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

Abstract

Aims: 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.

Materials & methods: Here, we used a larval zebrafish vertebrate host model of Aspergillus fumigatus 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.

Results: 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 A. fumigatus spores inside infected hosts but that this drug does not significantly combat fungal hyphal growth post-germination.

Conclusions: 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.