Probable Invasive Fungal Infections Research Articles

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

Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

The evaluation of atorvastatin as an adjunct to fluconazole for the anti-fungal prophylaxis in acute myeloid leukemia: a multicenter, triple-blinded, randomized clinical trial.

The development of invasive fungal infections (IFIs) is a serious complication in acute myeloid leukemia (AML) patients who undergo an induction to remission chemotherapy. Given the increased mortality in AML patients with IFI despite prophylaxis, we need to address this problem. Statins have traditionally been employed in clinical settings as agents for reducing lipid levels. Nonetheless, recent investigations have brought to light their antifungal properties in animals, as well as in vitro studies. The objective of this study was to assess the effectiveness of atorvastatin when added to the routine IFI prophylaxis regimen in patients diagnosed with AML. A randomized, multicenter, triple-blind study was conducted on 76 AML patients aged 18-70, who received either placebo or atorvastatin in addition to fluconazole. Patients were followed for 30days in case of developing IFIs, patient survival, and atorvastatin- related adverse drug reactions. Data were analyzed with SPSS version 26.0. A level of significance of 0.05 was utilized as the threshold for all statistical tests. The data were analyzed by adjusting for the effect of age, regarding that there was a significant difference between the two groups, and showed that atorvastatin reduced the development of both probable and proven IFI (based on EORTC/MSGERC criteria) compared to placebo. IFI-free survival was also significantly better in the atorvastatin group. The incidence of developing aspergillosis did not differ between the two groups. No serious adverse events related to atorvastatin were observed. The present investigation has substantiated the antecedent in vitro and animal research on the fungicidal impact of statins and has suggested the need for additional research involving larger sample sizes and an extended duration of follow-up. Trial registration: This study was registered on the Iranian registry of clinical trials as IRCT20210503051166N1 (Date of confirmation 2021.05.03).

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.

Epidemiology and Clinical Outcomes of Hematologic Patients with Proven and Probable Invasive Fungal Infections: A Latin American Tertiary Care Centre Experience

Introduction Although diagnostic and therapeutic strategies for invasive fungal infections (IFI) have evolved in the last decade, their identification and management within patients with hematologic diseases (HD) continues to be a challenge. For this group, in addition to the increased risk of developing an IFI, mortality has been reported as high as 39.1%. The incidence and etiology vary across regions, suggesting an influence of patient-specific characteristics, environment, and clinician's practices. Literature regarding low- and middle-income countries, reflecting the real-world approach and management for this high-risk group is scarce. Our aim was to describe patients' clinical and microbiological characteristics, treatment strategies, and outcomes in a tertiary care hospital in Mexico City. Methods Retrospective single-center study that included all consecutive cases of IFI occurring in adult patients with HD or hematopoietic stem cell transplant (HSCT) between January 2013 and December 2019. We included only proven and probable cases of IFI according to the mycoses study group of the European Organization for Research and Treatment of Cancer (EORTC) guidelines. Clinical data, diagnostic work-up, treatment modalities, and outcomes were extracted from the medical records. Results In a total of 119 patients, 129 IFIs were diagnosed; criteria were fulfilled for proven in 38% ( n = 49) and probable in 62% ( n = 80). The median age was 39 years (range, 18-87) and HD was acute leukemia at 46.5%. At the time of IFI, 83.7% had active HD and 82.2% were on active treatment. HSCTs were allogeneic in 11 patients and autologous in 2 patients. A 31.8% and 91.5% presented with at least one comorbidity and/or risk factor, respectively. Severe neutropenia was present in 67.4% with a median of 13 days (range, 0-167) from the start of neutropenia to IFI diagnosis. Additional characteristics are shown in Table 1. The median time from the HD/HSCT to IFI was 73 days (range, 0-1,598); 30.2% being diagnosed within the treatment induction phase. Identified pathogenswere Aspergillus sp in 62.4%, Candida sp in 21.3%, Mucor spin10.6%, Fusarium sp in 3.5%, and Histoplasma capsulatum in 2.1%. In 10 (7.8%) cases, fungal coinfection was identified. For proven cases, sites where the microorganism was isolated or identifiedwere: blood 48.3%, lung 25.9%, sinuses 13.8%, CSF 3.4%, bone marrow 3.4%, skin 1.8%,and others 3.4%. For probable IFI, sitesof infection were: lung 91.8%, sinuses 5.9%, and other 2.4%. A 92.8% of aspergillosis and 80% of mucormycosis infections were localized in the lungs, while 86.7% of candidiasis were identified in the blood. Forty-five (35.4%) patients were receiving antifungal prophylaxis (fluconazole n = 24, itraconazole n = 13, posaconazole n = 3, voriconazole n = 3, anidulafungin n = 2). Antifungal treatment was given to24 (96.1%) of patients; 5 died before IFI diagnosis. Frontline agents included voriconazole ( n = 62), amphotericin n = 26), anidulafungin ( n = 16), caspofungin ( n = 6), fluconazole ( n = 5), clinical trial (posaconazole vs. voriconazole, n = 5) itraconazole ( n = 3), and posaconazole ( n = 1). Overall survival (OS) at 6 weeks was 59.7% and at 12 weeks was 51.9%. Overall response rate (ORR) was 48.4% ( n=60) and 54.8% ( n=68) at 6 and 12 weeks, respectively. On univariate analysis risk factors associated with increased mortality at 12-weeks were: age >40 ( p=0.001), active HD ( p = 0.020), CVC 30 days prior to IFI ( p=0.032), IMV 30 days prior to IFI ( p=0.026), and admission to ICU 30 days prior to IFI ( p=0.009). Aspergillosis was associated with reduced 12-week mortality ( p=0.001).On multivariate analysis age >40 ( p=0.010) and aspergillosis (p =0.002) remained independently associated with increased and reduced mortality, respectively. Conclusion This study reports unique information regarding proven and probable IFI in hematologic patients diagnosed under EORTC 2020 guidelines. Our epidemiology was similar to that reported by other countries, including most common etiologic agents and a higher proportion of AL and on active chemotherapy patients.Mortality rates were higher, possibly explained by the exclusion of possible IFI cases, higher proportion of active primary disease, and limited antifungal prophylaxis. Better survival among patients with aspergillosis, suggest that current diagnostic tests lead to earlier diagnosis and treatment with an impact on patients' prognosis.

Invasive Fungal Infections after CAR T-Cell Therapy for B-Cell Lymphoma: A Study from the French Descart Registry

Introduction: Chimeric antigen receptor (CAR) T cell therapy has emerged as an important treatment option for patients with B-cell malignancies. Despite its major clinical impact, CAR T cell therapy holds a potential risk of increased susceptibility to infections, including invasive fungal infections (IFI). Since data about the prevalence and impact of fungal infections in this population are limited, we aimed to provide a comprehensive overview of IFI using real-world data from the national DESCAR-T registry. Methods: We performed a multi-center retrospective cohort study, quering the French DESCAR-T registry (NCT04328298), to describe type, frequency and outcomes of IFI in adults with refractory or relapsed (R/R) B cell lymphomas. In addition, healthcare providers were contacted to declare any missing cases. Demographic, biological and clinical characteristics were collected retrospectively. Each IFI case was reviewed by an infectious disease specialist and a microbiologist, and classified according to the European Organization for Research and Treatment of Cancer (EORTC) criteria (Donnelly et al. Clinical Infect Dis 2020). Results: Among the 1144 patients included in the registry from 2018 to 2022, we identified 57 suspected IFI cases. After exclusion of 25 patients not adjudicated for IFI, 32 patients (3%) were identified as having presented a proven (n = 14), probable (n = 12), or possible (n = 6) IFI. DLBCL was the primary diagnosis for 30 patients and axi-cel was the most frequent CAR T product (23/32, 72%). Seven patients (22%) had received a previous hematopoietic stem cell transplantation. All patients experienced cytokine release syndrome (including 8 grade ≥ 3) and 21 (66%) experienced immune effector cell-associated syndrome (including 13 grade ≥ 3). Overall, 27 (84%), 21 (66%), and 5 (16%) received tocilizumab (median 960mg, range 120-2880mg), corticosteroids, and anakinra, respectively. Among known risk factors for IFI, grade 4 neutropenia and late neutropenia (< 1g/L) at day 28 after infusion were identified in 25 (78%) and 14 (44%) patients respectively. Overall, 8 (25%) patients received antifungal prophylaxis, posaconazole was used for 4 of them. Over half of the IFI cases occurred between 0 and 30 days after CAR T-cell infusion (18/32, 56%), with a median onset time of 29.5 days (IQR 16.5 - 79.5). The most frequently observed infections were invasive Aspergillosis (n = 13), with pulmonary involvement in 10/13 (77%) of patients, leading to a fatal issue in 3/13 patients (23%). Other mold infections included Mucormycosis (n = 5), with pulmonary involvement in 4/5 patients and a fatal outcome in 1/5, as well as Fusariosis (n = 1). Yeast infections (n = 12) were mostly identified as Candidemia (92%) with a mortality rate of 3/12 (27%). The median overall survival of patients with IFI was 186.5 days (IQR 79-506), 7 deaths being related to IFI and 3 to lymphoma relapse. Median progression-free survival was 94 days (IQR 31 - 252). Conclusions: This study represents one of the largest investigations about IFI in B-cell lymphoma patients treated with CAR T-cells. Even though IFI represent a rare complication after CAR T-cell therapy, the related-mortality is high. Selective antifungal prophylaxis may benefit high-risk patients, while rapid preemptive diagnostic workup, particularly for lung involvement, is mandatory. Analysis to define potential risk factors for IFI are ongoing.

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

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis

This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.

Incidence of invasive fungal infections in patients with chronic lymphocytic leukemia receiving ibrutinib within the veteran's healthcare administration.

Ibrutinib is a tyrosine kinase inhibitor that is increasingly prescribed in chronic lymphocytic leukemia (CLL). Invasive fungal infections (IFIs) have been reported early after ibrutinib initiation. Timing of IFIs is within 6 months and commonly reported fungal infections include Cryptococcus, Aspergillus, and Pneumocystis. Currently, there are no recommendations for routine prophylaxis against IFIs in patients receiving ibrutinib for CLL. The objective of this study was to evaluate the incidence of IFIs in patients receiving ibrutinib for CLL in first-line and relapsed/refractory (R/R) settings. This was a retrospective, cohort study of patients diagnosed with CLL and initiated on ibrutinib in the Veterans Health Administration (VHA) from October 1, 2013 to March 31, 2018. Patients were included if diagnosed with a proven or probable IFI from the start date of ibrutinib to 30 days after the last dose of ibrutinib. Fourteen out of 1069 patients met inclusion criteria for IFI while on ibrutinib for CLL. All patients included were male with a median age of 78 years. Fifty percent of patients were initiated on ibrutinib within 3 months of last chemotherapy. IFIs occurred within 3 months (50%) and 6 months (71%) of ibrutinib initiation. Seventy-one percent of patients were continued on ibrutinib with concurrent IFI diagnosis. The reported IFI incidence of 1.3% is comparable to current estimates of 1.2%. Future studies should examine the relationship of ibrutinib and incidence of IFIs in first-line and R/R settings in addition to identifying clinical risk factors predisposing patients to IFIs.

Breakthrough invasive fungal infection in patients with myeloid malignancy receiving posaconazole tablet prophylaxis: clinical features, risk factors, and posaconazole profiles.

Posaconazole (PSC) delayed-release tablet prophylaxis is the standard of care for preventing invasive fungal infection (IFI) in patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. The clinical features, risk factors, and PSC profiles of breakthrough IFI (bIFI) in patients receiving PSC tablet prophylaxis were investigated. A single-center retrospective cohort study was conducted, including adult patients with myeloid malignancy who received prophylactic PSC tablets while undergoing chemotherapy from June 2016 to June 2021. Logistic regression analysis was used to identify risk factors for breakthrough IFI. A receiver operating characteristic curve was used to predict the relationship between PSC trough level at steady-state and breakthrough IFI. A total of 434 patients with myeloid malignancy who received PSC tablets were screened. Ten patients with bIFI were compared with 208 non-IFI patients. There were four proven and six probable IFI cases, nine due to Aspergillus and one due to Fusarium species. The bIFI patients had higher in-hospital mortality (30.0%) than the non-IFI patients (1.9%; P<0.001). History of allogeneic hematopoietic stem cell transplantation (OR 6.27; 95% CI 1.63-24.09), prolonged neutropenia≥28 days (OR 4.33; 95% CI 1.20-15.70), and low plasma PSC concentration<0.7μg/mL (OR 16.33; 95% CI 4.15-64.26) were risk factors for bIFI. The optimal cut-off value of plasma PSC concentration predicting bIFI was 0.765μg/mL (sensitivity, 60.0%; specificity, 91.3%; area under the curve, 0.746). bIFI was not uncommon in patients with myeloid malignancy receiving PSC tablets prophylaxis and associated with poor outcomes. Therapeutic drug monitoring may still be necessary, even in patients receiving PSC tablets.

New Perspectives on Primary Prophylaxis of Invasive Fungal Infection in Children Undergoing Hematopoietic Stem Cell Transplantation: A 10-Year Retrospective Cohort Study

Allogenic hematopoietic stem cell transplantation (a-HCT) remains a therapeutic treatment for many pediatric hematological diseases. The occurrence of invasive fungal infections (IFIs) is a complication for which ECIL-8 recommends primary antifungal prophylaxis. In this study, we evaluated the impact of our local strategy of not systematically administering primary antifungal prophylaxis in children undergoing a-HCT on the occurrence and mortality of IFIs. We performed a retrospective monocentric study from 2010 to 2020. We retained all proven and probable IFIs diagnosed during the first year post a-HCT. 308 patients were included. Eighteen patients developed twenty IFIs (thirteen proven, seven probable) (6.5%) among which aspergillosis (n = 10, 50%) and candidosis (n = 7, 35%) were the most frequently diagnosed infections. Only 2% of children died because of an IFI, which represents 14% of all deaths. Multivariate analysis found that age > 10 years (OR: 0.29), the use of a therapeutic antiviral treatment (OR: 2.71) and a low neutrophil count reconstitution (OR: 0.93) were significantly associated with the risk of IFI occurrence. There was also a trend of malignant underlying disease and status ≥ CR2 but it was not retained in multivariate analysis. IFI occurrence was not higher in our cohort than what is reported in the literature with the use of systematic antifungal prophylaxis, with a good survival rate nonetheless. Thus, a prophylaxis could be considered for children with a high risk of IFI such as those aged over 10 years.

Real-life epidemiology and current outcomes of hospitalized adults with invasive fungal infections.

We aimed to describe the current epidemiology of both hosts with invasive fungal infections (IFIs) and causative fungi. And, detail outcomes of these infections at 12 weeks in a real-life cohort of hospitalized patients. The study was retrospective and observational to describe IFI diagnosed in a tertiary hospital (February 2017-December 2021). We included all consecutive patients meeting criteria for proven or probable IFI according to EORTC-MSG and other criteria. A total of 367 IFIs were diagnosed. 11.7% were breakthrough infections, and 56.4% were diagnosed in the intensive care unit. Corticosteroid use (41.4%) and prior viral infection (31.3%) were the most common risk factors for IFI. Lymphoma and pneumocystis pneumonia were the most common baseline and fungal diseases. Only 12% of IFI occurred in patients with neutropenia. Fungal cultures were the most important diagnostic tests (85.8%). The most frequent IFIs were candidemia (42.2%) and invasive aspergillosis (26.7%). Azole-resistant Candida strains and non-fumigatus Aspergillus infections represented 36.1% and 44.5% of the cases, respectively. Pneumocystosis (16.9%), cryptococcosis (4.6%), and mucormycosis (2.7%) were also frequent, as well as mixed infections (3.4%). Rare fungi accounted for 9.5% of infections. Overall, IFI mortality at 12 weeks was 32.2%; higher rates were observed for Mucorales (55.6%), Fusarium (50%), and mixed infections (60%). We documented emerging changes in both hosts and real-life IFI epidemiology. Physicians should be aware of these changes to suspect infections and be aggressive in diagnoses and treatments. Currently, outcomes for such clinical scenarios remain extremely poor.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Invasive Fungal Infections in Acute Haematological Malignancies: A Cross-sectional Study

Introduction: Fungal infections are common complications of acute haematological malignancies i.e. acute myeloid and acute lymphoblastic leukaemia. The cells in these two groups are different morphologically and immunologically. Hence the interaction with the different types of fungi may vary. Aim: To identify the acute leukaemia cases and fungal infection among myeloid and lymphoid groups and to find out association of types of invasive fungal infection according to cell line affected. Materials and Methods: A cross-sectional observational hospital-based prospective study was conducted in a risk group of acute haematological malignancy over a period of six months from July 2021 to December 2021 in a tertiary care Hospital, Medical College Kolkata, West Bengal, India. Study tools were questionnaire based on European Organisation for Research and Treatment of Cancer /Mycoses Study Group (EORTC/MSG) criteria, clinical reports and standard laboratory procedures were practiced in Microbiology laboratory. The data was entered in excel spreadsheet and analysed using Statistical Package for the Social Sciences (SPSS) 28th version. Results: A total of 24 cases of Invasive Fungal Infections (IFI) were observed out of the 78 patients included in the study. This corresponds to an IFI prevalence of 30.77%. Patients with proven IFI constituted 8 (33.33%), probable IFI accounted for 15 (62.5%) where as those with possible IFI accounted for 1 (4.2%) of total IFI cases. There were age and sex wise variation in IFI. The prevalence of IFI was found to be higher in Acute Myeloid Leukaemia (AML) (48.5%) patients as compared to Acute Lymphoblastic Leukaemia (ALL) (19.14%). Of all AML patients invasive candidiasis was the most common type followed by aspergillosis. In ALL patients invasive candidiasis also constituted 44.44% followed by dematiaceous mycosis, followed by aspergillosis. Conclusion: AML patients suffer more from IFI than ALL ones. Invasive non albicans candidiasis affected both types but more incidence was seen in AML affected group. Aspergillus spp. affected lungs of both groups but dematiaceous fungi were isolated only from ALL affected paediatric patients and in samples other than pulmonary or blood sample.

1726. Patterns of Isavuconazole Use for Invasive Fungal Infections

Abstract Background Isavuconazole (ISA) is a relatively recent triazole antifungal with several attractive qualities and so increased clinical experience and data on the use of ISA are desirable. However, the data on the pattern of ISA use in invasive fungal infections (IFI) is limited. Methods We conducted a retrospective study of patients with probable or proven IFI treated with ISA at Mayo Clinic from 1/1/2015 to 4/1/2020 to examine temporal trends and characteristics of ISA use. Results The use of ISA rose over this period, from 4 cases in 2015 to 42 cases in 2019. Of 131 patients identified, ISA was used as the initial antifungal in 15 (11.5%) patients and as the secondary agent in 116 (88.5%) patients. The most cited reasons for choosing ISA as first-line therapy were drug-drug interactions (5, 33%) and baseline QTc prolongation (3, 20%). In cases of ISA used as a secondary agent, the reasons for transitioning to ISA were QTc prolongation (22, 19%), followed by judged failure of the primary therapy (20, 17%), drug-drug interactions (12, 10%), and various toxicities with the first agent. ISA was discontinued early in 81 (62%) patients. Common reasons for early discontinuation were patient death or comfort care (27, 33%), intolerance (18, 22%), failure of therapy (17, 21%), cost or access (6, 7%), drug-drug interaction (3, 4%), issues with absorption or drug delivery (3, 4%), and microbe susceptibility (1, 1%). ISA was judged successful and used as definitive treatment in the remaining 50 (38%) patients. About 30 patients took &amp;gt;1 year of ISA, and no major adverse effects from long-term therapy were noted. Conclusion Although ISA is approved for pulmonary aspergillosis and mucormycosis, we found that few patients were treated with ISA as either primary or salvage therapy. In cases where it was used, shortening the QTc and fewer drug-drug interactions were its most attractive qualities. Although it is a newer azole, the morbidity common with other antifungals should prompt more studies on ISA’s efficacy to increase clinicians’ confidence in this option. Disclosures All Authors: No reported disclosures.

High rate of invasive fungal infections during early cycles of azacitidine for patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a form of cancer that is characterized by infiltration of the bone marrow, blood, and other tissues by proliferative, clonal, abnormally differentiated, and occasionally poorly differentiated cells of the hematopoietic system. Patients with acute myeloid leukemia (AML) receiving azacitidine (AZA) alone or in combination with venetoclax (VEN-AZA) are at increased risk for invasive fungal infections (IFIs). We compared the incidence and risk of IFI during these treatment regimens in a single Taiwan hospital. A total of 61 patients with AML received at least one course of AZA in the hematology ward of China Medical University Hospital (Taichung, Taiwan) between September 2012 and June 2020. Thirty-eight patients (62.3%) received AZA monotherapy; 23 (37.7%) received VEN-AZA. Incidence rates of probable and proven IFI were 18% and 1.6%, respectively, during AZA treatment. One proven case of Fusarium spp. infection was isolated by skin and soft tissue culture. Most (75%) IFI cases occurred during the first cycle of AZA therapy. Half of all IFI cases occurred in patients with prolonged neutropenia. The risk of IFI was significantly higher for the European LeukemiaNet (ELN) nonfavorable-risk group (intermediate- and adverse-risk group) versus the ELN favorable-risk group and for patients with prolonged neutropenia versus those without (P<0.05 for both comparisons). In this study, median OS did not differ significantly between patients with and without IFIs during AZA-containing regimens (14.6 months vs 13.7 months; P=0.59). The incidence of IFI was high in this AML cohort treated with AZA-containing regiments in Taiwan. The majority of IFI cases occurred during the early cycles of AZA (cycles 1-2). Prospective studies are needed to determine the optimal choice of antifungal prophylaxis agent during VEN-AZA therapy for AML.

P10 Biomarker Driven Antifungal Stewardship in Acute Leukaemia (BioDriveAFS)—a multicentre randomized controlled trial to assess clinical and cost effectiveness

BackgroundThe BioDriveAFS trial aims to investigate whether a biomarker-based antifungal stewardship strategy is superior to a prophylactic antifungal strategy, including existing standard of care, in reducing antifungal therapy use in patients with acute leukaemia, without impacting health-related quality of life at 12 months. The trial will be commencing in the UK in 2022 and aims to recruit 500 patients across 40 sites. We hypothesized that a biomarker-led monitoring approach would be non-inferior to the standard of care approach utilizing antifungal prophylaxis.Patients and methodsPatients diagnosed with acute leukaemia who are planned to have intensive chemotherapy will be randomly allocated to one of two arms. The biomarker arm will consist of twice-weekly galactomannan and β-d-glucan until the end of intensive chemotherapy; positive biomarker results, neutropenic fever non-responsive to broad-spectrum antibacterials, or clinical suspicion will lead to investigation for potential invasive fungal infection as per international guidelines. Patients with proven or probable invasive fungal infection (IFI), as per the consensus definitions, will receive therapeutic antifungals, whereas those with possible or no IFI will have antifungals withheld. The control arm consists of local standard-of-care antifungal prophylaxis, including mould-active, without regular biomarker monitoring.ResultsPrimary outcome measures are exposure to therapeutic antifungal therapy and patient quality of life at 12 months versus baseline. Secondary outcome measures include total antifungal exposure, adverse events and complications, proven and probable IFI and treatment outcome, overall survival, all-cause mortality and IFI-related mortality. Resource use to determine cost-effectiveness and antifungal resistance in fungi will also be measured.FundingThe trial is funded by the National Institute for Health Research Health Technological Assessment Programme (NIHR132674) and supported by BSAC.

Invasive and Subcutaneous Infections Caused by Filamentous Fungi: Report from a Portuguese Multicentric Surveillance Program.

Invasive fungal infections (IFI) have significantly increased over the past years due to advances in medical care for the at-risk immunocompromised population. IFI are often difficult to diagnose and manage, and can be associated with substantial morbidity and mortality. This study aims to contribute to understanding the etiology of invasive and subcutaneous fungal infections, their associated risk factors, and to perceive the outcome of patients who developed invasive disease, raising awareness of these infections at a local level but also in a global context. A laboratory surveillance approach was conducted over a seven-year period and included: (i) cases of invasive and subcutaneous fungal infections caused by filamentous/dimorphic fungi, confirmed by either microscopy or positive culture from sterile samples, (ii) cases diagnosed as probable IFI according to the criteria established by EORTC/MSG when duly substantiated. Fourteen Portuguese laboratories were enrolled. Cases included in this study were classified according to the new consensus definitions of invasive fungal diseases (IFD) published in 2020 as follows: proven IFI (N = 31), subcutaneous fungal infection (N = 23). Those proven deep fungal infections (N = 54) totalized 71.1% of the total cases, whereas 28.9% were classified as probable IFI (N = 22). It was possible to identify the etiological fungal agent in 73 cases (96%). Aspergillus was the most frequent genera detected, but endemic dimorphic fungi represented 14.47% (N = 11) of the total cases. Despite the small number of cases, a high diversity of species were involved in deep fungal infections. This fact has implications for clinical and laboratory diagnosis, and on the therapeutic management of these infections, since different species, even within the same genus, can present diverse patterns of susceptibility to antifungals.

A multisite evaluation of antifungal use in critical care: implications for antifungal stewardship.

BackgroundICUs are settings of high antifungal consumption. There are few data on prescribing practices in ICUs to guide antifungal stewardship implementation in this setting.MethodsAn antifungal therapy (AFT) service evaluation (15 May–19 November 2019) across ICUs at three London hospitals, evaluating consumption, prescribing rationale, post-prescription review, de-escalation and final invasive fungal infection (IFI) diagnostic classification.ResultsOverall, 6.4% of ICU admissions (305/4781) received AFT, accounting for 11.41 days of therapy/100 occupied bed days (DOT/100 OBD). The dominant prescribing mode was empirical (41% of consumption), followed by targeted (22%), prophylaxis (18%), pre-emptive (12%) and non-invasive (7%). Echinocandins were the most commonly prescribed drug class (4.59 DOT/100 OBD). In total, 217 patients received AFT for suspected or confirmed IFI; 12%, 10% and 23% were classified as possible, probable or proven IFI, respectively. Hence, in 55%, IFI was unlikely. Proven IFI (n = 50) was mostly invasive candidiasis (92%), of which 48% had been initiated on AFT empirically before yeast identification. Where on-site (1 → 3)-β-d-glucan (BDG) testing was available (1 day turnaround), in those with suspected but unproven invasive candidiasis, median (IQR) AFT duration was 10 (7–15) days with a positive BDG (≥80 pg/mL) versus 8 (5–9) days with a negative BDG (<80 pg/mL). Post-prescription review occurred in 79% of prescribing episodes (median time to review 1 [0–3] day). Where suspected IFI was not confirmed, 38% episodes were stopped and 4% de-escalated within 5 days.ConclusionsAchieving a better balance between promptly treating IFI patients and avoiding inappropriate antifungal prescribing in the ICU requires timely post-prescription review by specialist multidisciplinary teams and improved, evidence-based-risk prescribing strategies incorporating rapid diagnostics to guide AFT start and stop decisions.

Donor and Peri-Transplant Hospitalization Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients

<h3>Purpose</h3> Invasive fungal infections (IFIs) remain a frequent complication in the lung transplant (LTx) population even in the current era of antifungal prophylaxis. The organ donor and peri-transplant period risk factors for IFI remain ill-defined. Our study goal is to identify novel risk factors for IFI, focusing on the organ donor and the recipient's transplant hospitalization. <h3>Methods</h3> We performed a single-center, case-control study. The source cohort included all adults who underwent LTx between 1/1/12-3/31/17. The primary outcome was a Probable or Proven IFI within 6 months of transplantation, as defined by EORTC/MSG criteria. Multivariable logistic regression and Cox proportional hazard regression analyses were used to identify independent risk factors for IFI. <h3>Results</h3> Of 329 LTx recipients, 45 (14%) developed IFI. The median time to IFI was 50 days (IQR: 25-110) after transplantation. Independent risk factors for IFI included: donor steroid pre-conditioning (aOR 2.24, 95%CI: 1.05-4.77, p=0.04); cardiopulmonary bypass (aOR 3.07, 95%CI: 1.06-8.87, p=0.04); ICU length of stay >30 days (aOR 3.34, 95%CI: 1.48-75, p<0.01); and bronchial anastomotic dehiscence (aOR 14.06, 95%CI: 1.99-99.34, p=0.01). Mold isolated on donor respiratory culture increased the hazard of IFI in LTx recipients (Table 1). Peri-transplant hospitalization complications that increased the hazard of IFI included: multiple positive fungal cultures, airway ischemia, and prolonged ICU stay (Table 1). Fungal treatment for ≥90 days after transplant was protective against development of IFI (Table 1). <h3>Conclusion</h3> IFI was common in our LTx cohort. Certain donor characteristics and peri-transplant complications increased the likelihood of IFI. Interventional studies, targeting the modifiable risk factors identified in this study, are needed to reduce IFI risk in LTx recipients.

Management of Invasive Fungal Infections in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: The Turin Experience.

BackgroundAllogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are exposed to an increased risk of invasive fungal infections (IFIs) due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GvHD) and incomplete immune reconstitution. Although clinical benefit from antifungal prophylaxis has been demonstrated, IFIs remain a leading cause of morbidity and mortality in these patients. In the last decades, attention has also been focused on potential risk factors for IFI to tailor an antifungal prevention strategy based on risk stratification.Aim of the StudyThis retrospective single-center study aimed to assess the epidemiology and the prognostic factors of IFI in a large cohort of allo-HSCT patients.MethodsBetween January 2004 and December 2020, 563 patients with hematological malignancies received an allo-HSCT at the Stem Cell Transplant Unit in Turin: 191 patients (34%) received grafts from a matched sibling donor, 284 (50.5%) from a matched unrelated donor, and 87 (15.5%) from an haploidentical family member. The graft source was peripheral blood in 81.5% of the patients. Our policy for antifungal prophylaxis included fluconazole in matched related and unrelated donors, while micafungin was administered in patients receiving haploidentical transplant. According to this practice, fluconazole was administered in 441 patients (79.6%) and micafungin in 62 (11.2%), while only 9 patients received mold-active prophylaxis. Galactomannan testing was routinely performed twice a week; patients with persisting fever unresponsive to broad spectrum antibiotics were evaluated with lung high-resolution computed tomography (HRCT) scan. In case of imaging suggestive of IFI, bronchoalveolar lavage (BAL) was performed whenever feasible.Statistical AnalysisOnly probable/proven IFI (PP-IFI) occurring during the first 12 months after transplant have been evaluated. IFIs were classified as probable or proven according to the new revised European Organization for Research and Treatment of Cancer (EORTC)/Mycoses Study Group (MSG) consensus criteria. Multivariate competing risk regression, binary logistic, and proportional hazard models were performed to identify risk factors for PP-IFI.ResultsA total of 58 PP-IFIs (n = 47 probable; n = 11 proven) occurred in our patients resulting in a cumulative incidence of 4.1%, 8.1%, and 9.6% at 30, 180, and 365 days, respectively. Molds were the predominant agents (n = 50 Aspergillus; n = 1 Mucor), followed by invasive candidemia (n = 5 non-albicans Candida; n = 1 Candida albicans; n = 1 Trichosporon). Lung was the most frequent site involved in patients with mold infections (47/51, 92.2%). Median time from HSCT to IFI was 98.44 days (0–365 days). Only 34.5% of patients with IFI were neutropenic at the time of infection. The presence of IFI had a significant impact on overall survival at 1 year (IFI, 32.8% vs. non-IFI, 54.6%; p < 0.001). IFI-related mortality rate was 20.7% in the overall population, 17% in patients with probable IFI, and 36% in patients with proven IFI. Multivariate competing risk regression revealed that donor type was the factor significantly associated to the risk of IFI [subdistribution hazard ratio (SDHR), 1.91, IC 1.13–3.20; p = 0.015]. BAL was informative in a consistent number of cases (36/57, 63.2%) leading to the identification of fungal (21), bacterial (4), viral (3), and polymicrobial (8) infections. Overall, 79 patients (14%) received a diagnostic-driven treatment, and 63 patients (11.2%) received a fever-driven treatment. Liposomal amphoteric B was the drug used in the majority of patients receiving diagnostic-driven therapy (30/79, 38%), while caspofungin was administered more frequently in patients who received a fever-driven strategy (27/63, 42.9%).ConclusionAccording to our experience, a non-mold active prophylaxis in patients undergoing allo-HSCT is feasible when combined with an intensive diagnostic work-up including CT scan and BAL. BAL performed at the onset of the disease may provide informative results in most patients. A diagnostic-driven treatment strategy may contribute to limit the use of costly antifungal therapies.