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Animal Models for Studying Triazole Resistance in Aspergillus fumigatus
Russell E Lewis1, Paul E Verweij2,3
1Infectious Diseases Unit, S. Orsola-Malpighi Hospital, Department of Medical and Surgical Sciences, University of Bologna, Italy.
Abstract:
Infections caused by triazole-resistant Aspergillus fumigatus are associated with a higher probability of treatment failure and mortality. Because clinical experience in managing these infections is still limited, mouse models of invasive aspergillosis fulfill a critical void for studying treatment regimens designed to overcome resistance. The type of immunosuppression, the route of infection, the timing of antifungal administration, and the end points used to assess antifungal activity affect the interpretation of data from these models. Nevertheless, these models provide important insights that help guide treatment decisions in patients with triazole-resistant invasive aspergillosis. Animal models confirmed that a high triazole minimal inhibitory concentration corresponded with triazole treatment failure and that the efficacy of other classes of drugs, such as the polyenes and echinocandins, was not affected by the presence of triazole resistance mutations. Furthermore, the feasibility of triazole dose escalation, combination therapy, and prophylaxis were explored as strategies to overcome resistance.
Insights
Triazole-resistant Aspergillus fumigatus infections lead to treatment failure. Mouse models show triazole resistance predicts failure, but other antifungals remain effective, guiding new treatment strategies.
Area of Science:
- Medical Mycology
- Infectious Diseases
- Animal Models
Background:
- Triazole-resistant Aspergillus fumigatus infections present a significant clinical challenge with high treatment failure and mortality rates.
- Limited clinical data necessitates the use of animal models to study effective treatment strategies for invasive aspergillosis caused by resistant strains.
Purpose of the Study:
- To investigate the utility of mouse models in evaluating antifungal treatment regimens against triazole-resistant Aspergillus fumigatus.
- To understand how various factors in animal models influence the interpretation of antifungal efficacy data.
Main Methods:
- Utilizing mouse models of invasive aspergillosis to simulate human infections.
- Assessing the impact of triazole resistance on antifungal drug efficacy, including polyenes and echinocandins.
- Exploring therapeutic strategies such as dose escalation, combination therapy, and prophylaxis in animal models.
Main Results:
- Mouse models demonstrated a direct correlation between high triazole minimum inhibitory concentrations and treatment failure.
- The efficacy of antifungal agents like polyenes and echinocandins was not compromised by triazole resistance mutations.
- The study explored the potential of triazole dose escalation, combination therapy, and prophylactic use to overcome resistance.
Conclusions:
- Animal models are crucial for guiding treatment decisions in patients with triazole-resistant invasive aspergillosis.
- These models confirm that triazole resistance significantly impacts treatment outcomes, while other antifungal classes maintain efficacy.
- Investigational strategies like dose escalation and combination therapy show promise for managing resistant fungal infections.
