Risk Of Invasive Fungal Infections Research Articles

Challenging antibiotic stewardship: antibiotic use in the management of acute pancreatitis without waiting for a CT scan or CRP marker

Madam, Acute pancreatitis is an acute inflammation of the pancreas presenting as severe abdominal pain and elevated pancreatic enzymes. The global burden of Acute pancreatitis has increased by 3.07% per year, for the last 56 years.1 Gallstones, chronic alcohol, and hypertriglyceridemia are the main risk factors involved in the pathogenesis of Acute pancreatitis worldwide.2 However, in Pakistan gall stones impacting the common bile duct and hypertriglyceridemia are the main culprits. There has been an extensive debate regarding the use of prophylactic antibiotics and the outcome of acute pancreatitis. The cumulative evidence suggests that the prompt use of antibiotics, before obtaining serum markers, is not associated with a significant decrease in secondary pancreatic infection.3 Multiple studies have shown that the use of antibiotics, deviating from the recent guidelines, boosts antibiotic resistance and the risk of invasive fungal infections. A 2020 study conducted by Soulountsi has also rendered this practice unjustified.4 In studies supporting the use of prophylactic antibiotics in improving outcomes, the quality of evidence is low suggesting that the approach should be more tailored to individual patient conditions while adhering to the guidelines. Despite the sterile nature of the early stages of acute pancreatitis, some clinicians continue to opt for prophylactic use, however, it is strictly against the international consensus. Unfortunately, in Pakistan, there is a common practice of using antibiotics in acute pancreatitis within 72hrs, without waiting for the CT scan results and inflammatory markers screening. Antimicrobial resistance is an anticipated outcome of such practice. The prevalence of antimicrobial resistance to commonly prescribed antibiotics is already very high.5 Not weighing the risk-benefit ratio will not only contribute to increasing resistance but also predispose to avoidable and potentially fatal fungal infections. The appropriate approach to management of Acute pancreatitis should be based on a thorough knowledge of recent guidelines, carrying out proper investigations, and making an individualized plan for the patient based on clinical findings. This will not only minimize the burden of complications but also provide more room for improvements in the management of acute pancreatitis.

A-273 Rapid, Portable Invasive Fungal Infection Diagnostic and Candida Antimicrobial Susceptibility Testing

Abstract Background Traumatic wounds are associated with a higher risk of invasive fungal infections (IFI), which lead to a significant increase in amputation or death. Actionable treatment decisions are hampered because true infections can be difficult to differentiate from external wound contaminates, and tissue biopsy and quantification of fungal load is required to determine if treatment is necessary, which currently takes several days. GeneCapture is developing the CAPTURE 60-minute, portable infection identification platform to detect infectious levels of common fungi including the genera Aspergillus, Fusarium, and Scedosporium, the family Herpotrichiellaceae, and the order Mucorales. The company is also pursuing rapid identification and antimicrobial susceptibility testing for Candida species from multiple infection types. Methods This study seeks to determine the Limit of Detection (LoD), sensitivity and specificity of the CAPTURE ID assay for fungal pathogens. Since tissue biopsy samples must be used to assess the presence of IFI in wounds, GeneCapture has developed a manual process for the crude homogenization of muscle tissue to allow this matrix to be used as the starting sample for the ID assay. Mock samples were tested for inclusivity and exclusivity on a series of IFI ID panels against multiple strains of the included fungi, against fungi not yet specifically detected on the panel, and against bacteria that commonly infect wounds. While the LoD for yeasts may be determined in CFU/mL, there is no similar, easy-to-define metric for molds. GeneCapture has developed a quantitative PCR method to detect the single copy beta-tubulin gene to roughly correlate fungal dry mass and nuclei number to assay signal for molds cultured in Potato Dextrose Broth. Determining beta-tubulin copy numbers for extracts from mock samples then allowed detection of the progression of IFI over the course of infection. Lastly, antimicrobial susceptibility testing (AST) was performed on two species of Candida to validate utilizing GeneCapture’s rapid phenotypic AST method for fungal infections. Results To date, the CAPTURE ID panel has been tested against 27 included or excluded strains of fungi or bacteria with 97% sensitivity and 100% specificity. The current LoD for mold organisms varies from approximately 1,000 nuclei for Aspergillus species, to 100,000 nuclei for Fusarium species. Additional work to understand this range is underway. Lastly, we have correctly determined the susceptibility of Candida species using our novel approach within 4-6 hours. Conclusions GeneCapture’s ID and AST technology offer a unique solution to address the increasing prevalence of fungal infections. Our platform can identify the most common fungal components in a wound within 60 minutes of receiving a tissue biopsy sample. Candida infections occur across multiple matrices and rapidly identifying the species of Candida and then determining its phenotypic susceptibility profile will have a large impact on treating these difficult pathogens.

Shift from widespread to tailored antifungal prophylaxis in lymphoma patients treated with CD19 CAR T- cell therapy: results from a large retrospective cohort

BackgroundPatients undergoing CD19 chimeric antigen receptor (CAR) T-cell therapy exhibit multiple immune deficits that may increase their susceptibility to infections. Invasive fungal infections (IFI) are life-threatening events in the setting of hematological diseases. However, there is ongoing debate regarding the optimal role and duration of antifungal prophylaxis in this specific patient population. ObjectivesThe objective of this study was to provide a comprehensive overview of the evolution of IFI prophylactic strategies over time and to assess IFI incidence rates in a cohort of patients with relapsed or refractory (R/R) lymphoma treated with CAR-T cell therapy. Study DesignSingle-center, retrospective study from a cohort of patients with R/R B-cell lymphoma treated with CD19 CAR-T cell therapy between April 2016 and March 2023. Group A (April 2016- August 2020) consisted of patients primarily treated with fluconazole, irrespective of their individual IFI risk profile. In Group B (September 2020- March 2023) antifungal prophylaxis was recommended only for high-risk patients. ResultsOverall, 330 patients were included. Antifungal prophylaxis was prescribed to 119/142 (84%) patients in Group A and 58/188 (31%) in Group B (p<0.001). Anti-mold azoles were prescribed to 8 (5.6%) patients in Group A and 21 (11.2%) patients in Group B. In Group A, 42 (29%) patients switched to another antifungal, 9 (21%) because of toxicity, with 6 cases of transaminitis and 3 cases of prolonged QTc. In Group B, 21 (11.2%) patients switched the antifungal drug, mainly from fluconazole or micafungin to a mold-active agent following revised guidelines. No difference was found in liver toxicity between the two groups at infusion, day 10, and day 30. No significant differences were observed between the groups. IFI following CAR T-cell therapy were rare, with one case of cryptococcal meningoencephalitis in group A (0.7%) and one case of invasive aspergillosis in group B (0.5%), both occurring in patients on micafungin prophylaxis. ConclusionIn this large single-center cohort of patients with R/R lymphoma treated with CAR T-cells, we show that individualized prophylaxis, alongside careful management of CAR T-cell related toxicities like CRS, was associated with a very low IFI rate, avoiding the risk of unnecessary toxicities, drug-drug interactions, and high costs.

Invasive fungal infections are rare in pediatric and young adult autologous hematopoietic stem cell transplant patients.

Pediatric and young adult patients undergoing autologous hematopoietic stem cell transplant (auto-HSCT) face a crucial, yet understudied, risk of invasive fungal infections (IFI), especially compared to allogeneic transplants. This gap underscores the need for research in pediatric patients undergoing auto-HSCT. Our objective was to evaluate the incidence of IFI in pediatric and young adult patients during the first year after auto-HSCT. We conducted a single-center retrospective analysis of 150 pediatric and young adult auto-HSCT patients who underwent transplant from January 2013 to January 2023. We focused on IFI incidence within the first-year post transplant, using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria for IFI identification. Among the 150 patients analyzed, with 240 unique transplant episodes, the primary indication was neuroblastoma (37.3%), and micafungin was extensively used for prophylaxis (82.7%). There was an absence of IFI from yeast and mold species, suggesting a low IFI risk in this cohort. The incidence of IFI in pediatric auto-HSCT recipients receiving micafungin primary antifungal prophylaxis is rare. The findings advocate for further research to refine prophylaxis guidelines and highlight the need for individualized risk assessment to optimize post-transplant care.

What do we know About the Usefulness of 18F-FDG PET-CT for the Management of Invasive Fungal Infection? An International Survey.

Recent data support 18F-FDG PET-CT for the management of infections in immunocompromised patients, including invasive fungal infection (IFI). However, its role is not well established in clinical practice. We performed an international survey to evaluate the knowledge of physicians about the usefulness of 18F-FDG PET-CT in IFI, in order to define areas of uncertainty. An online survey was distributed to infectious diseases working groups in December 2023-January 2024. It included questions regarding access to 18F-FDG PET-CT, knowledge on its usefulness for IFI and experience of the respondents. A descriptive analysis was performed. 180 respondents answered; 60.5% were Infectious Diseases specialists mainly from Spain (52.8%) and Italy (23.3%). 84.4% had access to 18F-FDG PET-CT at their own center. 85.6% considered that 18F-FDG PET-CT could be better than conventional tests for IFI. In the context of IFI risk, 81.1% would consider performing 18F-FDG PET-CT to study fever without a source and around 50% to evaluate silent lesions and 50% to assess response, including distinguishing residual from active lesions. Based on the results of the follow-up 18F-FDG PET-CT, 56.7% would adjust antifungal therapy duration. 60% would consider a change in the diagnostic or therapeutic strategy in case of increased uptake or new lesions. Uncovering occult lesions (52%) and diagnosing/excluding endocarditis (52.7%) were the situations in which 18F-FDG PET-CT was considered to have the most added value. There was a great variability in responses about timing, duration of uptake, the threshold for discontinuing treatment or the influence of immune status. Although the majority considered that 18F-FDG PET-CT may be useful for IFI, many areas of uncertainty remain. There is a need for protocolized research to improve IFI management.

Revision of antifungal strategies definitions for invasive fungal infections (proven/probable/possible) in 461 patients with haematological malignancies (REDEFI-SEIFEM).

Invasive fungal infections (IFI) are a relevant cause of morbidity and mortality among patients with haematological neoplasms (HMs). Since 2002, a classification of IFI based on host factors, clinical and radiological features and mycological tests was published for research purpose. These criteria are widely used in clinical practice to identify patients at risk for IFI. The aim of the study was to evaluate the clinical applicability of EORTC/MSG 2008 criteria for the diagnosis of IFI in daily practice. This multicentre, non-interventional, observational, prospective study gathered all consecutive inpatients with HMs in which an intravenous antifungal treatment was started. Exclusion criteria were a previous or concomitant transplant procedure, outpatient status and oral antifungal therapy. EORTC/MSG 2008 criteria were used to classify patients at the beginning of antifungal therapy and at 30 days. An independent board reviewed the classification of IFI given by local clinicians at T0 and T30. The highest percentage of agreement was found for possible IFI (96%), while a lower agreement was reported for proven IFI (74%), and the highest variability was observed for probable IFI (56%). At T30, the board re-evaluation confirmed a strict agreement for possible IFI only (98%). Among 306 patients classified as possible, 156 (51%) patients showed non-typical radiological findings and 45 (15%) patients presented host factors only. In real life, the EORTC/MSG criteria can be applicable only for possible IFI. As non-typical radiological findings are reported in possible IFI, introducing a new IFI category should be considered.

Mobile air-decontamination units: Can they be used for immunocompromised patients at high risk for fungal infections?

Immunocompromised patients in the hematology department are usually hospitalized in areas protected by the high-efficiency particulate air (HEPA) filtration system. Renovations may require moving these patients at risk for invasive fungal infection to areas without HEPA. Mobile air handling units may be a solution in these cases. For renovation purposes, we evaluated the efficiency of mobile air handling units called Plasmair® as well as their optimization, by comparing two generations of devices.Particle counts were performed to determine a particle cleanliness classification according to the ISO 14644–1 standard (high ISO classes correspond to a degraded particulate cleanliness). Mycological air samples were also taken to determine the percentage of positive samples and the median number of filamentous fungi colonies.Without air treatment, only 18 % (38/216) of particle counts were classified as ISO 6. With the use of mobile air treatment units, this proportion increased to 71 % (205/288). The positivity rate of mycological samples without air treatment was 86 % (31/36) with a median number of fungal colonies of 3 (1–5)/0.5m3. A significant decrease in fungal pressure was observed when using Plasmair®. Percentages of positive air samples and the median number of colonies found between the old generation Plasmair® (T2006) and the new generation Plasmair® (Guardian) were significantly different, respectively 55.6 % (20/36) versus 22.2 % (8/36) and 1(0–1) versus 0 (0–0).Finally, we confirm Plasmair® were effective in reducing airborne fungal pressure, the new generation especially. However, they were not effective enough to obtain negative mycological air samples as usually observed with the HEPA system, whatever the generation.

Real-World Experience with Isavuconazole in Allogeneic Stem Cell Transplantation in Spain

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile.

Additive and Dose-Dependent Effect of Rituximab on Pediatric Patients’ Outcomes Concurrently Receiving Immunosuppressive Chemotherapy, A Prospective Cohort Study

Background: Rituximab (RTX) is approved for treating CD20-positive B-cell malignancies, including non-Hodgkin lymphoma, when used alongside chemotherapy. It has the potential to interact with and alter the host immune system, putting patients at a heightened risk of infection. Therefore, the use of RTX necessitates a meticulous assessment of infectious risks based on the latest evidence. Objectives: We conducted a prospective investigation into infectious complications and mortality among children undergoing RTX treatment over the observation period of the study. Methods: In this observational cohort study, we included 61 pediatric patients treated with RTX for malignancy and immune thrombocytopenic purpura (ITP), as well as 122 cancer patients who had never received RTX (the unexposed group). These patients were prospectively monitored for febrile neutropenia (FN), bloodstream infection (BSI), invasive fungal infection (IFI), and mortality. All infectious complications were documented starting from the initial dose of RTX and continuing for at least six months following the last dose. Logistic regression and Cox regression analyses, with consideration for the proportional hazards assumption, were utilized to evaluate the impact of covariates on mortality and infection-related outcomes. Results: Infectious complications were observed in 52.5% of children treated with RTX. These complications were notably more prevalent in children with malignancy compared to those with chronic ITP (89.5% versus 10.5%, respectively). RTX was found to be associated with an increased likelihood of mortality in children with malignancy (OR [95% CI]: 1.54 [0.41, 5.69]). According to Cox regression analysis, RTX was linked to a higher risk of IFIs, death, FN events, and BSIs over a 36-month observation period (4.33 [1.21, 15.52], 3.26 [1.008, 10.59], 1.68 [0.83, 3.41], and 1.59 [0.27, 9.17], respectively). The total dose of RTX administered was also associated with adverse patient outcomes, with the odds of infectious events and death increasing in the second, third, and fourth quartiles of the total RTX dose administered. Furthermore, the estimated one-year and two-year survival rates for cancer patients treated with RTX were 77% and 58%, respectively. Conclusions: RTX treatment, when used concurrently with immunosuppressive chemotherapy for hematologic malignancies in children, showed additive and dose-dependent effects on clinical outcomes.

Clinical impact of fungal colonization of burn wounds in patients hospitalized in the intensive care unit: a retrospective cohort study

BackgroundInvasive fungal infections in burn victims significantly increase mortality and hospitalization. The effect of fungal burn wound colonization has not been established.MethodsAll adult patients hospitalized in the intensive care unit...

Patterns and Drivers of Antifungal Prescribing in Acute Leukemia: A Retrospective Cohort Study.

Patients with hematological malignancy are at high risk of invasive fungal infections (IFIs). Diagnosis is challenging, which can lead to overtreatment. Reducing exposure to inappropriate antifungal prescribing is likely to improve patient safety, but modifying prescribing behavior is difficult. We aimed to describe patterns and drivers of therapeutic antifungal prescribing in a large tertiary hemato-oncology center in the United Kingdom. We studied adults receiving treatment for acute leukemia at our center between 1 April 2019 and 14 October 2022. We developed a reproducible method to analyze routinely collected data on antifungal therapy episodes in a widely used electronic health record system. We report antifungal use in days of therapy stratified by level of diagnostic confidence, as defined by consensus diagnostic guidelines (European Organisation for Research and Treatment of Cancer/Mycoses Study Group). Two hundred ninety-eight patients were included in the analysis; 21.7% of inpatient antifungal use occurred in cases of proven/probable IFI. Substantial antifungal use occurred in the absence of strong evidence of infection in patients receiving high-intensity first-line chemotherapy or approaching death (81.0% and 77.9%, respectively). Approximately 33% of high-resolution computed tomography (HRCT) reports were indeterminate for IFI. Indeterminate reports were around 8 times more likely to be followed by a new antifungal therapy episode than a negative report. Antifungal stewardship remains challenging in the absence of reliable diagnostics, particularly in more unwell patients. The proportion of antifungal therapy given for proven/probable infection is a new metric that will likely be useful to target antifungal stewardship programs. The thoracic HRCT report is an important contributor to diagnostic uncertainty.

Risk of Invasive Fungal Infections in Patients With Chronic Lymphocytic Leukemia Treated With Bruton Tyrosine Kinase Inhibitors: A Case-Control Propensity Score-Matched Analysis.

Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitor (BTKi) for treatment of chronic lymphoid malignancies such as chronic lymphocytic leukemia (CLL), but precise estimates are lacking. We aim to characterize the prevalence of IFIs among patients with CLL, for whom a BTKi is now the first-line recommended therapy. We queried TriNetX, a global research network database, to identify adult patients with CLL using the International Classification of Diseases, Tenth Revision code (C91.1) and laboratory results. We performed a case-control propensity score-matched analysis to determine IFIs events by BTKi use. We adjusted for age, sex, ethnicity, and clinical risk factors associated with an increased risk of IFIs. Among 5358 matched patients with CLL, we found an incidence of 4.6% of IFIs in patients on a BTKi versus 3.5% among patients not on a BTKi at 5 years. Approximately 1% of patients with CLL developed an IFI while on a BTKi within this period. Our adjusted IFI event analysis found an elevated rate of Pneumocystis jirovecii pneumonia (PJP) (0.5% vs 0.3%, P = .02) and invasive candidiasis (3.5% vs 2.7%, P = .012) with the use of a BTKi. The number needed to harm for patients taking a BTKi was 120 and 358 for invasive candidiasis and PJP, respectively. We found an adjusted elevated rate of PJP and invasive candidiasis with BTKi use. The rates are, however, low with a high number needed to harm. Additional studies stratifying other IFIs with specific BTKis are required to identify at-risk patients and preventive, cost-effective interventions.

Low-dose fluconazole as a useful and safe prophylactic option in patients receiving allogeneic hematopoietic stem cell transplantation.

Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low-dose fluconazole (FLCZ) prophylaxis (100 mg/day). We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low-dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post-transplant. Of the 107 patients, 70 received low-dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection-related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44-8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02-4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. Low-dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.

Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship

DISCUSSION INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2]. ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated . MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023. Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission. Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change. RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease. Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI. There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825.Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.

2716. Epidemiology of invasive fungal infection in pediatric liver transplant recipients: A retrospective, single-center study, 2012-2022

Abstract Background Studies on liver transplant (LT) recipients have reported an incidence of invasive fungal infection (IFI) ranging from 2.5 to 5%; however, antifungal prophylaxis has not yet been approved by the Ministry of Food and Drug Safety in Korea. We investigated the incidence of early-onset IFI and its characteristics in pediatric LT recipients in Korea, and also explored the risk factors for IFIs. Methods This is a retrospective, single-center study on children (&amp;lt; 19 years of age) who have undergone LT from 2012 to 2022 at Severance Hospital, Korea. IFI was defined as the detection of fungus in sterile fluid, tissue, and/or blood with symptoms of a fungal infection. Superficial fungal infection and colonization on the skin or urine were excluded. The primary outcome is the occurrence of IFI within 90 days of LT. The logistic regression method was used to analyze the risk factors for IFI. Results A total of 104 LT children were included, among whom 6 received multiple transplantations, resulting in 111 LT cases. 42% (n = 44) were male, and the median age at LT was 4.0 years of age (IQR 1.0–11.0). Two thirds of the patients received LT due to biliary atresia (n = 69, 66%), and the remaining were diagnosed with acute liver failure (n = 17, 16%), miscellaneous causes (n = 11, 11%), and so on (n = 7, 7%). Antifungal prophylaxis, except nystatin gargle, was done in 12.8% of recipients. IFI was identified in 19 patients (18%), and due to five multiple IFI events per patient, a total of 23 IFI events were noted at a median time of 16.5 days after LT (IQR 10-38). 87% of the pathogens detected were Candida species (C. albicans 40%, C. parapsilosis 35%, C. auris 15%), and Aspergillus fumigatus (13%). Antifungal susceptibility patterns are described in Table 1. The risk of IFI was significantly increased in those who underwent acute re-transplantation, postoperative intervention, or surgery due to bleeding, vascular, and bile duct complications (OR = 4.6; 95% CI, 1.5–13.6; P = 0.006) 8) and renal replacement therapy (OR=3.2; 95% CI, 1.1-8.8; P=0.028).Table.Antifungal susceptibility patterns of identified pathogens according to Clinical and Laboratory Standards Institute (CLSI). a Number of cases identified with the fungal pathogen b Antifungal susceptibility testing has to be additionally requested, so it was not performed in all cases. c 1 case had a fluconazole-resistant C.parapsilosis strain with intermediate resistance to other antifungal agents (MIC: fluconazole 32, micafungin 2, caspofungin 2, voriconazole 0.12, amphotericin B 0.5). d CLSI does not provide a tentative MIC breakpoint for voriconazole and other second generation azoles, but that of fluconazole may be considered as a surrogate. Conclusion The incidence of early IFI after LT in Korean children is considerable; therefore, universal antifungal prophylaxis is necessary. High-risk IFI patients, such as those undergoing reoperation, intervention, or renal replacement therapy, require attention and close monitoring. Disclosures All Authors: No reported disclosures

2690. Risk of Invasive Fungal Infections in Patients with Chronic Lymphocytic Leukemia Treated with Bruton Tyrosine Kinase Inhibitors - A Case-Control Propensity Score Match Analysis

Abstract Background Invasive fungal infections (IFIs) have been reported with increasing frequency in patients with chronic lymphocytic leukemia (CLL) treated with Bruton tyrosine kinase inhibitors (BTKi). High-quality real world data examining the frequency of IFIs and identifying risk factors to guide preventive measures in this patient population is lacking. We characterized the risk of IFIs among patient with CLL on BTKi one year after diagnosis using a global health research network. Methods We used TrinetX to identify patients with CLL based on diagnosis codes and stratified based on treatment with BTKi. Patients from each group were matched based on demographics, comorbidities, and medications to analyze the frequency of IFIs and outcomes at one year after CLL diagnosis. Results A total of 17,624 patients with CLL underwent propensity score matching. Approximately 82% of patients were white, 64% were male with a mean age of 69.5 years. Use of systemic corticosteroids, anti-CD20 antibodies, voriconazole, and fluconazole was higher in patients treated with BTKi (p &amp;lt; 0.001 for each drug). TMP/SMX administration was slightly higher in the BTKi group (18% vs. 17%, p = 0.01). At one year after CLL diagnosis, hospitalization was similar among groups (12.2% vs. 11.15%, p = 0.07), while mortality was lower in patients with CLL on a BTKi (9.9% vs. 12.3%, p &amp;lt; 0.001). Invasive candidiasis was less common (1.6% vs. 2.1%, p = 0.01) while pneumocystis was more common (0.3% vs. 0.1%, p = 0.007; risk ratio: 2.6, 95% CI: 1.3-5.4) in patients taking BTKi one year following diagnosis. The proportion of patients with invasive aspergillosis (0.1% vs. 0.2%, p = 0.143) or cryptococcosis (0.2% vs. 0.1%, p = 0.238) was similar between groups. Conclusion The overall frequency of IFIs was very low in patients with CLL on BTKi despite a higher frequency of steroid administration and only significant for PJP, albeit at a low annual risk of 0.3%. We calculated 500 patients needed prophylaxis to prevent one episode of PJP in patients with CLL on BTKi. This finding does not support routine PJP primary prophylaxis, considering the historical PJP risk of greater than 6.2% per person-year as the recommended threshold for primary prophylaxis in non-HIV immunocompromised patients. Disclosures All Authors: No reported disclosures

2739. Evaluation of a Perioperative Fungal Prophylaxis Protocol Change in Orthotopic Liver Transplant

Abstract Background Orthotopic liver transplant (OLT) carries a high rate of fungal infections, including invasive fungal infections (IFI). A targeted antifungal prophylaxis protocol can identify OLT patients who warrant antifungal prophylaxis and optimize agent selection. In January 2021, a targeted antifungal prophylaxis post-liver transplant protocol was implemented at Cleveland Clinic. Since its introduction, rates of fungal infections and adherence to the protocol have not been assessed. The goal of this project is to describe the impact of a protocol change in OLT recipients. Methods This was a retrospective observational cohort study of patients ≥ 18 years old with an OLT +/- sequential kidney transplant at Cleveland Clinic. Review of perioperative fungal prophylaxis from June 1, 2019 – May 31, 2020 was performed and used as the baseline. The post-intervention period was June 1, 2021 – May 31, 2022. The primary objective was to determine adherence to the new OLT fungal prophylaxis protocol on post-operative day (POD) 0. Secondary objectives included the 90-day incidence of proven or probable IFI post-OLT before and after implementation. Study Population Results A total of 134 patients pre-protocol and 166 patients post-protocol were included. Prior to protocol implementation, 73% patients were prescribed clotrimazole, 13% fluconazole, 13% micafungin, and 1% nystatin. After protocol implementation, 63% were prescribed clotrimazole, 16% fluconazole, and 21% micafungin. In the post-protocol group, there was an adherence rate of 66% on POD0 which increased to 84% over the duration of prophylaxis. Prior to initiation of the antifungal protocol, 6.7% of patients developed an IFI while 3.6% of patients developed an IFI post-protocol (p=0.22). Median time to IFI was 8 days (IQR 2-19) pre-protocol and 15 days (IQR 6-17) post-protocol. Mortality and ICU length of stay were comparable between groups. Primary and Secondary Results OLT: orthotopic liver transplant; POD: post-operative day; ICU: intensive care unit; IFI: invasive fungal infection Characteristics of Patients with Invasive Fungal Infections IFI: invasive fungal infection; TPN: total parenteral nutrition; IAI: intra-abdominal infection; n/a: not applicable; pRBC: packed red blood cells; OR: operating room; RRT: renal replacement therapy; ICU: intensive care unit; Dose dep.: dose dependent; GI: gastrointestinal Conclusion The implementation of a targeted antifungal prophylaxis post-liver transplant protocol can be a powerful strategy for promoting consistency in antifungal prophylaxis within a population at high risk for IFIs. Our study showed an 84% adherence rate to the implemented protocol, with numerically lower rates of IFIs post-protocol compared to pre-protocol. Disclosures All Authors: No reported disclosures

Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study.

Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.

Rare Invasive Fungal Infections in Hematologic Patients: A Large Unicentric Series

Introduction: Invasive fungal infections (IFI) are a major cause of infectious mortality in immunocompromised hematologic patients. While Candida spp and Aspergillus spp account for most cases, IFI by so-called “rare” fungi (about 1% of all IFI) are clinically relevant, with challenging diagnoses (including difficult phenotypic identification and misinterpretation as contaminants) and insufficient data on antifungal susceptibility to guide treatment guidelines. International efforts to record the epidemiology of these rare IFIs are fundamental to help overcome the lack of data that hinders successful diagnosis and treatment. Methods: We reviewed all fungal infections diagnosed in our Hematology Department in adults (18 years and over) from 06.01.2006 to 03.31.2023, selecting cases with identification of rare fungi by mycologic methods. The date of “Diagnosis” (Dx) was that of collection of the first positive sample. Results: A total of 67 patients (pts, 52.2% male) with a median age of 63.6 years (mean: 59.2, range: 23.2-90.0) were included; 68.7% had acute leukemias - 89.4% of which myeloid (AML), 13.0% lymphoblastic, 4.4% promyelocytic and 2.2% of ambiguous lineage - and 4.5% had myelodysplastic syndromes; 20.9% had a chronic lymphoproliferative disease, 3.0% had aplastic anemia and 3.0% had plasma cell dyscrasias. There was an average of 4 cases of rare IFI per year (range: 0-9), with a peak in 2017 (13.4% of total); 50.8% of all infections diagnosed over the nearly 17 years of the study occurred in the 5 years between 2013-2017, a period of renovation work in our hospital. Time to Dx ranged from 0 (collection on the day of hospitalization) to 98 days (mean: 25.4; median: 22 days). Identification of the fungus took a median of 5 days (mean: 5.6, range: 2-16 days) from the time of collection. In 8 patients (12.9%), the lab report with a fungal identification was released post-mortem; in these pts, results were available a median of 3.5 days after exitus (mean: 5.4, range: 1-13 days). In 79.1% of pts, a yeast was isolated (68.7% Geotrichum-like), while in 20.9% a filamentous fungus was identified (3.0% Mucorales). The most frequent genera were Geotrichum (62.7%), Saprochaete (5.8%), Fusarium and Alternaria (4.5% each). Cryptococcus, Trichosporon and Penicillium accounted for 3% of infections each, with 9 additional species identified in single pts. Fungemia was found in 58.2% of pts (in peripheral blood in 52.2%; in central access blood in 38.8%; in both in 32.8%). Pulmonary isolates were obtained in 26.9% of pts (in sputum in 19.4%; in bronchial aspirate or lavage in 10.4%; in both in 3.0%). Urinary isolates were found in 6.0% of pts; 13.4% had fungi in other biologic samples. The median overall survival was 20 days; 32.6% of pts died within a week of Dx, 45.6% within the first fortnight and 60.9% within the first month; 26.1% died between 1 and 3 months from Dx; and 13.0% died over 3 months after Dx. At the time of the study, 5 pts (7.5% of the cohort) were still alive, all with yeast infections; survivors had evidence of fungemia in 20% of cases and pulmonary involvement in 60%. Discussion: In our large clinical series, AML was responsible for nearly 2/3 of cases of rare IFI, reflecting its overall increased risk for IFI. The rarity of these agents was highlighted by the fact that our tertiary hematology center, serving a population of 2.3 million, had an average of 4 cases of rare IFI per year; yearly variations were in part accounted for by construction work (which releases fungal spores). Dx varied from the day of admission to over 3 months into hospitalization, reflecting a range from community-acquired to nosocomial infections; the average pt had been in hospital for 3 weeks by the time they were diagnosed. There were 4-fold more yeast infections than filamentous fungi, with Geotrichum and related yeasts accounting for 2/3 of cases. Fungemia was present in over half of patients, and pulmonary infiltrates in 1/4, a proportion that was reversed in survivors. Fungal identification took up to a fortnight, and over 10% of patients were dead before a Dx was established, not benefiting from directed treatment. The high lethality of these infections was underlined by the fact that 1/3 died within a week of Dx, with a median OS of 3 weeks. About 1/10 of pts died more than 3 months from Dx, with progressive hematologic disease being the most likely cause of death in that pt subset; less than 10% of the cohort is currently alive, and in remission.

Rethinking the definition of 'less intensive' for venetoclax-combining regimens in acute myeloid leukaemia patients.

Invasive fungal infections (IFIs), mainly due to pulmonary aspergillosis, are considered a serious complication in acute leukaemia, with an unfavourable impact on patient. In this well-conducted retrospective study, Reynolds et al. suggest that the use of posaconazole prophylaxis in association with venetoclax plus hypomethylating agents or chemotherapy leads to a reduction of IFI incidence. Therapeutic drug monitoring of posaconazole levels is suggested, even if no correlation with IFI risk has been demonstrated. Commentary on: Reynolds et al. Invasive fungal infection following venetoclax and posaconazole co-administration. Br J Haematol 2023;203:593-598.