Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review

Background Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis.Methods We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023.Results We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%.Conclusions In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management. This systematic review of breakthrough invasive fungal infection cases occurring among patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis shows that most reported infections are aspergillosis, mucormycosis, candidiasis, and fusariosis, with different relative proportions according to prophylactic antifungal agent.