Abstract
Of 319 children with invasive candidiasis, 67 (21%) transitioned from intravenous to enteral antifungal therapy. Eight (12%) transitioned back to intravenous antifungal therapy, one due to perceived treatment failure defined by clinical progression or worsening. Global treatment response at study completion was successful in 66 participants who transitioned to enteral therapy.
Keywords: antifungal agent, candidemia, fluconazole, invasive candidiasis, oral drug administration
INTRODUCTION
Children who are immunocompromised or otherwise medically complex are at risk for invasive candidiasis [1]. Infectious Diseases Society of America (IDSA) guidelines support the option to transition from intravenous to enteral therapy for most forms of invasive candidiasis in patients with blood culture clearance, clinical stabilization, and fluconazole-susceptible isolates [2]. Enteral therapy transition has been primarily studied in adults [3–5]. The goal of this study was to characterize the outcomes of the transition to enteral antifungal therapy in children with invasive candidiasis.
Methods
Design
A secondary analysis was conducted of PEdiatric Antifungal Comparative Effectiveness (PEACE), a prospective multicenter observational cohort study of children (≥4 months–17 years) with invasive candidiasis [6]. Each site obtained institutional review board approval; the need for informed consent was determined locally. Data were collected in REDCap case report forms (CRF). Day 0 was the day of collection for the initial diagnostic culture. Antifungal selection, route, and duration of therapy were chosen by treating clinicians. Other management decisions such as central venous catheter (CVC) management were also made by treating clinicians. The secondary analysis study eligibility criteria, outcomes, outcome definitions, and analysis plan were developed before the detailed review of intravenous to enteral transition data.
Participants
Starting from the parent study cohort [6], we excluded participants with intestinal failure, or who received parenteral nutrition throughout the study follow-up (30 days). The rationale is that these conditions often preclude enteral medication administration. We excluded episodes in which endocarditis was detected by echocardiogram because IDSA guidelines recommend intravenous antifungal therapy for the entirety of endocarditis treatment [2]. We excluded episodes caused by Candida species with documented triazole non-susceptibility or by Nakaseomyces glabratus (Candida glabrata) or Pichia kudriavzevii (Candida krusei). Though these organisms can sometimes be treated with enteral triazole therapy, our rationale was to select episodes in which IDSA guideline recommendations favoring transition to enteral therapy would be most likely to apply. Triazole susceptibility was classified using laboratory results recorded by study sites, with minimum inhibitory concentrations (MIC) of ≤2 μg/mL as the breakpoint for fluconazole, ≤0.125 μg/mL for voriconazole, and ≤0.064 μg/mL for posaconazole [7, 8]. If MICs were not provided, the reported interpretation was used. We excluded episodes in which there were no positive sterile site cultures at onset, repeat episodes in the same participant, episodes with <7 days of study follow-up, and episodes in which there was no initial intravenous antifungal treatment (days 0–7).
Exposure
Antifungal agents administered, administration routes, and reasons for changes were captured (Supplementary Table 1). The exposure of interest was transition to an enteral triazole antifungal after initial intravenous therapy. The transition could occur at any time up to day 30. Episodes in which participants received intravenous antifungal and then were changed to enteral antifungal therapy between days 0 and 3, and then changed back to intravenous therapy for all subsequent days were classified as “intravenous therapy only.” The rationale was that these transitions may have occurred before culture results were available.
Outcomes
Outcomes were intended to characterize (1) feasibility of the enteral transition strategy and (2) longer-term control of invasive candidiasis. Feasibility outcomes in the intravenous to enteral transition group were transition back to intravenous antifungal therapy for any reason, and transition specifically for treatment failure as perceived by treating clinicians. In the intravenous therapy-only group, we also evaluated changes to other intravenous antifungals for perceived treatment failure to provide a comparison. The rationale for reporting change due to perceived treatment failure separately from other types of change was that this is considered a more serious outcome that may be challenging to address by changing back to intravenous therapy. The CRF options to describe reasons for the change were “changed due to treatment failure,” “changed due to antifungal toxicity,” “changed due to step-down therapy,” “changed after susceptibility data showed decreased susceptibility/increased resistance,” and “other” with free text response (Supplementary Table 1). Reasons were reported by site personnel based on the best assessment of treating clinicians’ intent from record review.
Free text responses were re-classified as “changed due to treatment failure” if they referred to worsening symptoms or a new or progressive imaging abnormality. The rationale for this re-classification was to align with definitions of treatment failure used in invasive fungal disease clinical trials. For the parent study, site investigators were trained to use global response definitions per Mycoses Study Group/European Organization for Research and Treatment of Cancer (MSG/EORTC) Consensus Criteria [9]. Site investigators and personnel would have been familiar with these criteria as they were included in the CRF (Supplementary Table 1) and captured as the primary outcome for the PEACE study [6]. The global response outcome was recorded at day 30, or end of follow-up if earlier, and centrally adjudicated. In this secondary analysis, we report the dichotomized (“success” or “failure”) 30-day global response outcome as a measure of longer-term control of candidiasis. With these definitions, it would be possible to change therapy early in the course due to perceived treatment failure but have a 30-day global response of “success” by MSG/EORTC criteria.
Statistical Analysis
Categorical variables were described as percentages with between-group comparisons conducted by Fisher’s exact test. Continuous variables were summarized using medians with interquartile range, with between-group comparisons conducted by Wilcoxon rank-sum test. Statistical analysis was conducted in Stata/SE 15.1 and 17.0 (StataCorp, College Station, TX).
Results
Participant Characteristics and Enteral Therapy Transition
Of 750 episodes in the PEACE cohort [6], 319 from 42 study sites met the study eligibility criteria (selection flow chart, Supplementary Figure 1). The most frequent reasons for exclusion were intestinal failure (n = 229) and receipt of parenteral nutrition throughout study follow-up (n = 70). There were 67/319 (21%) participants who transitioned from intravenous antifungal therapy to enteral triazole antifungal therapy. Participant characteristics are shown in Table 1. The most common causative Candida species were C. albicans (n = 112, 35%), C. parapsilosis or ortholopsis (n = 103, 32%), and C. tropicalis (n = 47, 14%) (Supplementary Table 2).
Table 1.
Baseline Characteristics of Study Population, Overall and by Treatment Group
| Characteristic | Overall Study Population (N = 319) | Intravenous Therapy Only Group (N = 252) | Intravenous to Enteral Transition Group (N = 67) | P, Comparison Between Treatment Groupsa |
|---|---|---|---|---|
| Age (median, IQR) | 3.6 (1.9–10.0) | 3.5 (1.9–10.0) | 4.1 (1.7–10.2) | 0.72b |
| Underlying conditionsc (N, %) | ||||
| Hematologic malignancy | 77 (24) | 65 (26) | 12 (18) | 0.20 |
| Solid tumor malignancy | 71 (22) | 56 (22) | 15 (22) | >0.99 |
| Surgery or trauma | 39 (12) | 28 (11) | 11 (16) | 0.29 |
| Heart and/or lung disease | 36 (11) | 30 (12) | 6 (9) | 0.66 |
| Congenital/genetic/metabolic syndrome | 33 (10) | 26 (10) | 7 (10) | >0.99 |
| Neurologic disease | 23 (7) | 17 (7) | 6 (9) | 0.60 |
| Kidney and/or liver disease | 22 (7) | 18 (7) | 4 (6) | >0.99 |
| Bone marrow or hematologic disease | 18 (6) | 14 (6) | 4 (6) | >0.99 |
| Solid organ transplant recipient | 17 (5) | 14 (6) | 3 (4) | >0.99 |
| Primary immunodeficiency | 11 (3) | 11 (4) | 0 (0) | 0.13 |
| Hematopoietic cell transplant recipientd | 34 (11) | 26 (10) | 8 (12) | 0.66 |
| Neutropenia at episode onset (N, %)e | 85 (27) | 71 (28) | 14 (21) | 0.28 |
| Central venous catheter (N, %)e | 287 (89) | 230 (91) | 54 (81) | 0.03 |
| Intensive care unit admission (N, %)e | 111 (35) | 93 (37) | 18 (27) | 0.15 |
aUnless noted, P-values calculated by Fisher exact test, 2-sided.
bFrom Wilcoxon rank sum test.
cMultiple selections were allowed for underlying conditions. Additional underlying conditions were reported in <10 participants.
dHematopoietic transplantation history was reported as a distinct variable in addition to underlying condition(s).
eEach of these baseline characteristics refers to risk factors present at onset of invasive candidiasis, on or before day 0.
Treatment Course Preceding Enteral Therapy Transition
Of 67 participants who transitioned to enteral therapy, 53 (79%) had candidemia without positive cultures from other sterile sites, 12 (18%) had Candida species recovered from other sterile sites without candidemia, and 2 (3%) had both candidemia and other sterile site involvement (Supplementary Table 3). Findings of disseminated candidiasis were reported in 3 participants based on diagnostic imaging studies (detail in Supplementary Table 3). The median duration of candidemia was 2 days (IQR 1–4 days). Among those with candidemia, 48/55 had CVC(s) at diagnosis and 40/48 had all CVCs removed with at least 1 day of interruption in CVC access, within a median of 3 days (IQR 2–9 days) from episode onset. For participants without interruption in CVC access, we did not evaluate other catheter management strategies (retention vs. exchange) used in conjunction with intravenous to enteral transition. Enteral therapy was preceded by therapy with intravenous triazoles in 47 (70%) participants, echinocandins in 32 (48%), and polyenes in 21 (31%). Some participants received multiple antifungals prior to transition. Transition to enteral therapy occurred at a median of study day 10 (IQR 7–15).
Treatment Course Following Transition to Enteral Therapy
After the transition, 58 (87%) participants received enteral fluconazole and 9 (13%) received enteral voriconazole. Figure 1 shows a swimmer plot of participant trajectories in the route of antifungal therapy. Eight (12%) participants underwent the transition back to intravenous therapy. One had “treatment failure” selected as the reason, in this instance the intravenous to-enteral transition occurred at day 5 and there were positive blood cultures for Candida species thereafter, with a transition back to intravenous therapy on day 10. Other reasons for transition back to intravenous therapy were vomiting (n = 2), reestablishment of intravenous access after temporary enteral transition for lost access (n = 2), desire to change therapeutic class for potential improvement in spectrum or tolerability (n = 2), and “unknown” (n = 1). In addition to participants who transitioned back to intravenous therapy directly from enteral therapy, there were 2 who had interruptions in receiving antifungal therapy (#38 and #44 in Figure 1) and later restarted an intravenous antifungal. Rationales for restarting intravenous antifungal therapy were not clearly documented.
Figure 1.
Swimmer plot showing individual participant trajectories in route of antifungal therapy administration in the enteral antifungal transition group. Each bar represents a single participant, numbers on Y-axis represent rank order from earliest to latest transition. The X-axis represents follow-up time from day 0, the day of qualifying culture collection, to day 30. Darker bar components represent time on intravenous antifungal therapy, and lighter bar components represent time on exclusively enteral antifungal therapy. Dashed lines represent ongoing study follow-up without antifungal therapy administered. The open diamond represents an episode with a global response to failure.
The MSG/EORTC global response at the end of follow-up was “success” in 66/67 (99%) participants who transitioned to enteral therapy. The participant with the global response of “failure” died 3 days after enteral transition, due to “underlying disease with active candidal infection.” The participant had prolonged candidemia (10 days) and ongoing neutropenia at the time of enteral transition. For comparison in participants receiving intravenous therapy only, the median duration of candidemia was 2 days (IQR 1–5 days), 41 (16%) had antifungal therapy changes for perceived treatment failure, and 232/252 (92%) had a 30-day global response of “success.”
Post-Hoc Analysis of Fluconazole Dose Trajectories
To evaluate the possibility that transitions from intravenous to enteral therapy later in the study period may have been intended as transitions from active treatment to prophylaxis (which was not included among the options to select as a reason for change), we evaluated participant trajectories in fluconazole dose (Supplementary Table 4). All decreases in fluconazole daily dose by ≥3 mg/kg/day occurred before day 14 and involved a single day at higher dosing, followed by lower dosing thereafter. This is consistent with the initial loading dosing that was recommended to sites when initiating fluconazole treatment.
Discussion
In this secondary analysis, we found that 21% of study-eligible participants were treated with an intravenous to enteral transition strategy. Outcomes of the enteral transition were favorable with most participants in this group completing the study without conversion back to intravenous therapy, and 99% having control of invasive candidiasis with 30-day MSG/EORTC global response of “success.” One participant died following the transition to enteral therapy, however, the transition occurred in the context of persistent candidemia, which is outside guideline-recommended parameters for intravenous to enteral transition [2]. It is possible that treatment was modified in this case due to palliative care goals. Our eligibility criteria were broad and did not fully account for time-varying factors that may have influenced treatment outcomes. Given these broad criteria, overall outcomes in the enteral transition group are reassuring, with the caveat that 12% receiving enteral therapy transitioned back to intravenous therapy. The high 30-day global response may reflect clinician preference for enteral transition in participants with favorable initial responses and low risk for complications.
To the best of our knowledge, there are no prior systematic evaluations of the transition to enteral triazole therapy for pediatric invasive candidiasis. Fluconazole has high enteral bioavailability in children, so anticipated exposure would be comparable between intravenous and enteral administration [10]. Conversion to enteral triazole therapy after 5 days of intravenous echinocandin therapy was permitted in adult clinical trials of echinocandin therapy [3–5]. Per clinician discretion, ~30% of trial participants underwent an enteral transition, and outcomes of participants who transitioned early in their course (<7 days) were comparable to the overall study population [3]. Our findings are qualitatively similar, though smaller numbers limit comparisons based on the timing of transition. With our selection criteria focused on identifying participants able to take enteral medications, it is surprising that most received intravenous therapy only, especially when the duration of candidemia and baseline characteristics were similar between groups. The reasons for these differences are unknown.
Our study has important limitations. We excluded participants who were followed for <7 days, to focus on those with adequate time to meet IDSA criteria to transition to enteral therapy. This may introduce bias in the evaluation of treatment response, however, there were few episodes excluded for this reason. We lack sufficient numbers or measured covariates to account for confounders of treatment response. Therefore, conclusions about comparability or differences in outcomes between the enteral transition strategy vs. entirely intravenous therapy are limited. There is also potential for misclassification of treatment strategy; we did not systematically capture whether enteral therapy was intended for ongoing invasive candidiasis treatment or for other indications, such as prophylaxis. However, our post hoc analysis of fluconazole dose trajectories did not show trajectories that would be expected if the enteral transitions were conversions to prophylaxis. Another limitation is that many participants received long total durations of antifungal treatment with a median time to transition at day 10. The optimal treatment duration for invasive candidiasis is unknown, so some participants may have been adequately treated with intravenous therapy prior to transition.
Conclusions
Our findings support the feasibility of transition to enteral triazole therapy for pediatric invasive candidiasis treatment. Further studies focused on early transition in defined clinical subgroups would be valuable.
Supplementary Data
Supplementary materials are available at the Journal of The Pediatric Infectious Diseases Society online (http://jpids.oxfordjournals.org).
Contributor Information
Robert F T Bucayu, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA; Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Craig L K Boge, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Inci Yildirim, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA; Yale Institute for Global Health, Yale University, New Haven, Connecticut, USA; Yale Center for Infection and Immunity, Yale University School of Medicine, New Haven, Connecticut, USA; Department of Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA.
Martha Avilés-Robles, Department of Infectious Diseases, Hospital Infantil de México Federico Gómez, Mexico City, Mexico.
Surabhi B Vora, Department of Pediatrics, University of Washington and Division of Infectious Diseases, Seattle Children’s Hospital, Seattle, Washington, USA.
David M Berman, Medical Affairs, Karius, Inc., Redwood City, California, USA.
Tanvi S Sharma, Division of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Lillian Sung, Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Canada.
Elio Castagnola, Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Debra L Palazzi, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas, USA.
Lara Danziger-Isakov, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
Dwight E Yin, Department of Pediatrics, Children’s Mercy Kansas City, University of Missouri-Kansas City, Missouri, USA.
Emmanuel Roilides, Infectious Diseases Unit, 3rd Department of Pediatrics, Aristotle University and Hippokration Hospital, Thessaloniki, Greece.
Gabriela Maron, Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
Alison C Tribble, Department of Pediatrics, Division of Pediatric Infectious Diseases, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, Michigan, USA.
Pere Soler-Palacin, Department of Paediatrics, Paediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d’Hebron, Barcelona, Catalonia, Spain.
Eduardo López-Medina, Centro de Estudios en Infectología Pediátrica, Clínica Imbanaco Grupo Quirónsalud and Universidad del Valle, Cali, Colombia.
José Romero, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Kiran Belani, Pediatric Infectious Diseases, Children’s Minnesota, Minneapolis, Minnesota, USA.
Antonio C Arrieta, Department of Infectious Diseases, Children’s Hospital of Orange County, Orange, California, USA; Department of Pediatrics, University of California Irvine, Irvine, California, USA.
Fabianne Carlesse, Instituto de Oncologia Pediatrica–IOP/GRAACC-UNIFESP, São Paulo, Brazil.
Dawn Nolt, Division of Pediatric Infectious Diseases, Oregon Health & Science University and Doernbecher Children’s Hospital, Portland, Oregon, USA.
Natasha Halasa, Department of Pediatrics, Vanderbilt University Medical Center and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee, USA.
Daniel Dulek, Department of Pediatrics, Vanderbilt University Medical Center and Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tennessee, USA.
Sujatha Rajan, Division of Pediatric Infectious Diseases, Northwell, Cohen Children’s Medical Center, New Hyde Park, New York, USA.
William J Muller, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
Monica I Ardura, Division of Infectious Diseases and Host Defense Program, Department of Pediatrics, Nationwide Children’s Hospital and The Ohio State University, Columbus, Ohio, USA.
Alice Pong, Department of Pediatrics, University of California San Diego and Rady Children’s Hospital San Diego, San Diego, California, USA.
Blanca E Gonzalez, Center for Pediatric Infectious Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Christine M Salvatore, Division of Pediatric Infectious Diseases, Weill Cornell Medicine and Komansky Children’s Hospital, New York, New York, USA.
Anna R Huppler, Department of Pediatrics, Medical College of Wisconsin and Children’s Wisconsin, Milwaukee, Wisconsin, USA.
Catherine Aftandilian, Division of Pediatric Hematology, Oncology, Stem Cell Transplant and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California, USA.
Mark J Abzug, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USA.
Arunaloke Chakrabarti, Doodhadhar Burfani Hospital and Research Institute, Haridwar, India.
Michael Green, Department of Pediatrics, UPMC Children’s Hospital of Pittsburgh, Pennsylvania, USA.
Irja Lutsar, Department of Microbiology, University of Tartu, Tartu, Estonia.
Elizabeth D Knackstedt, Division of Pediatric Infectious Diseases, University of Utah, Salt Lake City, Utah, USA.
Sarah K Johnson, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
William J Steinbach, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Brian T Fisher, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Rachel L Wattier, Department of Pediatrics, University of California San Francisco, San Francisco, California, USA.
Notes
Acknowledgments. We thank the clinical research assistants at all participating institutions for their commitment to patient screening and chart abstraction.
Disclaimer. The content of this article is solely the responsibility of the authors and does not reflect the official views of the National Institutes of Health, the US Department of Health and Human Services, or the US government.
Financial support. This work is a secondary analysis of the PEdiatric Antifungal Comparative Effectiveness (PEACE) study which was supported by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health [5R01AI103315]. I.Y. receives funding from National Institutes of Health for research unrelated to this manuscript. L.S. is supported by the Canada Research Chair in Pediatric Oncology Supportive Care. A.C.T. receives funding from AHRQ and the Cystic Fibrosis Foundation for research unrelated to this manuscript. N.H. receives funding from National Institutes of Health and Centers for Disease Control and Prevention for research unrelated to this manuscript. M.J.A. receives funding from National Institutes of Health for research unrelated to this manuscript. M.G. receives funding from National Institutes of Health for research unrelated to this manuscript. B.T.F. receives funding from National Institutes of Health, Food Drug and Aministration, and Centers for Disease Control and Prevention for research unrelated to this manuscript. R.L.W. is supported by grant 1K12DK111028 from the National Institute of Diabetes, Digestive, and Kidney Diseases.
Role of the funder/sponsor. The National Institute for Allergy and Infectious Diseases was the original parent study sponsor. The study sponsor did not have a role in the conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.
Potential conflicts of interest. I.Y. has received funds from her institution to conduct clinical research unrelated to this manuscript from Pfizer, Merck, Astellas, and Moderna. M.A.R. receives support from Merck. S.B.V. has received payment from Astellas as an expert consultant. D.M.B. is employed as a Medical Director at Karius, Inc., and has served as a consultant to Precision Health Solutions. E.C. provided consultant services for Mundipharma and served as speaker in symposia sponsored by Astellas, Gilead, and F2g. D.L.P. receives royalties from UpToDate. L.D.I. has received support from Astellas, Merck, Ansun Biopharma, Takeda, and Pfizer. D.E.Y. was previously an unpaid technical advisor for the non-profits Cover the Globe and Maipelo Trust; although currently employed at the NIH, he was an investigator for this study while with his prior employer. E.R. receives research funding to his institution from Astellas, MSD, Scynexis, Shionogi, GSK, Pfizer, Gilead, and Allergan, and has served as a consultant to Amplyx, Astellas, Gilead, MSD, Pfizer, Scynexis, GSK and Shionogi. G.M. receives research funding from Astellas and Symbio Pharmaceuticals. P.S.P. receives research funding from Pfizer, Astellas, and Gilead. A.C.A. receives research funding from Astellas, Merck, and Pfizer. F.C. received funding from Pfizer, Sandoz, and Knight for educational lectures. N.H. received past grant support from Sanofi and Quidel, and current grant support from Merck. W.J.M has received funding from Ansun Biopharma, Astellas Pharma, AstraZeneca, DiaSorin Molecular LLC, Eli Lilly and Company, Enanta Pharmaceuticals, F. Hoffmann-La Roche Ltd (Roche), Gilead Sciences, Invivyd, Janssen Biotech, Karius, Inc., Melinta Therapeutics, Inc., Merck, Sharpe & Dohme, Moderna, Nabriva Therapeutics, plc, Paratek Pharmaceuticals, Inc., Pfizer, ProventionBio, Sanofi Pasteur LLC, Seqirus, and Tetraphase Pharmaceuticals, Inc. M.I.A. received research funding from Miravista and provided consultant services for Karius. C.M.S. received payment from GlaxoSmithKline as an expert consultant. A.R.H. has patent 10 160 974. M.G. is a consultant and serves on Data Safety Monitoring Boards for ITB-Med and Bristol Myers Squibb. W.J.S. receives funding from Sfunga. B.T.F. served on a data safety monitoring board for an Astellas study of the outcomes of isavuconazole in pediatric patients, and receives funding from Merck, Pfizer, and Allovir to conduct research unrelated to this manuscript. All other authors have nothing to disclose.
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