Azole drugs have differential efficacy in varied models of immunosuppression in larval zebrafish hosts

Fungal infections are an increasing cause of mortality in immunosuppressed human patients, and antifungal drug treatments are still ineffective in a significant percentage of cases. A gap in our understanding of antifungal drug treatment is whether different drugs have differential efficacy in hosts that are experiencing different forms of immunosuppression. Here, we used a larval zebrafish vertebrate host model of <i>Aspergillus fumigatus</i> infection to compare the efficacy of four different triazole drugs in five different immunosuppressed or immunodeficient conditions, including larvae treated with immunosuppressive drugs and genetically phagocyte-deficient larvae. We report that voriconazole and posaconazole are highly effective in all host backgrounds tested, while isavuconazole and itraconazole exhibit host-specific efficacy and toxicity. Repeated daily imaging of whole live larvae treated with posaconazole demonstrates that posaconazole treatment can prevent germination of <i>A. fumigatus</i> spores inside infected hosts but that this drug does not significantly combat fungal hyphal growth post-germination. This study demonstrates the utility of the larval zebrafish host model for testing the efficacy of antifungal drugs in varied host backgrounds and determining the effects of these drugs on fungi living and growing inside infected hosts. Individuals who are immunosuppressed, due to inherited genetic deficiencies or treatment with immunosuppressive drugs for autoimmune disease or to promote successful organ transplantation, for example, are at risk of infection by opportunistic fungal pathogens, including <i>A. fumigatus</i>. These patients are commonly treated with triazole antifungal drugs but not much is known about how the type of immunosuppression a patient is experiencing can influence the efficacy of drug treatment. This study used a zebrafish animal model to induce different forms of immunosuppression and test how well different triazole antifungal drugs controlled <i>A. fumigatus</i> infection. Two triazole antifungal drugs, voriconazole and posaconazole, were broadly effective in animals experiencing both genetically-induced and drug-induced immunosupression, while isavuconazole and itraconazole had decreased efficacy or increased toxicity in some cases. These results indicate that there may be specific human patient situations in which one antifungal drug works better than another.