Antifungal Drug Susceptibility of Cryptococcus neoformans

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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.