneous mechanisms of azole resistance in Candida albicans clinical isolates from an HIV-infected patient on continuous fluconazole therapy for oropharyngeal candidosis. J Antimicrob Chemother 49:515-24
Perea, Sofia; Gonzalez, Gloria; Fothergill, Annette W et al. (2002) In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother 46:3039-41
Bachmann, Stefano P; VandeWalle, Kacy; Ramage, Gordon et al. (2002) In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 46:3591-6
Lin, A L; Johnson, D A; Patterson, T F et al. (2001) Salivary anticandidal activity and saliva composition in an HIV-infected cohort. Oral Microbiol Immunol 16:270-8

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