Therapeutic Failure in Invasive Fungal Infections: Beyond Antifungal Resistance-A Narrative Review

Invasive fungal infections (IFIs) are associated with high morbidity and mortality, particularly in immunocompromised or critically ill patients and in those with complex comorbidities. Despite advances in mycological diagnosis and antifungal therapy, outcomes remain poor in a significant proportion of patients. In clinical practice, a poor response is often attributed to microbiological resistance. This interpretation may lead to empirical treatment escalation, combination therapy without a clear indication, increased toxicity, clinically relevant drug-drug interactions, and inefficient use of healthcare resources. However, therapeutic failure rarely results from a single mechanism. More often, it reflects the interaction among host vulnerability, pathogen characteristics, delayed, incomplete, or incorrect diagnosis, insufficient antifungal exposure, and inadequate source control. This narrative review presents a structured clinical approach to evaluating suboptimal responses in IFIs without attributing them solely to antifungal resistance. It examines cross-cutting determinants and specific patterns associated with invasive aspergillosis, invasive candidiasis and persistent candidemia, cryptococcal meningitis, mucormycosis, infections caused by rare filamentous fungi, and disseminated endemic mycoses. It also presents clinical algorithms, checklists, and potential quality indicators to distinguish true from apparent failure, identify modifiable factors, and support transparent clinical decision-making within antifungal stewardship programs. The proposed framework supports the assessment of non-response through systematic diagnostic and therapeutic reassessment, timely source control, and identification of modifiable gaps in care.