Antifungal antagonism as a cause of treatment failure for invasive mycoses

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An estimated 1.5 million people die each year from invasive fungal infections (IFIs), with millions more afflicted by debilitating mucosal and subcutaneous mycoses. Current antifungal therapies have serious deficiencies including limited spectrum of activity, patient toxicity and the emergence of fungal isolates with genetically encoded resistance. A larger concern is the modest efficacy of all three major classes of antifungal drug, as this is likely a major driver of the excessively high rates of mortality in patients with IFIs, and persistence of mucosal infections. For unexplained reasons, the majority of treatment failures occur in patients infected by fungal isolates that are seemingly sensitive to the selected antifungal therapy, as determined by in vitro susceptibility testing. For example, approximately one-third of patients with a disseminated Candida infection involving isolates deemed susceptible according to current clinical breakpoints, fail to respond to treatment with an azole antifungal. Several host-related factors have been proposed to explain the discordance between in vitro susceptibility tests and patient outcomes, such as inadequate drug distribution to the site of infection or severity of patient immune dysfunction. However, there is only limited evidence to support these arguments, and many treatment failures remain unexplained. While drug-drug interactions are a serious concern from the perspective of patient toxicity, the effect of most co-administered medications upon fungal physiology and antifungal susceptibility, is largely unknown. Using a simple screen of mainly off-patent medications, we recently found that a staggering 139 of the 1280 compounds examined exhibit antagonistic interactions with fluconazole in at least one medically important Candida species. Our preliminary studies have also revealed that non-antifungal medications can have a profound impact upon fungal physiology and upon the outcome of infection in mice. The objective of this study is to uncover the full scope of antifungal drug-drug antagonistic interactions and assess their potential clinical impact upon treatment outcomes in patients with IFIs. In aim 1 we will conduct a comprehensive and systematic set of screens to identify currently approved medications that antagonize the activity of the most relevant antifungal drugs, in four of the most prevalent human fungal pathogens. Those acting at pharmacologically relevant concentrations will then be selected, and the extent to which antifungal activity is diminished compared. Aim 2 will focus upon defining the molecular mechanisms by which antifungal antagonists act and examine their effects upon fungal physiology. Finally, in aim 3 we will use a mouse model of invasive candidiasis and conduct a retrospective analysis of patient outcomes to determine if coadministration of antagonistic drugs is sufficient to influence the clinical efficacy of antifungal therapy. The long-term goal is to improve patient outcomes through establishing integrated treatment protocols that minimize clinically relevant antagonistic drug-interactions to and therefore maximize antifungal efficacy.