Cryptococcal meningitis is a frequently lethal fungal infection of the lining of the brain. The most common predisposing condition is advanced AIDS, although cryptococcal meningitis may occur in other circumstances where there is impairment of systemic immunity. Cryptococcal meningitis affects approximately one million people in the world each year and the mortality rate is 60-70%. Recent estimates suggest that cryptococcal meningitis kills more people in sub-Saharan Africa each year than tuberculosis. Unfortunately, there are relatively few active antifungal drugs to treat this infection and each has significant limitations. The best clinical outcomes result from early rapid killing of the fungus in the brain. In the UK this is usually achieved with induction therapy that consists of 2-weeks of intravenous antifungal therapy. Unfortunately, in much of the developing world, it is simply not possible to administer intravenous drugs for any length of time. Hence, the best therapy is not given and clinical outcomes are persistently unsatisfactory. This research aims to develop new induction regimens that can be used in the developing world. Shorter regimens (even a single day) would facilitate the use of optimal induction therapy and represents an important mechanism to improve clinical outcomes. We will conduct all our research using well-validated experimental models of cryptococcal meningitis. We will study antifungal agents alone and in combination to understand the relationship between concentrations of drug(s) in the brain and the killing of the fungus. We will then use mathematical models and computer simulation techniques to identify human antifungal regimens that we predict will result in the same or better activity to the current standard of care that is delivered in the UK. After the completion of this research, we will seek further funding to conduct clinical trials in subSaharan Africa to test these new regimens. Our research offers the real possibility of making significant advances for the care of patients with a lethal and neglected disease.