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. 2024 Jul 19;79(1):151-160.
doi: 10.1093/cid/ciae203.

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

Catherine-Audrey Boutin  1   2 , Florence Durocher  1 , Stéphanie Beauchemin  3 , Daniela Ziegler  4 , Claire Nour Abou Chakra  3 , Simon Frédéric Dufresne  1   3   5
Affiliations

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

Catherine-Audrey Boutin et al. Clin Infect Dis. .

Abstract

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.

Keywords: breakthrough; invasive fungal infections; posaconazole; prophylaxis; voriconazole.

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Conflict of interest statement

Potential conflicts of interest . S. F. D. has received honoraria for consultancy and research funding from AVIR Pharma Inc and Merck & Co. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart. Abbreviations: CINAHL, Cumulative Index to Nursing and Allied Health; CRD, Centre for Reviews and Dissemination; EBM, evidence-based medicine; HTA, health technology assessment; IFI, invasive fungal infection; POSA, posaconazole; PPx, prophylaxis; VORI, voriconazole. This Figure was created using Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. Available at www.covidence.org.
Figure 2.
Figure 2.
Distribution of fungal pathogens according to antifungal agent (n = 1093). P values represent a χ2 test for observed and expected frequencies.
Figure 3.
Figure 3.
Patterns of resistance according to antifungal agent. A, Distribution of resistance categories among 343 resistant pathogens. B, Susceptibility profile of 105 pathogens with antifungal susceptibility testing data. All putatively resistant pathogens in the voriconazole group (n = 148) represent intrinsically resistant organisms, among which 144 are Mucorales species; P values represent a χ2 test for observed and expected frequencies.
See this image and copyright information in PMC

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