Despite recent increase in the number of antifungal agents available for the treatment of systemic fungal diseases, morbidity and mortality are substantial; noting that invasive candidiasis (IC) is the fourth most common cause of nosocomial bloodstream infection in the United States chiefly among immunocompromised patients and that IC is associated with the highest crude mortality of all bloodstream infections (ca. 40%). Given the dismal outcomes for IC, combination of antifungal agents is increasingly being considered. However, pharmacodynamic (PD) properties for established and novel combinations of antifungal agents are ill-defined in terms of dose selection, dose fractionation, predictive PD index (PDI), and post-antibiotic effect (PAE) in relation to treatment efficacy and host toxicity. The major goal of this research project is to characterize the PD properties of established and novel combinations of antifungal agents in a neutropenic murine model of IC, aiming for novel insights and progress in IC beyond the present scope of research and therapy, which is usually single agent-based. Towards enabling in vivo PD studies, we made exciting progress in combination delivery (co-delivery) of amphotericin B (AmB) with other antifungal agents via self-assembled polymers, fulfilling requirements in solubility, safety, stability, and synergy, which ca now be achieved by the coincident action of combination antifungal agents administered simultaneously. We hypothesize that AmB and 5-fluoro- cytosine (5-FC) delivered together intravenously will exert potent antifungal activity, with low or no conversion of 5-FC into 5-fluorouracil (5-FU), observed after oral 5-FC, resulting in decreased bone marrow toxicity. We hypothesize that AmB and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat shock protein 90 (Hsp90) inhibitor, will exert potent antifungal activity with low renal toxicity. Specifc Aims: (1) To characterize PK of micellar AmB and 5-FC, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose (dose fractionation) regimens: PAE; predictive PDI (for maximum antifungal efficacy and optimal dosing regimen); and hematology relative to oral 5-FC. (2) To characterize PK of micellar AmB and 17-AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; and renal and hepatic toxicity. (3) To characterize PK of micellar AmB, 5-FC, and micellar 17- AAG, antifungal activity in a neutropenic murine model of IC, and toxicity in single and multiple dose regimens: PAE; predictive PDI; hematology; renal toxicity; and histopathology in major organs.
Invasive fungal infections are rising worldwide along with the number of immunocompromised patients. While several new antifungal agents have entered clinical practice, the armamentarium of antifungal agents is still limited, and morbidity and mortality remain high. Given the limited success of current treatment regimens for systemic fungal diseases, combination antifungal therapy has high appeal. The goal of this project is to study the antifungal efficacy of combination antifungal therapy in a neutropenic murine model of invasive candidiasis (IC), relating outcomes to pharmacokinetics (PK) of drug combinations. Antifungal efficacy of an established antifungal combination-amphotericin B (AmB) and 5-fluorocytosine (5-FC)-will be characterized in terms of dose/dose regimen in relation to antifungal efficacy and toxicity, exploring intravenous combination delivery (co-delivery) of AmB and 5-FC via self-assembled polymers (polymeric micelles). Similarly, antifungal efficacy of a novel combination-AmB and 17-allylamino-17-demethoxygeldanamycin (17-AAG)-will be characterized in terms of dose/dose regimen in relation to antifungal efficacy and toxicity, exploring the consequences of fungal heat shock protein 90 (Hsp90) inhibition. Outcomes from this research will be defined predictive indices of anti- fungal efficacy in a neutropenic murine model of IC, defining optimum dosing strategies for antifungal combinations. We highlight the novelty and potential clinical impact of a co-delivered, 3-drug combination of AmB, 5- FC, and 17-AAG for the treatment of life-threatening fungal diseases.
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