Совместное управление триазолами с хемапаевыми и/или иммунозопрессивными агентами, известными умеренным взаимодействием между наркотиками и наркотиками у пациентов с гематологическими заболеваниями, госпитализировано в связи с инвазивным аспергиллозом.

Introduction

Invasive aspergillosis (IA), mostly caused by Aspergillus fumigatus , is estimated to occur annually in more than 2 million people worldwide [ 1 ]. Patients with hematologic malignancies (HMs), such as acute leukemias and lymphomas, are at a substantial risk of development of IA, particularly during periods of prolonged chemotherapy (CT)-induced neutropenia and immunosuppression [ 2 – 4 ]. The incidence of IA in these patients can range from 5.1–11.7%, with mortality rates often exceeding 50%, and reaching as much as 90% in hematopoietic cell transplant (HCT) recipients [ 5 , 6 ].

Current guidelines recommend a mold-active triazole to be used as first-line for the prevention and treatment of IA for most patients [ 7 , 8 ]. A key factor when considering mold-triazole use in patients with IA is the possibility of serious pharmacokinetic (PK) drug-drug interactions (DDIs). Many CT and immunosuppressant (IS) agents used to treat HMs undergo hepatic metabolism through cytochrome P450 (CYP) 3A4 isoenzyme or through drug transporters such as P-glycoprotein (P-gp) [ 9 , 10 ]. Triazoles are moderate-to-strong inhibitors of the CYP3A4 and P-gp transporter molecules. Co-administration of triazoles with CT and IS agents that are substrates for CYP3A4 or P-gp may increase drug exposure and risk of serious adverse events (SAEs).

Data describing the real-world frequency of concurrently administering triazoles for IA with CT and/or IS agents known to have moderate-to-strong PK (CYP3A4 and/or P-gp) interactions are limited. We, therefore, sought to describe concomitant administration of triazoles with these agents in HM patients newly hospitalized for IA.

Methods

This was a retrospective cohort study utilizing nationwide United States (US) claims data from the IQVIA New Data Warehouse [ 11 ]. This dataset includes deterministically linked data from professional fee and prescription claims data and IQVIA’s hospital charge data master (CDM) database for facilities across the US. These data contain ~ 1 billion professional fee claims per year (representing more than 870,000 practitioners per month) with diagnoses, procedures, and office-administered medications; approximately 1.6 billion retail or mail-order prescription claims representing dispensed prescriptions for about 85% of all pharmacies; and records from more than 450 hospitals, including inpatient and outpatient encounters within a facility with medication, procedure, diagnosis, and charge data for the entire stay.

Adults admitted for IA or developing IA during admission were identified based on International Classification of Diseases-10th-Revision (ICD-10) codes (B44.0, B44.1, B44.7) in the primary or non-primary hospital claim coding position between October 1, 2015 and November 30, 2022 (IA identification period). The first admission with IA during the patient identification period was utilized. The admission date was defined as the index date. To be included, patients had to have evidence of systemic antifungal therapy orders for ≥ 3 days during the hospitalization, link to the professional fees and pharmacy claims data sets during the study period, have activity denoted as ≥ 1 medical claim in the professional fee data set and ≥ 1 claim in the pharmacy claims data set during the baseline period, and exhibit pharmacy stability (i.e., consistent reporting of data from the pharmacy most frequently visited by the patient during each month of the baseline period). Patients with evidence of non-IA invasive fungal infection (e.g. invasive candidiasis) during the index hospitalization were excluded.

The study cohort was then limited to patients with HM. Data for the 6 months prior to the index date (baseline period) was used to assess patient baseline comorbidities, including HM defined as the presence of ≥ 1 claim associated with any type of encounter with an ICD-10 diagnosis code of C81-C96.

Triazole, CT and IS use was identified using National Drug Codes (NDCs) and Healthcare Common Procedure Coding System (HCPCS) codes starting day 0 of the hospital admission for IA. To be considered concurrently administered, the triazole and substrate CT and/or IS agents had to have overlapping usage based on inpatient medication use records and/or outpatient pharmacy claims data at some point between the day of admission (day 0) through last available follow-up (post-index period). The determination of CT or IS’s PK DDI severity with triazoles were determined based on published literature [ 9 ] and the National Aspergillosis Centre, Antifungal Trust’s Antifungal Interactions Database (available at: https://www.antifungalinteractions.org ) [ 12 , 13 ].

The concurrent administration of triazoles and CT and/or IS agents known to have moderate-to-severe PK interaction potential during the post-index period was assessed. Categorical data were reported as counts and percentages and continuous data as means ± standard deviations (SDs). Database management and statistical analysis was performed using SAS version 9.4 (SAS Inc., Cary, NC, USA).

All data were accessed in compliance with the Health Insurance Portability and Accountability Act (HIPAA). Institutional review board approval was not required for this retrospective analysis of de-identified secondary data. The data utilized in this study are available only by license through IQVIA.

Results

Among the 317 patients with HM and IA, there were 699 CT/IS agents administered for a mean of ~ 2 agents per patient. Most of these patients (86.1%) were over 45 years of age and 63.4% were male (Table 1 ). The most common payer type was commercial (38.5%) and nearly two-thirds occurred in the West US Census region. Leukemias were the most common type of HM (82.0%), 55.5% of patients had neutropenia, and 34.7% had a history of bone marrow transplant (BMT) or HCT. Table 1 Characteristics of hospitalized patients with hematologic malignancies and invasive aspergillosis Characteristic N = 317 n (%) Age 18–44 years 44 (13.9) 45–64 years 138 (43.5) ≥ 65 years 135 (42.6) Male sex 201 (63.4) Geographic Census region West 227 (71.6) South 36 (11.4) Midwest 31 (9.8) Northeast 23 (7.3) Payer type # Commercial 122 (38.5) Medicare 111 (35.0) Unknown/other 58 (18.3) Medicaid 26 (8.2) Year of index hospitalization 2015* 7 (2.2) 2016 36 (11.4) 2017 70 (22.1) 2018 54 (17.0) 2019 76 (24.0) 2020 33 (10.4) 2021 21 (6.6) 2022* 20 (6.3) Types of malignancy † Leukemia 260 (82.0) Non-Hodgkin lymphoma 71 (22.4) Comorbidities ∫ Neutropenia 176 (55.5) Immunodeficiencies 124 (39.1) BMT/HCT 110 (34.7) Diabetes mellitus 92 (29.0) Autoimmune conditions 7 (2.2) Human immunodeficiency virus 5 (1.6) End-stage kidney disease 3 (0.9) Post-index triazole use ‡ 308 (97.2) BMT/HCT = bone marrow transplantation or hematopoietic cell transplantation * Partial year of data † Not a complete list or mutually exclusive ‡ Triazole use for ≥ 3 days during the hospitalization for invasive aspergillosis # Commercial includes private and employer-sponsored health insurance plans; Medicare includes federal health insurance programs for adults ≥ 65 years and eligible younger individuals with disabilities or end-stage renal disease; Medicaid includes joint federal–state programs for low-income individuals; Unknown/other indicates payer type not documented or payer types outside the categories above ∫ International Classification of Diseases, Tenth Revision codes for comorbidities included neutropenia (D70), immunodeficiencies (D80–D84, D86, D89), BMT/HCT (T86.0, T86.5, Z94.81, Z94.84), diabetes mellitus (E10-E11, E13, O24.0), autoimmune conditions (G35, G70, K90, L93, M05, M06, M08, M31.5, M32, M35.3), human immunodeficiency virus (B20, B97.35, O98.7, Z21), end-stage kidney disease (N18.6)

The mean duration of antifungal use, starting at the time of IA admission, was 146 ± 217 (median of 64) days. Triazoles were used in 308 of 317 (97.2%) patients over the course of treatment in the cohort (Table 2 ). The most prescribed triazoles were isavuconazole (61.0%) and voriconazole (53.6%), followed by posaconazole (27.6%), and itraconazole (1.6%). Amphotericin B and echinocandins were used in 35.3% and 60.6% of patients during the post-index period, including as monotherapy in 1.3% and 13.9% of patients, respectively. Table 2 Triazole Use in Patients with Hematologic Malignancies Who Were Hospitalized with Invasive Aspergillosis Triazole N = 308 n (%)* Strength of PK Interaction with CYP3A4 † Isavuconazole 188 (61.0) + + Voriconazole 165 (53.6) + + + Posaconazole 85 (27.6) + + + Fluconazole 64 (20.8) + + Itraconazole 5 (1.6) + + + * More than one triazole may have been used per patient; thus, the column will total > 100% † Strong severity (+ + +); moderate severity (+ +); mild severity ( +); no/minimal interaction (—)[ 9 ]

In total, 78.2% of patients who received triazoles also received a CT and/or IS agent with the potential for moderate-to-severe PK interactions (Table 3 ). The most frequent CT or IS agent administered during triazole therapy included corticosteroids (n = 218, 70.8%), calcineurin inhibitors (CNIs) or mammalian target of rapamycin (mTOR) inhibitors (n = 77, 25.0%) (of which 65/77 (84.4%) were tacrolimus), alkylating agents (n = 43, 14.0%) (33/43, 76.7% were cyclophosphamide), the B-cell lymphoma-2 inhibitor venetoclax (9.7%), anthracyclines (6.2%), and the vinca alkaloid vincristine (n = 18, 5.8%). Table 3 Proportion of Patients Concomitantly Administered Triazoles with Chemotherapy and/or Immunosuppressants Known to Have Moderate-to-Severe Drug-Drug Interactions in Patients with Hematologic Malignancies and Invasive Aspergillosis Chemotherapy or Immunosuppressant* N = 308 n (%) † At least one agent 241 (78.2) Corticosteroids 218 (70.8) Dexamethasone 153 (49.7) Methylprednisolone 133 (43.2) Calcineurin or mTOR inhibitors 77 (25.0) Tacrolimus 65 (21.1) Sirolimus 38 (12.3) Cyclosporine 5 (1.6) Alkylating agents 43 (14.0) Cyclophosphamide 33 (10.7) Busulfan 9 (2.9) Ifosfamide 4 (1.3) BCL-2 inhibitor (venetoclax) 30 (9.7) Anthracyclines 19 (6.2) Doxorubicin 7 (2.3) Idarubicin 7 (2.3) Daunorubicin 6 (1.9) Vinca alkaloids (vincristine) 18 (5.8) FLT3 inhibitors 7 (2.3) Midostaurin 4 (1.3) Gilteritinib 4 (1.3) BCR-ABL inhibitors 6 (1.9) Dasatinib 3 (1.0) Ponatinib 2 (0.6) Nilotinib 1 (0.3) Imatinib 1 (0.3) JAK inhibitors 5 (1.6) Ruxolitinib 4 (1.3) Fedratinib 1 (0.3) Proteasome inhibitor (bortezomib) 5 (1.6) BTK inhibitor (ibrutinib) 3 (1.0) Immunomodulatory imide (lenalidomide) 2 (0.6) HDAC inhibitor (romidepsin) 2 (0.6) Hedgehog inhibitor (glasdegib) 1 (0.3) Arsenic trioxide 1 (0.3) * Chemotherapy and immunosuppressant agents with zero usage were not reported in the table † More than one chemotherapy and/or immunosuppressant may have been used per patient; and others did not receive an interacting chemotherapy and/or immunosuppressant, so the column will not total to 100%

Discussion

In this contemporary cohort of HM patients newly hospitalized with IA, triazoles were used in nearly all cases. Isavuconazole and voriconazole were used in more than 50% of HM patients, despite their known potential for DDIs with CT/IS agents. A potential triazole-CT/IS PK interaction known to be at least of moderate severity was present in more than 75% of patients. The most frequently concomitantly administered CTs included cyclophosphamide, venetoclax, and vincristine (range: 5.8–14.0% of cases). IS agents were also commonly used along with a triazole and included corticosteroids (70.8% of cases) and tacrolimus (84.4%).

CT or IS use in patients with HMs increases their risk for IA, particularly among patients with prolonged drug-induced neutropenia [ 2 – 4 ]. Current guidelines recommend mold-active triazoles as preferred antifungal agents for treatment of IA in most patients [ 7 , 8 ]. All triazoles have PK interactions with most regimens used to treat HM, mainly through CYP3A4 and P-gp inhibition, albeit to varying degrees [ 9 , 14 , 15 ]. Itraconazole is a potent inhibitor of CYP3A4 and P-gp, posaconazole a potent inhibitor of CYP3A4, voriconazole a potent inhibitor of CYP3A4, CYP2C19 and CYP2C9, while isavuconazole is a moderate inhibitor of CYP3A4 and a mild inhibitor of P-gp, CYP2B6, organic cation transporter 2, and UDP-glucuronosyltransferase [ 14 ]. Isavuconazole was used more than other triazoles, possibly because of lesser inhibition of CYP3A4 and P-gp and despite higher acquisition cost compared to other azoles. Voriconazole is both an inhibitor and substrate of CYP2C19, CYP2C9, and CYP3A4 with the potential for a greater range of adverse DDIs than those of other triazoles [ 16 – 19 ].

While 78.2% of HM patients admitted for IA received a triazole known to have a moderate-to-severe PK DDI with their CT or IS agent(s), not all such interactions will lead to serious adverse events (SAEs) or will require pre-emptive dose adjustment. Increased vigilance may be sufficient in many cases.

Triazoles have different inhibitory potencies of CYP3A4 and P-gp [ 14 , 15 ], while CT/IS agents may have wide or narrow therapeutic windows. The narrower the therapeutic window, the lower the exposure threshold needed for toxicity, which once surpassed, is more likely to result in an SAE [ 15 ]. Moreover, the types of toxicities associated with a particular CT or IS agents need to be considered. For example, in our study, we found triazole and venetoclax or vincristine were ordered during overlapping time frames in 9.7% and 5.8% of patients, respectively.

Clinically meaningful interactions such as with narrow therapeutic index drugs, such as calcineurin inhibitors (CNIs), tyrosine kinase inhibitors, and chemotherapeutic agents, such as vincristine and cyclophosphamide warrant dosage adjustment of the agent (CNI), the triazole, or complete avoidance of simultaneous administration. The FDA package insert for ruxolitinib warns against the concomitant use of CYP3A4 inhibitors during treatment of GVHD, myelofibrosis, and polycythemia vera (PCV), which may cause neutropenia and thrombocytopenia. In order to prevent these events, some programs reduce the dosage of fluconazole or posaconazole for antifungal prophylaxis or definitive therapy. A thoughtful patient-centered assessment throughout the course of cancer therapy, immunomodulation, and HCT transplant of the potential serious DDIs assures dosage adjustment or change to another antifungal agent reduces the probability of adverse events.

All triazoles have at least a moderate level PK interaction with venetoclax (considered a severe interaction with itraconazole, posaconazole and voriconazole, and a moderate interaction with isavuconazole via CYP3A4 inhibition). When a triazole is concomitantly administered with venetoclax, patients experience a higher rate of tumor lysis syndrome (particularly, during the initiation and dose-titration phases) [ 16 – 19 ]. Similarly, vincristine has the potential for a moderate-to-severe PK interaction with all triazoles due to CYP3A4 inhibition and P-gp, and when concurrently administered, is associated with a higher rate of severe neurotoxicity, [ 14 , 20 – 22 ]. In both examples, if these CT agents must be concomitantly administered with a triazole, several approaches may be implemented including substantial dose reductions of the CT agent [ 9 , 15 , 17 ], withholding of the triazole for an interval before and after administration of the CT [ 21 ], or utilization of alternative non-triazole antifungal agents. While DDI/physiological base and pharmacokinetic analysis suggests that isavuconazole is less likely to induce vincristine neuropathy [ 23 ], prescribing information for isavuconazole states that the two medications should not be co-administered owing to an estimated two-fold increased exposure of the vinca alkaloid [ 24 ].

Another SAE that HM patients are at an increased risk due to concurrent administration of a triazole and certain CT/IS agents includes QTc prolongation and the possible subsequent development of life-threatening arrhythmia Torsades de Pointes (TdP). Specific CT agents to treat HM that are associated with important QTc prolongation include a wide range of compounds: arsenic trioxide, cyclophosphamide (alkylating agent), gilteritinib and midostaurin (FLT3 inhibitors), glasdegib (Hedgehog inhibitor), lenalidomide (immunomodulatory amide), and nilotinib (BCR-ABL inhibitor) [ 25 , 26 ]. When triazoles inhibit these agents' metabolism through CYP3A4, the increased drug exposure to the CT agent can further prolong QTc interval, placing patients at higher risk for TdP and sudden cardiac death. Importantly, both posaconazole and voriconazole also cause QTc prolongation [ 9 , 14 , 15 ] which may further exacerbate the QTc prolongation caused by their concurrent administration with CT/IS agents. Isavuconazole, which shortens the QTc interval [ 27 ], has been used in lieu of other triazoles when required for administration with QTc-prolonging CT/IS agents.

The demographic data in this study reveal that approximately 43% of patients were 65 years of age. Elderly patients have increased risk for development and more serious adverse outcomes of DDIs in relation to altered hepatic, renal, and metabolic status that affects the pharmacokinetics and pharmacodynamics of drugs, especially those with narrow therapeutic indices in the elderly population compared to those of younger cohorts. [ 28 , 29 ]. Given that 29% of patients had concomitant diabetes mellitus, diabetes-related renal and hepatic dysfunction, may further add to the limitations of age-dependent declines. Depending upon the age, co-morbidities, possible drug combinations, as well as hepatic and renal functions, further dosage adjustment may be needed to prevent and adverse DDI.

Clinicians should be trained to anticipate and recognize drug interactions in these high-risk patients, and while guidance is available on how to proactively avoid such drug interactions [ 8 , 9 ], clinicians should be prepared to individualize plans for avoiding and managing potential PK DDIs [ 9 , 14 , 15 ]. Clinicians may preferentially choose triazoles with comparatively lower PK DDI potential, such as isavuconazole, to perform therapeutic drug monitoring (TDM) of both the triazole and CT/IS, dose reduce the interacting CT/IS agent based upon recommendations from prescribing information, practice guidelines, or other reliable sources, or avoid certain azole-CT/IS agent interactions (e.g., a triazole + vincristine) altogether by using amphotericin B or an echinocandin to treat IA. In fact, in our study, we observed substantial use of these antifungal agents, including monotherapy. Finally, patients should always be monitored closely for signs or symptoms of toxicities, including, neuropathy, tumor lysis syndrome, hepatotoxicity, QTc prolongation, and cardiac arrhythmias [ 14 ].

Our study has several limitations. First, IA was identified by ICD-10 diagnosis codes, but neither a formal diagnosis nor the severity of IA could be verified due to the lack of available clinical and laboratory data in our data set (i.e., potential for misclassification bias) [ 4 , 7 , 8 , 11 , 30 ]. To optimize our study’s specificity in capturing invasive disease, we restricted out inclusion to the presence of codes B44.0, B44.1, B44; notably excluding B44.8x (other forms of aspergillosis) and B44.9 (aspergillosis, unspecified). This methodology likely decreased the sample size of our study but increased the probability that we captured true cases of invasive aspergillosis. Similarly, the absence of clinical and/or laboratory data meant we were unable to provide more specific data on comorbidities such as the severity of neutropenia or end-stage kidney disease. Second, while we used both published literature and an antifungal DDI database [ 9 , 12 – 15 ], expert opinion or guidelines on the clinical relevance of DDIs between specific triazoles and CT or IS agents will no doubt vary in routine practice. While triazoles and CT/IS agents were frequently used concomitantly for IA, due to a lack of laboratory data the dataset did not permit an evaluation of the simultaneity of dosing adjustment to avoid an SAE. The dataset also was unable to assess the frequency of treatment-related triazole-induced adverse events. The diverse nature or potential adverse events make capturing them in a claims-based dataset complex and unreliable. Thirdly, medication usage could have occurred outside of IQVIA's data partners [ 11 ]. Such utilization would not be captured in our data set and could result in missed triazole and/or CT/IS medication usage instances. Next, as data for this study spanned 2015–2022, changes in routine practice patterns for IA and/or HM management may have changed. Finally, our population of HM patients with IA captured from the IQVIA’s New Data Warehouse may not be entirely representative of all such patients in the US. This, in part, may explain the geographic distribution of HM patients with IA seen in our study, though prior data also suggests IA infection is highest in the West and low in the Northeast [ 31 ].

In summary, concurrently administered triazoles and CT/IS agents with potential for moderate-to-severe PK interactions occurred in most patients with HM who were hospitalized for IA. These interactions have the potential to cause SAEs if not anticipated. Prevention or mitigation of triazole DDIs may consume already limited healthcare resources to perform dosage adjustments and TDM. The higher rate of isavuconazole observed in this population compared to other triazoles may be a signal of physicians’ recognition of the need to reduce the risk of DDI-related SAEs and toxicity. Choosing alternative antifungals, TDM of triazoles, alteration of dosing intervals of triazoles, and dosage adjustment of CT/IS agents should all be considered and evaluated in future studies of routine clinical practice. Antifungal agents, especially oral formulations, without or with a lesser potential for serious DDIs with CT and/or IS agents are needed for treatment of IA.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

None.

Author Contributions

Conceptualization: B.L., C.I.C.; data analysis: B.L., C.I.C; data interpretation: all authors; writing (original draft preparation): all authors; writing (review and editing): all authors; study supervision: B.L., C.I.C. All authors have read and agreed to the published version of the manuscript.

Funding

F2G, Inc, Princeton, NJ, USA.

Data Availability

The data utilized in this study are available only by license through IQVIA.

Declarations

Conflict of interest

The funder of this study had no role in the decision to publish this work. B.L. is an employee of F2G, Inc. and served as an author on this paper. B.D.A.: Consultant: Scynexis, GSK, Astellas, Merck, HealthTrackRx, Basilea, F2G, Inc.; Research Grant to My Institution: Karius; Clinical Trials (Site PI/Study PI): Scynexis, F2G, Inc.; Royalties (Chapter Author): UpToDate. M.J.: Research Grant to my Institution: Scynexis; Author Royalties: UpToDate; Licensed Technology: Biomeme, Patent Pending for gene expression classifiers of fungal infection. B.L.: Employee of F2G, Inc. C.I.C.: Consultant: F2G, Inc. TJW has received grant funding and consulting fees from the Henry Schueler Foundation; F2G, Inc., Omeros, Abbott Laboratories, Partner Therapeutics, Scynexis, Statera, T2 Biosystems, Shionogi, and Basilea. He has a leadership or fiduciary role at Medical Mycological Societies of the Americas, Center for Innovative Therapeutics and Diagnostics, ISHAM/ECMM Osteoarticular Mycoses Working Group, Henry Schueler Foundation, Save Our Sick Kids Foundation and the Mycoses Study Group Education and Research Consortium (MSG-ERC).

References

1. Denning DW Global incidence and mortality of severe fungal disease Lancet Infect Dis 2024 24 e428 e438 10.1016/S1473-3099(23)00692-8 38224705 Denning DW. Global incidence and mortality of severe fungal disease. Lancet Infect Dis. 2024;24:e428–38. 38224705 10.1016/S1473-3099(23)00692-8

2. Brown GD Denning DW Gow NA Levitz SM Netea MG White TC Hidden killers: human fungal infections Sci Transl Med 2012 4 165rv13 10.1126/scitranslmed.3004404 23253612 Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4:165rv13. 23253612 10.1126/scitranslmed.3004404

3. Herrera S Magyar U Husain S Invasive aspergillosis in the current era Infect Dis Clin North Am 2025 39 1S e33 e60 10.1016/j.idc.2025.01.002 40157842 Herrera S, Magyar U, Husain S. Invasive aspergillosis in the current era. Infect Dis Clin North Am. 2025;39(1S):e33–60. 40157842 10.1016/j.idc.2025.01.002

4. Donnelly JP Chen SC Kauffman CA Steinbach WJ Baddley JW Verweij PE Clancy CJ Wingard JR Lockhart SR Groll AH Sorrell TC Bassetti M Akan H Alexander BD Andes D Azoulay E Bialek R Bradsher RW Bretagne S Calandra T Caliendo AM Castagnola E Cruciani M Cuenca-Estrella M Decker CF Desai SR Fisher B Harrison T Heussel CP Jensen HE Kibbler CC Kontoyiannis DP Kullberg BJ Lagrou K Lamoth F Lehrnbecher T Loeffler J Lortholary O Maertens J Marchetti O Marr KA Masur H Meis JF Morrisey CO Nucci M Ostrosky-Zeichner L Pagano L Patterson TF Perfect JR Racil Z Roilides E Ruhnke M Prokop CS Shoham S Slavin MA Stevens DA Thompson GR Vazquez JA Viscoli C Walsh TJ Warris A Wheat LJ White PL Zaoutis TE Pappas PG Revision and update of the consensus definitions of invasive fungal disease from the European Organization for research and treatment of cancer and the mycoses study group education and research consortium Clin Infect Dis 2020 71 1367 1376 10.1093/cid/ciz1008 31802125 PMC7486838 Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and update of the consensus definitions of invasive fungal disease from the European Organization for research and treatment of cancer and the mycoses study group education and research consortium. Clin Infect Dis. 2020;71:1367–76. 31802125 10.1093/cid/ciz1008 PMC7486838

5. van de Peppel RJ Visser LG Dekkers OM de Boer MGJ The burden of invasive aspergillosis in patients with haematological malignancy: a meta-analysis and systematic review J Infect 2018 76 6 550 562 10.1016/j.jinf.2018.02.012 29727605 van de Peppel RJ, Visser LG, Dekkers OM, de Boer MGJ. The burden of invasive aspergillosis in patients with haematological malignancy: a meta-analysis and systematic review. J Infect. 2018;76(6):550–62. 29727605 10.1016/j.jinf.2018.02.012

6. Nicolle MC Bénet T Thiebaut A Bienvenu AL Voirin N Duclos A Sobh M Cannas G Thomas X Nicolini FE De Monbrison F Piens MA Picot S Michallet M Vanhems P Invasive aspergillosis in patients with hematologic malignancies: incidence and description of 127 cases enrolled in a single institution prospective survey from 2004 to 2009 Haematologica 2011 96 1685 1691 10.3324/haematol.2011.044636 21791468 PMC3208687 Nicolle MC, Bénet T, Thiebaut A, Bienvenu AL, Voirin N, Duclos A, et al. Invasive aspergillosis in patients with hematologic malignancies: incidence and description of 127 cases enrolled in a single institution prospective survey from 2004 to 2009. Haematologica. 2011;96:1685–91. 21791468 10.3324/haematol.2011.044636 PMC3208687

7. Patterson TG Thompson GR Denning DW Fishman JA Hadley S Herbrecht R Kontoyiannis DP Marr KA Morrison VA Nguyen MH Segal BH Steinbach WJ Stevens DA Walsh TJ Wingard JR Young JAH Bennett JE Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America Clin Infect Dis 2016 63 e1 e60 10.1093/cid/ciw326 27365388 PMC4967602 Patterson TG, Thompson GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1–60. 27365388 10.1093/cid/ciw326 PMC4967602

8. Ullmann AJ Aguado JM Arikan-Akdagli S Denning DW Groll AH Lagrou K Lass-Flörl C Lewis RE Munoz P Verweij PE Warris A Ader F Akova M Arendrup MC Barnes RA Beigelman-Aubry C Blot S Bouza E Brüggemann RJM Buchheidt D Cadranel J Castagnola E Chakrabarti A Cuenca-Estrella M Dimopoulos G Fortun J Gangneux JP Garbino J Heinz WJ Herbrecht R Heussel CP Kibbler CC Klimko N Kullberg BJ Lange C Lehrnbecher T Löffler J Lortholary O Maertens J Marchetti O Meis JF Pagano L Ribaud P Richardson M Roilides E Ruhnke M Sanguinetti M Sheppard DC Sinkó J Skiada A Vehreschild MJGT Viscoli C Cornely OA Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline Clin Microbiol Infect 2018 24 Suppl 1 e1 e38 10.1016/j.cmi.2018.01.002 29544767 Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(Suppl 1):e1–38. 29544767 10.1016/j.cmi.2018.01.002

9. Lewis R Niazi-Ali S McIvor A Kanj SS Maertens J Bassetti M Levine D Groll AH Denning DW Triazole antifungal drug interactions-practical considerations for excellent prescribing J Antimicrob Chemother 2024 79 1203 1217 10.1093/jac/dkae103 38629250 PMC11977760 Lewis R, Niazi-Ali S, McIvor A, Kanj SS, Maertens J, Bassetti M, et al. Triazole antifungal drug interactions-practical considerations for excellent prescribing. J Antimicrob Chemother. 2024;79:1203–17. 38629250 10.1093/jac/dkae103 PMC11977760

10. Douglas AP Lamoth F John TM Groll AH Shigle TL Papanicolaou GA Chemaly RF Carpenter PA Dadwal SS Walsh TJ Kontoyiannis DP American Society of Transplantation and Cellular Therapy Series: #8-management and prevention of non-Aspergillus molds in hematopoietic cell transplantation recipients Transplant Cell Ther 2025 31 194 223 10.1016/j.jtct.2025.01.892 39923936 Douglas AP, Lamoth F, John TM, Groll AH, Shigle TL, Papanicolaou GA, et al. American Society of Transplantation and Cellular Therapy Series: #8-management and prevention of non-Aspergillus molds in hematopoietic cell transplantation recipients. Transplant Cell Ther. 2025;31:194–223. 39923936 10.1016/j.jtct.2025.01.892

11. IQVIA. Available IQVIA data. Available at: https://www.iqvia.com/insights/the-iqvia-institute/available-iqvia-data . Accessed 23 May 2024.

12. National Aspergillosis Centre, Antifungal Trust’s Antifungal Interactions Database. Available at: https://www.antifungalinteractions.org (Last accessed on April 28, 2025).

13. Niazi-Ali S Atherton GT Walczak M Denning DW Drug-drug interaction database for safe prescribing of systemic antifungal agents Ther Adv Infect Dis 2021 8 20499361211010605 33996073 10.1177/20499361211010605 PMC8111513 Niazi-Ali S, Atherton GT, Walczak M, Denning DW. Drug-drug interaction database for safe prescribing of systemic antifungal agents. Ther Adv Infect Dis. 2021;8:20499361211010604. 33996073 10.1177/20499361211010605 PMC8111513

14. Azanza JR Mensa J Barberán J Vázquez L de Pérez Oteyza J Kwon M Yáñez L Aguado JM Cubillo Gracian A Solano C Ruiz Camps I Fortún J Salavert Lletí M Gudiol C Olave Rubio T Solano C García-Vidal C Rovira Tarrats M Suárez-Lledó Grande M González-Sierra P Dueñas Gutiérrez C Recommendations on the use of azole antifungals in hematology-oncology patients Rev Esp Quimioter 2023 36 236 258 10.37201/req/013.2023 37017117 PMC10238801 Azanza JR, Mensa J, Barberán J, Vázquez L, de Pérez Oteyza J, Kwon M, et al. Recommendations on the use of azole antifungals in hematology-oncology patients. Rev Esp Quimioter. 2023;36:236–58. 37017117 10.37201/req/013.2023 PMC10238801

15. Brüggemann RJ Verheggen R Boerrigter E Stanzani M Verweij PE Blijlevens NMA Lewis RE Management of drug-drug interactions of targeted therapies for haematological malignancies and triazole antifungal drugs Lancet Haematol 2022 9 e58 e72 10.1016/S2352-3026(21)00232-5 34890539 Brüggemann RJ, Verheggen R, Boerrigter E, Stanzani M, Verweij PE, Blijlevens NMA, et al. Management of drug-drug interactions of targeted therapies for haematological malignancies and triazole antifungal drugs. Lancet Haematol. 2022;9:e58–72. 34890539 10.1016/S2352-3026(21)00232-5

16. Huo BN Shu L Xiao JW Yin NG Ai ML Jia YT Song L Clinical drug interactions between voriconazole and 38 other drugs: a retrospective analysis of adverse events Front Pharmacol 2024 15 1292163 10.3389/fphar.2024.1292163 39403147 PMC11471622 Huo BN, Shu L, Xiao JW, Yin NG, Ai ML, Jia YT, et al. Clinical drug interactions between voriconazole and 38 other drugs: a retrospective analysis of adverse events. Front Pharmacol. 2024;15:1292163. 39403147 10.3389/fphar.2024.1292163 PMC11471622

17. Agarwal SK DiNardo CD Potluri J Dunbar M Kantarjian HM Humerickhouse RA Wong SL Menon RM Konopleva MY Salem AH Management of Venetoclax-Posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments Clin Ther 2017 39 359 367 10.1016/j.clinthera.2017.01.003 28161120 Agarwal SK, DiNardo CD, Potluri J, Dunbar M, Kantarjian HM, Humerickhouse RA, et al. Management of Venetoclax-Posaconazole interaction in acute myeloid leukemia patients: evaluation of dose adjustments. Clin Ther. 2017;39:359–67. 28161120 10.1016/j.clinthera.2017.01.003

18. Fischer K Al-Sawaf O Hallek M Preventing and monitoring for tumor lysis syndrome and other toxicities of venetoclax during treatment of chronic lymphocytic leukemia Hematol Am Soc Hematol Educ Program 2020 2020 357 362 10.1182/hematology.2020000120 PMC7727567 33275717 Fischer K, Al-Sawaf O, Hallek M. Preventing and monitoring for tumor lysis syndrome and other toxicities of venetoclax during treatment of chronic lymphocytic leukemia. Hematol Am Soc Hematol Educ Program. 2020;2020:357–62. 10.1182/hematology.2020000120 PMC7727567 33275717

19. Krapfl A McLeod C Myers R Venugopal P Seddon A Venetoclax ramp-up with concurrent voriconazole in a patient with chronic lymphocytic leukemia J Oncol Pharm Pract 2022 28 1898 1901 10.1177/10781552221082295 35179064 Krapfl A, McLeod C, Myers R, Venugopal P, Seddon A. Venetoclax ramp-up with concurrent voriconazole in a patient with chronic lymphocytic leukemia. J Oncol Pharm Pract. 2022;28:1898–901. 35179064 10.1177/10781552221082295

20. Huang D Zhang Y Liu L Yang M Zeng T Wang S Attention to the interactions between vincristine and triazole antifungals: perspectives from real-world retrospective analysis and pharmacovigilance assessment Expert Opin Drug Saf 2025 2025 1 12 10.1080/14740338.2025.2496432 40249035 Huang D, Zhang Y, Liu L, Yang M, Zeng T, Wang S. Attention to the interactions between vincristine and triazole antifungals: perspectives from real-world retrospective analysis and pharmacovigilance assessment. Expert Opin Drug Saf. 2025;2025:1–12. 10.1080/14740338.2025.2496432 40249035

21. Moriyama B Henning SA Leung J Falade-Nwulia O Jarosinski P Penzak SR Walsh TJ Adverse interactions between antifungal azoles and vincristine: review and analysis of cases Mycoses 2012 55 290 297 10.1111/j.1439-0507.2011.02158.x 22126626 PMC3345292 Moriyama B, Henning SA, Leung J, Falade-Nwulia O, Jarosinski P, Penzak SR, et al. Adverse interactions between antifungal azoles and vincristine: review and analysis of cases. Mycoses. 2012;55:290–7. 22126626 10.1111/j.1439-0507.2011.02158.x PMC3345292

22. Moriyama B Falade-Nwulia O Leung J Penzak SR JJingo C Huang X Henning SA Wilson WH Walsh TJ Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction Mycoses 2011 54 e877 e879 10.1111/j.1439-0507.2011.02016.x 21615537 PMC3164277 Moriyama B, Falade-Nwulia O, Leung J, Penzak SR, JJingo C, Huang X, et al. Prolonged half-life of voriconazole in a CYP2C19 homozygous poor metabolizer receiving vincristine chemotherapy: avoiding a serious adverse drug interaction. Mycoses. 2011;54:e877–9. 21615537 10.1111/j.1439-0507.2011.02016.x PMC3164277

23. Choules MP Otsuka Y Kovanda L Bonate P Sinnar S Desai A Physiological-based pharmacokinetic analysis of drug–drug interactions between isavuconazole and vincristine in pediatric subjects Open Forum Infect Dis 2023 10 Suppl 2 ofad500.2152 10.1093/ofid/ofad500.2152 Choules MP, Otsuka Y, Kovanda L, Bonate P, Sinnar S, Desai A. Physiological-based pharmacokinetic analysis of drug–drug interactions between isavuconazole and vincristine in pediatric subjects. Open Forum Infect Dis. 2023;10(Suppl 2):ofad500.2152.

24. Astellas Pharma US, Inc. CRESEMBA (isavuconazonium sulfate) prescribing information. Northbrook, IL: Astellas Pharma US, Inc.; 2025. Available from: https://www.astellas.us/docs/cresemba.pdf . Accessed 9 Nov 2025.

25. Abu Rmilah AA Lin G Begna KH Friedman PA Herrmann J Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors Int J Cancer 2020 147 3160 3167 10.1002/ijc.33119 32449208 PMC8772338 Abu Rmilah AA, Lin G, Begna KH, Friedman PA, Herrmann J. Risk of QTc prolongation among cancer patients treated with tyrosine kinase inhibitors. Int J Cancer. 2020;147:3160–7. 32449208 10.1002/ijc.33119 PMC8772338

26. Megías-Vericat JE Solana-Altabella A Ballesta-López O Martínez-Cuadrón D Montesinos P Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia Ann Hematol 2020 99 1989 2007 10.1007/s00277-020-04186-0 32683457 Megías-Vericat JE, Solana-Altabella A, Ballesta-López O, Martínez-Cuadrón D, Montesinos P. Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. Ann Hematol. 2020;99:1989–2007. 32683457 10.1007/s00277-020-04186-0

27. Van Matre ET Evans SL Mueller SW MacLaren R Fish DN Kiser TH Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center Ann Clin Microbiol Antimicrob 2019 18 13 10.1186/s12941-019-0311-3 30894179 PMC6427894 Van Matre ET, Evans SL, Mueller SW, MacLaren R, Fish DN, Kiser TH. Comparative evaluation of isavuconazonium sulfate, voriconazole, and posaconazole for the management of invasive fungal infections in an academic medical center. Ann Clin Microbiol Antimicrob. 2019;18:13. 30894179 10.1186/s12941-019-0311-3 PMC6427894

28. Zhou Z Slattum PW Ke A Zhang L Managing drug-drug interactions in older adults J Clin Pharmacol 2023 63 10 1083 1090 10.1002/jcph.2299 37408371 PMC10529698 Zhou Z, Slattum PW, Ke A, Zhang L. Managing drug-drug interactions in older adults. J Clin Pharmacol. 2023;63(10):1083–90. 10.1002/jcph.2299. 37408371 10.1002/jcph.2299 PMC10529698

29. Mallet L Spinewine A Huang A The challenge of managing drug interactions in elderly people Lancet 2007 370 14 185 191 10.1016/S0140-6736(07)61092-7 17630042 Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370(14):185–91. 10.1016/S0140-6736(07)61092-7. 17630042 10.1016/S0140-6736(07)61092-7

30. Gandhi SK Salmon JW Kong SX Zhao SZ Administrative databases and outcomes assessment: an overview of issues and potential utility J Manag Care Pharm 1999 5 215 222 Gandhi SK, Salmon JW, Kong SX, Zhao SZ. Administrative databases and outcomes assessment: an overview of issues and potential utility. J Manag Care Pharm. 1999;5:215–22.

31. Zuniga-Moya JC Papadopoulos B Atkinson A Mazi PB Rauseo AM Spec A Geographic distribution and associated mortality of invasive aspergillosis and mucormycosis among Medicare enrollees in the United States (2008–2015) J Infect 2025 91 106568 10.1016/j.jinf.2025.106568 40769427 Zuniga-Moya JC, Papadopoulos B, Atkinson A, Mazi PB, Rauseo AM, Spec A. Geographic distribution and associated mortality of invasive aspergillosis and mucormycosis among Medicare enrollees in the United States (2008–2015). J Infect. 2025;91:106568. 40769427 10.1016/j.jinf.2025.106568