(1) Background: Invasive aspergillosis is a life-threatening fungal infection, particularly in patients with hematologic malignancies. Isavuconazole, a broad-spectrum triazole, has emerged as a key treatment option, but real-world data in high-risk populations from middle-income countries remain limited. (2) Methods: We conducted a multicenter, retrospective study to evaluate the clinical response rate and tolerability of isavuconazole in patients with hematologic malignancies and probable or proven invasive aspergillosis across four medical centers in Brazil. (3) Results: We enrolled 50 patients aged 18 to 82 years (64% male) with proven or probable invasive aspergillosis, diagnosed in the context of complex hematologic conditions. Among them, 60% had active or refractory malignancies, and 22% had a prior COVID-19 infection. Isavuconazole was used as a first-line therapy in 64% of cases. No patients discontinued treatment due to toxicity. The 6-week overall survival was 60%. Prior COVID-19 infection was associated with a lower survival rate (44% vs. 69% in patients without COVID-19, p = 0.04). (4) Conclusions: This study provides real-world evidence supporting the efficacy and tolerability of isavuconazole in a high-risk population. The findings reinforce its role as a key antifungal therapy, particularly in patients with complex underlying conditions.

Breakthrough invasive fungal infections (bIFIs) are a challenging serious complication in high-risk hematologic patients and allogeneic hematopoietic stem cell transplantation recipients that may negatively impact their outcome. Despite advances in antifungal prophylaxis, diagnostics, and supportive care, bIFI occurrence reflects a complex interaction between host immunosuppression, emergence of resistant pathogens and pharmacological variables, including subtherapeutic drug exposure. Candida spp. have shifted towards non-albicans yeasts, whereas breakthrough mold infections more frequently involve non-fumigatus Aspergillus, Mucorales, Fusarium spp., and Scedosporium/Lomentospora spp. Early clinical recognition, rapid therapy escalation, aggressive diagnostic investigation, a switch to liposomal amphotericin B-based regimens in patients on azole prophylaxis, and therapeutic drug monitoring are essential to improve outcomes. Reducing the growing global burden of bIFIs will also require improved access to high-quality diagnostics and strengthened educational and stewardship efforts that prioritize antifungal resistance as an urgent health concern.

This chapter outlines recommendations for the control and management of infections following hematopoietic cell transplantation. Given the complexity and scope of the subject, the authors chose a format that considers the various interventions available to prevent, minimize, or when appropriate treat infections relevant to the hematopoietic cell transplantation setting. We consider the active and collaborative involvement of the transplant infectious disease specialist in transplantation centers to be essential in ensuring the best possible care for this vulnerable population.