Patients with high-risk hematological cancers, such as acute leukemia or those undergoing allogeneic stem cell transplants, face a significant risk of invasive fungal infections (IFIs) despite prophylactic antifungal measures. A recent systematic review published in Clinical Infectious Diseases sheds light on the characteristics, management, and outcomes of breakthrough IFIs (bIFIs) in this vulnerable population.
The review, led by Boutin CA et al., assessed 5293 entries, ultimately including 1076 cases of bIFI and 1093 isolated pathogens. The study highlights the influence of prophylactic agents like voriconazole and posaconazole on the types of pathogens isolated. Mucorales species were more prevalent in the voriconazole group, while Aspergillus and Fusarium species were more common in the posaconazole group. Furthermore, the choice of prophylactic agent affected the Aspergillus subspecies identified, with non-Aspergillus fumigatus species being more frequent in the voriconazole group. Candida species were isolated in 18% of the cases, with Candida glabrata being the most common subspecies in both prophylaxis groups, and Candida parapsilosis being more common in the posaconazole group.
Therapeutic Drug Monitoring and Subtherapeutic Levels
Therapeutic drug monitoring was reported in only 90 of the 1076 cases. A concerning 36% of these cases exhibited subtherapeutic levels, defined as less than 0.5 μg/mL for voriconazole and less than 0.7 μg/mL for posaconazole. In the posaconazole group, subtherapeutic levels were significantly more common with the suspension formulation (71%) compared to the delayed-release tablet (13%; P < .001). This underscores the challenges in achieving adequate drug concentrations with the suspension formulation, which requires administration after a full meal.
Management Strategies and Outcomes
In the majority (82%) of bIFI cases, management involved using an antifungal agent from a different class. Azoles were used in 38% of cases, either as part of combination therapy or as monotherapy. Infection-related mortality occurred in 117 (35%) of cases with reported survival data, highlighting the severity of these infections.
Resistance and Unexplained bIFIs
Notably, 20% to 33% of pathogens exhibited resistance to the prophylactic antifungal used. The authors identified resistance to the antifungal prophylactic agent, subtherapeutic dosing, or both as explanations for bIFI development in approximately 30% of cases. However, over 60% of bIFIs remained without an identifiable cause.
The study's findings support ongoing mold prophylaxis in high-risk hematological patients, with careful attention to accurate dosing and therapeutic drug monitoring, especially in patients with absorption or adherence concerns. The use of posaconazole delayed-release tablets instead of the oral suspension is also reinforced by these findings. Upon bIFI diagnosis, clinicians should consider switching to a different antifungal class and/or using an alternative azole antifungal.
Clinical Implications
"Findings from this study were a great reflection of recent practice and demonstrate the challenges clinicians face when preventing and treating bIFIs in this multifaceted patient population," the authors noted. They further support efforts to complete randomized and prospective research studies that also include isavuconazole. Management of bIFIs remains a patient-specific care plan, but clinicians should feel validated that class switching and combination therapy are warranted due to a high mortality rate of more than 30%.
