Risk Of Invasive Fungal Infections Research Articles

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 leukaemia: a retrospective cohort study

Abstract Background Patients with haematological malignancy are at high risk of invasive fungal infections (IFI). Diagnosis is challenging which can lead to overtreatment. Reducing exposure to inappropriate antifungal prescribing is likely to improve patient safety, but modifying prescribing behaviour is difficult. We aimed to describe patterns and drivers of therapeutic antifungal prescribing in a large tertiary haemato-oncology centre in the UK. Methods We studied adults receiving treatment for acute leukaemia at our centre between 1st April 2019 and 14th October 2022. We developed a reproducible method to analyse 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 (EORTC/MSG). Results 298 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% & 77.9%). 32.6% 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. Conclusions 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 which 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

Abstract Background Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitors (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 BTKi are now the first line recommended therapy. Methods We queried TriNetX, a global research network database, to identify adult patients with CLL using the ICD-10 codes (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. Results Among 5,358 matched patients with CLL, we found an incidence of 4.6% of IFIs in patients on a BTKi vs. 3.5% among patients with CLL not on a BTKi at five 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 Pneumocytis jirovecii pneumonia (PJP) (0.5% vs. 0.3%, p = 0.02) and invasive candidiasis (3.5% vs 2.7%, p = 0.012) 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. Conclusions 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 BTKi 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.

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.

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 (< 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 < 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 < 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.

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.

Fusariosis in patients with hematological malignancies: Two case reports

Immunosuppressed patients with hematological malignancies are at risk for invasive fungal infections (IFI), including infections with Fusarium species (spp.), which are increasingly reported. Particularly at risk are patients with acute myeloid leukemia (AML) treated with high-dose cytarabine as remission-induction therapy. Whether cytarabine increases the risk of IFI in comparison to other chemotherapy remains not fully determined. Additionally, no clear correlation between the in vitro established minimal inhibitory concentrations (MICs) of antifungal agents and clinical outcome has been established for fusariosis. To increase awareness and knowledge of invasive fusariosis, we report two cases of Fusarium spp. infections in neutropenic patients following treatment with cytarabine for AML. Despite high MICs for azoles both patients were treated with an azole in combination with liposomal amphotericin B. The combination therapy was successful in one patient, however the other patient did not survive the disseminated Fusarium infection.

Posaconazole and midostaurin in patients with FLT3-mutated acute myeloid leukemia: Pharmacokinetic interactions and clinical facts in a real life study.

Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3-mutated acute myeloid leukemia. Chemotherapy-induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin-related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real-life study to evaluate (i) how often concerns around PCZ-midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ-midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p < 0.001 for deviation from guidelines). In the 19 patients managed as per guidelines, PCZ-midostaurin interactions were more remarkable than previously characterized, such that at the end of induction therapy midostaurin minimum plasma concentration (Cmin ) was greater than three times higher than reported; moreover, midostaurin Cmin , maximum plasma concentration, and area under the curve were more than or equal to four times higher with PCZ than micafungin. Hematologic outcomes (complete remission and duration of severe neutropenia) and safety outcomes (midostaurin-related any grade or grade ≥3 AEs) were nonetheless similar for patients exposed to PCZ or micafungin, as was the number of breakthrough IFIs. In waiting for randomized phase III trials of new prophylaxis regimens, these findings show that PCZ should remain the antifungal of choice for the midostaurin-treated patient.

Bone Marrow Iron Stores Are Not Associated with Increased Risk for Invasive Fungal Infections in Patients with Newly Diagnosed Acute Leukemia or Myelodysplastic Syndrome in Transformation: Is There a Relationship?

Iron plays an important role in the pathogenesis of infections, including invasive fungal infections (IFIs). Studies suggested that iron overload might represent an additional risk factor for IFIs among patients with hematological malignancies. We conducted a prospective, multi-center study amongst adult patients with newly diagnosed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in transformation to determine whether baseline iron overload as measured using the bone marrow iron store (BMIS) score is an independent risk factor for the development of IFIs. We also measured baseline serum iron and ferritin levels. A total of 98 patients were enrolled (76 with AML) and were followed for 12 months. Twenty-two patients developed IFI during the follow-up period (invasive aspergillosis n = 16, candidemia n = 5, mucormycosis n = 1). A baseline BMIS score ≥ 3 indicated that iron overload was relatively common (38/98 patients, 38%), and its frequency was comparable between patients with no IFIs (31/76, 40.7%) and in those with IFIs (8/22, 36.4%). Univariate analysis showed that only the presence of AML was associated with increased risk for IFIs [OR (95% CI) 7.40 (1.05-325.42)]. Both univariate and multivariate analyses showed that an increased BMIS score (≥3) at baseline was not an independent risk factor for IFIs. Similarly, there was no difference in serum iron and ferritin between the two groups that had similar demographic characteristics. Indices of iron overload were not independent risk factors for IFIs in our cohort of Greek patients with newly diagnosed AML/MDS in transformation.

The Argentinian landscape of mycological diagnostic capacity and treatment accessibility.

Immunosuppressed patients, transplant recipients, and those with acute or chronic respiratory disease are at increased risk for invasive fungal infections in Argentina. Although the national public system guarantees universal access to health care for all citizens, little is known about the quality of available diagnostic and treatment armamentaria for invasive fungal infections in the country. Between June and August 2022, infectious disease clinicians from each of the 23 provinces and the Autonomous City of Buenos Aires were contacted to describe local access to fungal diagnostic tools and antifungal agents. The information collected included different aspects such as hospital characteristics, patients admitted and wards, access to diagnostic tools, estimated infection incidence, and treatment capacity. Thirty responses were collected from facilities throughout Argentina. Most institutions were governmental (77%). A mycology department was available in 83% of them. Histopathology was available in almost 93% of the sites, while automated methods and galactomannan tests were available in 57%, each; 53% of the sites had access to MALDI-TOF-MS through regional reference laboratories, and PCR was present in 20% of the sites. Susceptibility testing was available in 63% of the laboratories. Candida spp. (24%), Cryptococcus spp. (20%), Aspergillus spp. (18%), and Histoplasma spp. (16%) were described as the main pathogens. Fluconazole was the only antifungal agent available in all institutions. This was followed by amphotericin B deoxycholate (83%) and itraconazole (80%). If an antifungal agent was not available onsite, then 60% of the patients could receive adequate antifungal treatment within the first 48 h upon request. Although there are no significant differences in access to diagnostic and clinical management of invasive fungal infections among the Argentinean centres studied, national awareness-raising initiatives led by policymakers could help to improve their general availability.

Evidence of anti-Hcp100 antibodies in COVID-19 critically ill patients with detectable anti-histoplasmin antibodies in a highly endemic area for histoplasmosis.

Patients with severe COVID-19 are at increased risk for invasive fungal infections, which are underestimated. Histoplasmosis reactivation in endemic areas should not be overlooked in this population. In a previous study, seroconversion to anti-histoplasmin antibodies by ELISA was detected in 6/39 (15.4%) patients with severe COVID-19. In this work, samples were further investigated to detect seroconversion to antibodies against the Histoplasma capsulatum 100-kDa antigen (Hcp100) by ELISA. Seroconversion to anti-Hcp100 antibodies was detected in 7/39 patients, of whom 6 seroconverted also anti-histoplasmin antibodies. These results reinforce previous findings that show histoplasmosis as an underdiagnosed fungal entity complicating COVID-19.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

Antifungal Stewardship Programs in Children: Challenges and Opportunities.

D-index and invasive fungal infections (IFIs) in adult acute myeloid leukemia (AML) patients with the first episode of febrile neutropenia.

This study aimed to evaluate the performance of the D-index, a calculated measure of neutropenic burden, in predicting the risk of invasive fungal infections (IFIs) in acute myeloid leukemia (AML) patients. A retrospective study of adult AML patients who received the first induction chemotherapy and developed febrile neutropenia was conducted. Clinical characteristics, laboratory data, and the calculation of the D-index and cumulative D-index (c-D-index) were collected and analyzed between patients with and without IFIs. A total of 101 patients were included, with 16 (15.8%) patients who developed IFIs. Clinical characteristics, antifungal prophylaxis, and AML cytogenetic risk were similar between patients with or without IFIs. The results showed that the D-index and c-D-index were more effective in predicting IFIs than the duration of neutropenia. With the D-index cutoff of 7083, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 81.3%, 83.5%, 48.2%, and 95.9%, respectively. c-D-index at 5625 revealed sensitivity, specificity, PPV, and NPV for IFIs of 68.8%, 68.2%, 28.9%, and 92.1%, respectively. Using this cutoff of c-D-index, patients without IFIs were overtreated with an antifungal regimen in 45 (52.9%) cases. The D-index and c-D-index were helpful indicators for defining the risk of IFIs in AML patients with febrile neutropenia.

The impact of antifungal prophylaxis in patients diagnosed with acute leukemias undergoing induction chemotherapy: a systematic review and meta-analysis.

Acute leukemias are complex diseases to treat and have a high mortality rate. The immunosuppression caused by chemotherapy also causes the patient to become susceptible to a variety of infections, including invasive fungal infections. Protocols established in many countries attempt to prevent these infections through the use of pharmacological antifungal prophylaxis. This systematic review and meta-analysis investigates the existing evidence for the use of antifungal prophylaxis in patients undergoing induction chemotherapy for acute leukemia, and how prophylaxis can affect treatment response and mortality. Through the use of a population-variable-outcome strategy, keywords were utilized to search online databases. The included studies were selected and the data was collected to develop descriptive results for all studies, and, for studies that met the criteria, a meta-analysis of the Relative Risk (RR) was analyzed for infection rates, in-hospital mortality, and complete remission. A total of 33 studies were included in this systematic review, with most studies presenting positive results (n = 28/33) from the use of antifungal prophylaxis. Using a random effects model, the pooled results of the meta-analysis presented lower invasive fungal infections in AML (RR: 0.527 (95% CI: 0.391; 0.709). p < 0.001). p < 0.001) and ALL (RR: 0.753 (95% CI: 0.574; 0.988). p = 0.041). when antifungal prophylaxis was used. No discernible difference was encountered in the rate of complete remission when using prophylaxis. Antifungal prophylaxis provides a lower risk of invasive fungal infections and in-hospital mortality in acute leukemia patients undergoing induction chemotherapy.