Rate Of Invasive Fungal Infections Research Articles

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...

Evaluation of Candidemia in Solid-Organ Transplant Recipients.

Solid-organ transplant recipients have high rates of invasive fungal infections. Candida species are the most commonly isolated fungi. Our aim was to identify risk factors, clinical presentations, and outcomes of candidemia in solid-organ transplant recipients. We evaluated adult (≥18 years old) transplant recipients seen from May 2011 to December 2022 at Baskent University Ankara Hospital. From medical records, we retrospectively reviewed age, sex, transplant type, candidemia agent, risk factors, concomitant infections, and mortality of patients with Candida detected in blood culture. We used SPSS statistics software (version 25) to analyze data. There were 1080 organ transplants performed during the study period (717 kidney, 279 liver, 84 heart). There were 855 who were ≥18 years (655 kidney, 127 liver, 73 heart), of whom candidemia was detected in 26 (16 male; 11 kidney, 11 liver, 4 heart) with a median age of 47.5 years. The most common agents were Candida albicans and Candida glabrata. The most common chronic diseases were hypertension, cirrhosis, and cardiomyopathy. Eighteen patients had a concomitant focus of infection. Ten patients had pneumonia accompanying candidemia. The 30-day mortality rate was as high as 53.8%. The mean duration of candidemia after transplant was 23 months. Catheter-related candidemia was observed in 65% of patients. The 30-day mortality was found to be significantly higher in patients followed in the intensive care unit (P = .014), receiving total parenteral nutrition (P = .001), using broad-spectrum antibiotics (P = .001), and having pneumonia (P = .042) accompanying candidemia. For adult solid-organ transplant recipients with candidemia, careful monitoring is essential for successful management of total parenteral nutrition, central catheter, use of broadspectrum antibiotics, and invasive interventions.

Incidence of Invasive Fungal Infections in CAR T-Cell Therapy Recipients: A Single-Center Retrospective Analysis

Background: CAR T-cell therapy has transformed the treatment of hematologic malignancies, but challenges persist due to toxicities like cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Rates of invasive fungal infections (IFI) post CAR T-cell therapy are estimated to range from 1% to 7% (Haidar et al. Clin Infect Dis, 2020). Some centers use positive fungal biomarkers, such as serum (1à3)-β-D-glucan (B-DG) and galactomannan (GM), alongside surveillance radiographic imaging to guide preemptive fungal therapy in this population. The objective of the study was to assess the diagnostic performance of surveillance B-DG and GM for the diagnosis of IFI in recipients of BCMA and CD19-directed CAR T for multiple myeloma (MM) and non-Hodgkin lymphoma (NHL), respectively. Methods: We conducted a retrospective analysis on adult patients who received BCMA-directed CAR T therapy for MM or CD19-directed CAR T for NHL at our institution between 2018-2023. IFI was defined using the Revised European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) criteria (Donnelly et al. Clin Infect Dis, 2020). Only patients with proven or probable infection were included in the analysis. The choice of antifungal prophylaxis was determined based on the treating physician's discretion. In the most cases, B-DG and GM monitoring was done prior to apheresis, before CAR T infusion, and subsequently every 14 days for a duration of 6 months. All patients were followed until 7/12/2023, or until their data were censored at the last follow-up. The cumulative incidence was calculated using Kaplan-Meier method, considering the time to IFI, with IFI-free death and disease relapse as competing risks. Statistical analysis was performed using IBM SPSS (version 29.0). Result: Among the 148 subjects in this study, 51 patients (34.5%) received BCMA CAR T, and 97 (65.5%) received CD19 CAR T therapy. The median age at CAR T infusion was 66 years (range 36-78) in the BCMA cohort and 65 years (range 27-83) in the CD19 cohort (p=0.64). The BCMA cohort had a higher number of prior therapies, with a median of 6 (range 2-15) compared to the CD19 cohort, which had a median of 4 (range 2-12) (p<0.001). The median follow-up from CAR T infusion was 9.5 months (range 0-63) in both cohorts, with 12 months (range 0-63) in the BCMA cohort and 8 months (range 0-49) in the CD19 cohort. All patients received prophylactic antifungal agents, including anti-yeast (fluconazole, n=95), and anti-mold (micafungin n=5, isavuconazole n=1, or Posaconazole n=52). Among the BCMA cohort, 92% of the patients received anti-yeast prophylaxis, while 8% were given anti-mold prophylaxis. In the CD19 cohort, 49.5% received anti-yeast prophylaxis, while 50.5% received anti-mold prophylaxis. Out of the 148 patients, 21 individuals (14%) exhibited elevated B-DG levels, while only 2 patients (1%) showed elevated GM levels. However, 20 out of 21 (95%) cases with positive B-DG, and all cases with positive GM were deemed to be false positives. Among these false positives, 60% were attributed to IVIG administration, while the cause for the remaining cases remained unknown (Table 1). Only one patient in this study developed IFI. The patient received anti-yeast prophylaxis (Fluconazole) at CAR-T and had a disseminated Rhizopus infection on day 13 post CD19 CAR T, which ultimately resulted in the patient's death. The 1-year cumulative incidence of IFI, considering competing risks, was 0.7% (95% confidence interval [CI], 0- 2.1). The median progression-free survival (PFS) in the overall cohort was 11.7 months (95% CI, 6.9-16.6), with 8.6 months (95% CI, 3.2-13.97) in the BCMA cohort and 14.6 months (95% CI, NR-NR) in the CD19 cohort (p=0.324). The median overall survival (OS) of the study cohort was 32.4 months (95% CI, 16.3-48.4), with 41.4 months (95% CI, 16.74-66.08) in the BCMA cohort and 23.98 months (95% CI, NR-NR) in the CD19 cohort (p=0.260). Conclusion: The rate of IFI in our cohort was low (0.7%) post-CAR T therapy. The diagnostic performance of serial monitoring of B-DG and GM for the diagnosis of IFI is poor in recipients of BCMA-directed CAR T therapy for MM or CD19-directed CAR T for NHL.

From Widespread to Tailored Antifungal Prophylaxis in Lymphoma Patients Treated with CD19 CAR T- Cell Therapy: Less Is Better

Introduction: Invasive fungal infections (IFI) are a major threat in patients with hematological malignancies with substantial associated morbidity. Patients who receive CD19 CAR T-cell therapy have multiple immune defects that may predispose them to IFI. However, the role and duration of antifungal prophylaxis in this population is debated. Methods: This retrospective study at Memorial Sloan Kettering Cancer Center (MSK) describes the characteristics of antifungal prophylaxis and the frequency of IFI after CD19 CAR T-cell therapy in patients with R/R B-cell lymphoma. Two groups of patients were analyzed. Group A (2016-2020): patients primarily received fluconazole, as clinically indicated, regardless of clinical risk profile; Group B (2020-2023) standard guidelines were established in 2020 with antifungal prophylaxis recommended only in high-risk patients with prolonged neutropenia (≥ 3 weeks), those on systemic steroids (≥0.5 mg/kg/day of prednisone equivalent) for ≥ 3 days, or in patients with previous IFI; patients were treated based on a more restrictive mold-active and patient-tailored prophylactic strategy. Results: Three hundred thirty-two patients treated with CAR T-cell therapy for R/R lymphoma between 2016 and 2023 were analyzed. Group A was comprised of 144 patients, whereas group B had 188 patients. Patients' characteristics are described in Table 1. Overall antifungal prophylaxis was prescribed in 95 (66.4%) and 58 (30.9%) patients in group A and B, respectively. While fluconazole was most frequently given in both groups, there was 50% less use in group B (Figure 1). Anti-mold azoles were prescribed in 8.4% of group A patients, whereas for group B, it increased to 34.5%. In group A, a switch to another antifungal was observed in 42 (29%) patients, mainly to micafungin because of transaminitis with azoles. In group B, 21 (11.2%) patients switched their first antifungal drug, mainly from fluconazole or micafungin to a mold-active agent following updated guidelines. Median duration of grade IV neutropenia was 9 days (range 1-93) for group A and 12 days (range 1-90) for group B. Grade IV neutropenia was present at the start of prophylaxis in 30 (31.5%) patients in group A and 30 (51.7%) patients in group B. In the subgroup of patients without prophylaxis, only 13% in group A and 4% in group B were neutropenic. Bridging therapy was administered in 70% of patients in group A and 80% in group B. IFI infections after CAR T-cell therapy were rare: one patient had cryptococcal meningoencephalitis in group A (0.7%) and one had invasive aspergillosis in group B (0.5%), both on micafungin prophylaxis, not effective on molds and cryptococcus. These results show better rates for IFI compared to the FDA adverse events reporting system (FAERS) database: which is 3.1% considering the same CAR-T products. All-cause mortality was similar between both groups (A: 29.8% vs B: 35.7%). Conclusion: This large single-center cohort of R/R lymphoma patients after CAR T-cell therapy offers a valuable snapshot of two different antifungal prophylactic approaches with remarkably low rates of IFI in both strategies, even after the 2020 guideline update with more restrictive antifungal use. Given the risk of toxicity, drug-drug interactions, and concerns for emerging antifungal resistance with azoles, a restrictive prophylactic strategy seems the best choice in this setting.

The Microevolution of Antifungal Drug Resistance in Pathogenic Fungi.

The mortality rates of invasive fungal infections remain high because of the limited number of antifungal drugs available and antifungal drug resistance, which can rapidly evolve during treatment. Mutations in key resistance genes such as ERG11 were postulated to be the predominant cause of antifungal drug resistance in the clinic. However, recent advances in whole genome sequencing have revealed that there are multiple mechanisms leading to the microevolution of resistance. In many fungal species, resistance can emerge through ERG11-independent mechanisms and through the accumulation of mutations in many genes to generate a polygenic resistance phenotype. In addition, genome sequencing has revealed that full or partial aneuploidy commonly occurs in clinical or microevolved in vitro isolates to confer antifungal resistance. This review will provide an overview of the mutations known to be selected during the adaptive microevolution of antifungal drug resistance and focus on how recent advances in genome sequencing technology have enhanced our understanding of this process.

A Prospective Study to Evaluate the Effect of Therapeutic Drug Monitoring-Based Posaconazole Prophylaxis on Invasive Fungal Infection Rate During Acute Myeloid Leukemia Induction Therapy.

The online version contains supplementary material available at 10.1007/s12288-023-01709-3.

Invasive fungal infection following venetoclax and posaconazole co-administration.

The co-administration of venetoclax, a BCL-2 inhibitor, with a mould-active azole, such a posaconazole, has potential to both prevent invasive fungal infection (IFI) and reduce the required treatment dose, and cost, of venetoclax. Posaconazole drug-level monitoring is critical to ensuring adequate mould prophylaxis. A retrospective audit of 99 patients at a tertiary cancer centre, with myeloid malignancies co-prescribed venetoclax and posaconazole between January 2018 and April 2022, was undertaken to evaluate the adequacy of posaconazole prescribing and the rate of breakthrough IFI. Seventy-six patients (77%) had at least one posaconazole level measured in the study period, with 37% requiring a dose adjustment based on steady-state trough levels. Breakthrough IFI occurred in 4% of patients, typically within 1 month of commencing anti-mould prophylaxis. Close monitoring of posaconazole levels in venetoclax-treated patients, particularly in the early, outpatient setting, is critical.

Infectious complications among patients receiving ibrutinib for the treatment of hematological malignancies.

Ibrutinib is a Bruton's tyrosine kinase inhibitor used to treat multiple hematologic malignancies and graft-versus-host disease. Though less myelosuppressive than cytotoxic chemotherapy, increased infections, including invasive fungal infections (IFIs), have been reported with ibrutinib use. This study aimed to determine the characteristics and risk factors for infection associated with ibrutinib at our institution. Patients who received ibrutinib between June 2014 and August 2019 were included. Primary endpoints were the incidence of any infection and the incidence of serious infection (defined as hospitalization, parenteral antimicrobial therapy, or pneumonia regardless of hospitalization). Infection risk factors were assessed using logistic regression. One hundred thirty-two patients were identified (78% male; median age, 71 years). The most common indications for ibrutinib were chronic lymphocytic leukemia (67%) and mantle cell lymphoma (12%). Infection and serious infection occurred in 94 (71%) and 47 (36%) patients, respectively; when pneumonia was excluded as a criterion for serious infection, the serious infection rate was 27%. The median time from ibrutinib initiation to first infection was 125 days. Prior allogeneic hematopoietic stem cell transplantation (allo-HSCT) (odds ratio [OR], 4.60; 95% CI, 1.22-17.4) and corticosteroid use (OR, 5.55; 95% CI, 1.52-20.3) were significant risk factors for serious infection. IFIs were diagnosed in 7 patients (5%): 5 had Pneumocystis jirovecii pneumonia and 2 were infected with invasive molds. Serious infection and IFI rates are high but similar to those previously described. Risk factors for serious infection included allo-HSCT and corticosteroid use. Targeted antimicrobial prophylaxis should be evaluated in prospective studies in patients on ibrutinib to reduce serious infections and IFI.

Invasive Fungal Infection in Hematopoietic Stem Cell Transplant Recipient from an Indian Oncology Setting

Objective Invasive fungal infections (IFI) are one of the major causes of morbidity and mortality in post-hematopoietic stem cell transplant (HSCT) recipients. Data from India is limited. The objective of this study was to analyze the incidence, risk factors, and outcomes associated with IFI in our center. Materials and Methods Adult patients, who underwent marrow/stem cell transplantation between 2014 and 2018, in an oncology center in India, were included in this single-center retrospective observational study. The revised European Organization for Research and Treatment of Cancer/ Mycoses Study Group (EORTC/MSG) consensus group 2008 definition for IFI was considered to define cases. Incidence, risk factors, and outcomes associated with IFI were analyzed. Statistical Analysis All continuous variables were represented by mean ± standard deviation and categorical variables as percentage. Comparison of categorical variables was done by either the chi-squared test or Fisher's exact test. All “p” values less than 0.05 were considered statistically significant. Results Out of the 126 patients who underwent HSCT between January 2014 and December 2018, 56 (44.4%) patients had allo-HSCT, 64 (50.8%) had auto-HSCT, and 6 (4.8%) had haplo-identical HSCT. Eighty-three (63%) patients were male and 43 (34%) females, and 113 (83.9%) Asians and 13 (10.3%) Africans. Total 111 (88%) patients received myeloablative conditioning and 24 (19%) received total body irradiation. The hematological conditions were acute myeloid leukemia (n = 23; 18.25%), acute lymphoblastic leukemia (n = 16; 12.69%), chronic myeloid leukemia (n = 4; 3.17%), Hodgkin lymphoma (n = 17; 13.4%), non-Hodgkin lymphoma (n = 11; 8.73%), myeloma (n = 35; 27.7%), sickle cell disease (n = 13; 10.31%), etc. Most patients received fluconazole (78; 61.9%) followed by micafungin (23; 18.25%), posaconazole (20; 15.87%), voriconazole (4; 3.17%), and liposomal amphotericin B (1; 0.79%) as antifungal prophylaxis. The overall rate of IFI (possible cases included) was auto-HSCT (n = 5; 7.81%), and allo-HSCT (n = 5; 8.92%). Among auto-HSCT, the IFI was proven = 0, probable n = 1 (1.5%), and possible n = 4 (6.25%) and among allo-HSCT the IFI was proven = 0, probable n = 2 (3.57%), and possible n = 3 (5.35%). No patients in haplo-HSCT had IFI. The 1-year survival rate among the IFI cases was 8/10(80%). A meaningful comparison of the risk factors and the impact of prophylactic regimens were difficult because of the very low number of IFI cases. Conclusions The overall rate of IFI in HSCT patients in our setting was low compared to global data on IFI in HSCT.

Invasive Fungal Infections in Children With Acute Myeloid Leukemia: A Single-center Experience Over 19 Years.

Invasive fungal infections (IFIs) remain a significant cause of morbidity and mortality in children with acute myeloid leukemia (AML). This study aimed to evaluate the incidence, risk factors, etiology, and outcome of IFIs in children with AML and the effect of mold-active antifungal prophylaxis. We retrospectively reviewed pediatric patients treated for AML between January 2004 and December 2022. Proven, probable, or possible IFIs were defined using standardized definitions of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) classification published at 2008. A total of 298 febrile neutropenia episodes from 78 patients were evaluated. Proven, probable, and possible IFI rates were 3%, 2.6%, and 9.4%, respectively. Profound neutropenia was detected in 18 (58%) and prolonged neutropenia in 20 (64.5%) of the IFI episodes.. Invasive aspergillosis accounted for the majority of IFI episodes; however, non-albicans Candida spp. were the most isolated pathogens in the proven group. Patients with relapsed AML were particularly at risk for the development of IFI ( P =0.02). A significant decrease in IFI episodes was achieved with mold-active antifungal prophylaxis with voriconazole ( P =0.01, odds ratio: 0.288, %95 CI:0.104-0.797). The overall mortality was 35.8%, and the IFI-attributable mortality rate was 25%. In the multivariate analysis, relapsed disease was the most significant risk factor associated with mortality ( P =0.006, odds ratio:4.745; 95% CI: 1.573-14.316). Mold-active prophylaxis reduced the rate of IFIs in this cohort however IFI-related mortality was still high as 25% in pediatric AML patients. Relapsed AML was the most significant risk factor associated with mortality.

Hypoalbuminemia is a risk factor for invasive fungal infections and poor outcomes in infected kidney transplant recipients.

Invasive fungal infections (IFI), are estimated to occur in 2%-14% of kidney transplant recipients (KTRs) in the current era of immune suppression and are associated with high mortality rates. We hypothesized that hypoalbuminemia in KTRs is a risk factor for IFI and would be associated with poor outcomes. In this study, using data from a prospective cohort registry, we describe the frequency of IFI due to Blastomycosis, Coccidioidomycosis, Histoplasmosis, Aspergillosis, and Cryptococcus in KTRs with serum albumin levels measured 3-6months before diagnosis. Controls were selected based on incidence density sampling. KTRs were divided into three groups based on the pre-IFI serum albumin level: normal (≥4g/dL), mild (3-4g/dL), or severe (<3g/dL) hypoalbuminemia. Outcomes of interest were uncensored graft failure after IFI and overall mortality. A total of 113 KTRs with IFI were compared with 348 controls. The incidence rate of IFI among individuals with normal, mild, and severe hypoalbuminemia was 3.6, 8.7, and 29.3 per 100 person-years, respectively. After adjustment for multiple variables, the trend for risk of uncensored graft failure following IFI was greater in KTRS with mild (HR=2.1; 95% CI, .75-6.1) and severe (HR=4.47; 95% CI, 1.56-12.8) hypoalbuminemia (P-trend<.001) compared to those with normal serum albumin. Similarly, mortality was higher in severe hypoalbuminemia (HR=1.9; 95% CI, .67-5.6) compared to normal serum albumin (P-trend<.001). Hypoalbuminemia precedes the diagnosis of IFI in KTRs, and is associated with poor outcomes following IFI. Hypoalbuminemia may be a useful predictor of IFI in KTRs and could be incorporated into screening algorithms.

Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia

Invasive fungal infection (IFI) prophylaxis is recommended in patients with acute myeloid leukemia (AML) during induction chemotherapy. Posaconazole (POSA) is the recommended agent of choice; however, this medication can be associated with QTc prolongation, hepatotoxicity, and drug-drug interactions. Furthermore, there is conflicting evidence for the role of isavuconazole (ISAV) in this setting as an alternative to POSA. The primary objective of this study was to evaluate the use of ISAV prophylaxis for primary IFI prevention in patients with AML undergoing induction. Additionally, the study investigated the use of ISAV trough concentration monitoring and compared these results to the efficacy of POSA therapeutic drug monitoring (TDM). Other secondary objectives included assessing the rates of toxicities associated with either prophylactic agent. This study analyzed the impact these toxicities had on patient outcomes by examining the need to hold or discontinue therapy. The final endpoint considered the efficacy associated with multiple dosing strategies employed at the study institution. Specifically, this included the use of loading doses or foregoing these when initiating prophylaxis. This was a retrospective, single-center, cohort study. Patients included in this study were adults with AML admitted to Duke University Hospital between June 30, 2016 and June 30, 2021, who received induction chemotherapy and primary IFI prophylaxis for at least 7 days. Exclusion criteria included patients who received concomitant antifungal agents and patients who received antifungal agents as secondary prophylaxis. 241 patients met inclusion criteria with 12 (4.98%) participants in the ISAV group and 229 (95.02%) participants in the POSA group. The IFI incidence in the POSA group was 14.5%, while the ISAV group did not have any occurrences of IFI. No significant difference was found in the rate of IFI occurrence between the two treatment groups (p = 0.3805). Furthermore, it was demonstrated that the use of a loading dose when initiating prophylaxis could impact rates of IFI for this patient population. Due to no difference in incidence, patient specific factors such as concomitant medications and baseline QTc should influence the choice between prophylactic agent.

Real-life monocentric experience of venetoclax-based regimens for acute myeloid leukemia.

Combination of venetoclax and hypomethylating agents (HMAs) has become a standard of care in acute myeloid leukemia (AML) aged >75 years or who have comorbidities that preclude intensive induction chemotherapy. We conducted a monocentric retrospective analysis on adult patients affected by treatment-naïve AML not eligible for standard induction therapy or refractory/relapsed (R/R) AML treated with venetoclax combinations outside clinical trials. Venetoclax was administered at the dose of 400 mg/daily after a short ramp-up and reduced in case of concomitant CYP3A4 inhibitors. Sixty consecutive AML were identified. Twenty-three patients (38%) were affected by treatment-naïve AML and 37 (62%) by R/R AML. Median age was 70 years. Among R/R AML 30% had received a prior allogeneic stem cell transplantation (allo-HSCT). In combination with venetoclax, 50 patients (83%) received azacitidine. Antifungal prophylaxis was performed in 33 patients (55%).Overall response rate was 60%, with 53% of complete remission (CR; 78% for treatment-naïve and 49% for R/R, p 0.017). Median overall survival was 130 days for R/R patients and 269 days for treatment-naïve patients; median event free survival was 145 days for R/R cohort and 199 days for treatment-naïve AML.Measurable residual disease was negative in 26% of evaluable patients in CR/CR with incomplete hematologic recovery after 2 cycles and in 50% after 4 cycles, with no significant association with survival.Eleven patients (18%) received an allo-HSCT after venetoclax combinations. Most common grade 3/4 adverse events were infectious (51% of the patients), or hematological without infections (25% of the patients). Use of CYP3A4 inhibitors was associated with a trend to shorter cytopenias and with a lower rate of infections. Invasive fungal infections were less frequent among patients receiving azole prophylaxis (6% vs 26%; p 0.0659). Venetoclax-based regimens are a viable option for AML considered not eligible for standard induction therapy and a valid rescue therapy in the R/R setting.Azole prophylaxis did not significantly affect response and it was associated with a lower rate of invasive fungal infections. Despite a limited number of patients, the association of venetoclax and HMAs proved to be also a feasible bridging therapy to transplantation.

Corticosteroids Increase the Risk of Invasive Fungal Infections More Than Tumor Necrosis Factor-Alpha Inhibitors in Patients With Inflammatory Bowel Disease.

Invasive fungal infections are a devastating complication of inflammatory bowel disease (IBD) treatment. We aimed to determine the incidence of fungal infections in IBD patients and examine the risk with tumor necrosis factor-alpha inhibitors (anti-TNF) compared with corticosteroids. In a retrospective cohort study using the IBM MarketScan Commercial Database we identified US patients with IBD and at least 6 months enrollment from 2006 to 2018. The primary outcome was a composite of invasive fungal infections, identified by ICD-9/10-CM codes plus antifungal treatment. Tuberculosis (TB) infections were a secondary outcome, with infections presented as cases/100 000 person-years (PY). A proportional hazards model was used to determine the association of IBD medications (as time-dependent variables) and invasive fungal infections, controlling for comorbidities and IBD severity. Among 652 920 patients with IBD, the rate of invasive fungal infections was 47.9 cases per 100 000 PY (95% CI 44.7-51.4), which was more than double the TB rate (22 cases [CI 20-24], per 100 000 PY). Histoplasmosis was the most common invasive fungal infection (12.0 cases [CI 10.4-13.8] per 100 000 PY). After controlling for comorbidities and IBD severity, corticosteroids (hazard ratio [HR] 5.4; CI 4.6-6.2) and anti-TNFs (HR 1.6; CI 1.3-2.1) were associated with invasive fungal infections. Invasive fungal infections are more common than TB in patients with IBD. The risk of invasive fungal infections with corticosteroids is more than double that of anti-TNFs. Minimizing corticosteroid use in IBD patients may decrease the risk of fungal infections.

Incidence of Invasive Fungal Infections in Liver Transplant Recipients under Targeted Echinocandin Prophylaxis

Invasive fungal infections (IFIs) are one of the most important infectious complications after liver transplantation, determining morbidity and mortality. Antimycotic prophylaxis may impede IFI, but a consensus on indication, agent, or duration is still missing. Therefore, this study aimed to investigate the incidence of IFIs under targeted echinocandin antimycotic prophylaxis in adult high-risk liver transplant recipients. We retrospectively reviewed all patients undergoing a deceased donor liver transplantation at the Medical University of Innsbruck in the period from 2017 to 2020. Of 299 patients, 224 met the inclusion criteria. We defined patients as being at high risk for IFI if they had two or more prespecified risk factors and these patients received prophylaxis. In total, 85% (190/224) of the patients were correctly classified according to the developed algorithm, being able to predict an IFI with a sensitivity of 89%. Although 83% (90/109) so defined high-risk recipients received echinocandin prophylaxis, 21% (23/109) still developed an IFI. The multivariate analysis identified the age of the recipient (hazard ratio-HR = 0.97, p = 0.027), split liver transplantation (HR = 5.18, p = 0.014), massive intraoperative blood transfusion (HR = 24.08, p = 0.004), donor-derived infection (HR = 9.70, p < 0.001), and relaparotomy (HR = 4.62, p = 0.003) as variables with increased hazard ratios for an IFI within 90 days. The fungal colonization at baseline, high-urgency transplantation, posttransplant dialysis, bile leak, and early transplantation showed significance only in a univariate model. Notably, 57% (12/21) of the invasive Candida infections were caused by a non-albicans species, entailing a markedly reduced one-year survival. The attributable 90-day mortality rate of an IFI after a liver transplant was 53% (9/17). None of the patients with invasive aspergillosis survived. Despite targeted echinocandin prophylaxis, there is still a notable risk for IFI. Consequently, the prophylactic use of echinocandins must be critically questioned regarding the high rate of breakthrough infections, the increased occurrence of fluconazole-resistant pathogens, and the higher mortality rate in non-albicans Candida species. Adherence to the internal prophylaxis algorithms is of immense importance, bearing in mind the high IFI rates in case algorithms are not followed.

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.

Utilization of Antifungal Prophylaxis and Treatment for Newly Diagnosed AML Patients Treated with Venetoclax Based Regimens in Routine Clinical Practice - a Prospective Analysis from the Revive Study

Background: Venetoclax (VEN)-based low intensity combinations are approved for the treatment of patients (pts) with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. These combinations can be associated with prolonged cytopenias in particular neutropenia. Invasive fungal infections (IFIs) remain a major cause of morbidity and mortality in pts with AML but their incidence and impact on pts treated with VEN-based low intensity approach are uncertain. In the current study we assess real-world patterns of IFI's and antifungal treatments among newly-diagnosed (ND) AML patients treated with VEN-based low intensity therapies. Methods: The REVIVE study is a prospective, real-life, observational study that assesses patterns of pt. selection, efficacy and toxicity. ND pts with AML were enrolled at the time of VEN-based therapy initiation from 12 medical centers in Israel. Demographic, clinical and pt.-related baseline characteristics were documented. Antifungal medication selection for prophylaxis or therapy use and the incidence of IFIs were documented. The impact of prophylactic antifungal use on the incidence of IFIs and on leukemia related outcomes were assessed. Results: Between August 12, 2019, and April 15, 2022(data cut) ,189 AML pts were enrolled to receive VEN based therapy. Overall, the incidence of possible IFIs was relatively low and was observed in 17 patients (9% of patients). 23 pts (12.1%) were reported to have received prophylactic antifungal treatment, whereas 166 pts (87.8%) did not receive. Baseline characteristics of these two groups are shown in Table 1. Of note, pts. receiving antifungal prophylaxis were more likely to be treated as outpatients. A trend towards treatment in a tertiary center and unfavorable ELN risk was observed in pts. receiving antifungal prophylaxis vs. pts not receiving prophylaxis. All other characteristics seemed equally balanced between both groups. Antifungal prophylaxis included fluconazole (18 pts), voriconazole (6 pts) and posaconzole (1 pt). Of note, 2 patients received two different prophylactic treatments. The incidence of IFIs was not reduced in pts receiving antifungal prophylaxis. Of the 23 patients who received antifungal prophylaxis, 4 were considered to have an IFI (17.4%) compared with 13 in the non-prophylactic group (7.8%). Antifungal treatment in pts with an IFI included fluconazole (10pts) voriconazole (5 pts) posaconazole (1 pt) amphotericin B (1 pt) and anidulafungin (1pt). Of note, 3 patients received two different antifungal treatments. No difference in 30-day mortality was observed between the two groups:1 pt in the prophylaxis group died compared with 8 pts in the no-prophylaxis group (4.3% vs 4.8% respectively, p=0.92). Prophylactic antifungal treatment did not affect the rate of adverse events (AEs) leading to treatment discontinuation: 4 pts in the prophylaxis group and 31 pts in the no prophylaxis group discontinued VEN based treatment due to adverse events (17.4% vs 18.7%, p=0.88). The efficacy of VEN based treatment for AML was similar between pts who received or did not receive antifungal prophylaxis. Composite complete remission (CRc) rates were 60.9% in the antifungal prophylaxis group vs 54.2% in pts with no antifungal prophylaxis (p=0.54). A Kaplan-Meier analysis for overall survival (OS) showed no difference between the prophylaxis and no prophylaxis groups (p=0.505). 1year OS rates were: 50.6% (CI 28-73.3) and 39.4% (CI 30.5-48.3) for prophylaxis and no prophylaxis groups respectively. Median follow up in the prophylaxis group was 237 days (CI 56-878) compared with 173 days (CI 19-850) in the no-prophylaxis group. Conclusion: In this prospective 'real world' observational study, a low rate of IFIs were noted despite low utilization rates of antifungal prophylaxis, mostly with non-mold active azoles. Moreover, administration of antifungal prophylaxis was not associated with a reduced incidence of IFIs. Reassuringly, use of antifungal azoles as prophylactic treatment, which requires VEN dose adjustments, did not affect CRc and OS rates. Similarly, azole based prophylaxis did not affect for the rate of treatment discontinuation due to AEs or early mortality. This study does not support the routine use of antifungal prophylaxis and suggests that such treatment is safe if deemed necessary. Additional insights on antifungal treatment patterns and strategies are pending. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Outcomes in Acute Myeloid Leukemia Patients Receiving 7+3 Induction By Using Protocolized Antifungal Prophylaxis in a Community Setting

Introduction: Invasive fungal infections (IFI) are a leading cause of mortality in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy including "7+3” regimen of cytarabine and daunorubicin.1 Posaconazole improves survival and reduces IFI rates in comparison with fluconazole.2 The aim of our study was to compare outcomes of patients receiving induction chemotherapy for AML at our institution before and after implementation of a priority matrix (PM) including standardized antifungal prophylaxis. Our primary endpoint was incidence of IFI, and our secondary endpoints were mortality at 30 days and 1 year. Methods: All patients admitted with AML and receiving 7+3 induction chemotherapy at Gundersen Health System between January 2013 and January 2022 were included in our study. Patients were assigned either to Pre-PM or Post-PM group (whether induction was started before or after January 1, 2019, respectively). The priority matrix (Figure) included mandatory treatment with appropriate prophylaxis (posaconazole /voriconazole), patient education, electronic health record (EHR) updates, standardized work up for refractory fevers, and other optimization practices. Antifungal agent was given starting on day 8 after initiation of induction until resolution of neutropenia, defined as an absolute neutrophil count >500/uL. Treatment-related mortality rates (TRMR) and Charlson Comorbidity Index (CCI) were calculated at time of diagnosis. Statistical analyses using chi-square, Fisher exact, Wilcoxon rank sum tests, and Cox proportional hazards were done in SAS version 9.4. Results: The study population consisted of 37 patients: 23 in the Pre-PM group (prior to Jan 1, 2019) and 14 in the Post-PM group. The population was predominantly white, non-Hispanic with a median age 63 years, and was 60% male. Groups were similar with regard to median age, sex, TRMR, and CCI. Of the 23 Pre-PM patients, 6 received fluconazole. All patients in the Post-PM group received prophylaxis-1 with voriconazole, and 13 with posaconazole. Six Pre-PM patients (26%) developed IFI, compared with 1 Post-PM patient (7%; p=0.22). Five of the 6 Pre-PM patients who received fluconazole developed IFI, as did 1 Post-PM patient who received posaconazole (p<0.001). Four (17%) Pre-PM patients, none of whom received fluconazole died within 30 days, and there were no deaths in the Post-PM group (p=NS). Fifteen (65%) Pre-PM patients died within 1 year (5 had received fluconazole prophylaxis), compared with 3 (21%) Post-PM patients. Mortality rates were not significantly different between groups at 30 days (p=0.22)); however, mortality at 1 year was significantly higher in the Pre-PM group (log rank p=0.004), including in those receiving fluconazole (log rank p=0.0005). Conclusions: Our study shows significantly improved outcomes with use of a standardized protocol in AML patients receiving 7+3 induction by using posaconazole over fluconazole per our PM intervention. We reduced IFI rates to our goal of <10% in AML patients and improved 30-day and 1 -year survival at our institution, rates comparable to national averages. Because community health care facilities are increasingly treating patients with AML, we share our protocol to help improve care in this setting. References 1Hsu A. et al. Supportive Care in Cancer, . 2021;29(2):707-712. 2Cornely OA, et al. N Engl J Med. 2007;356:348-359 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence of Invasive Fungal Infections in Patients With Previously Untreated Acute Myeloid Leukemia Receiving Venetoclax and Azacitidine.

BackgroundAcute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined.MethodsThis retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence.Results144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) “proven,” 24% (n = 6) “probable,” and 68% (n = 17) “possible” per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0–9 days after starting VEN/AZA, at 8.39.ConclusionsIncidence of “proven” and “probable” IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased.

Oral Nystatin Prophylaxis for the Prevention of Fungal Colonization in Very Low Birth Weight Infants: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

We conducted this systematic review and meta-analysis of randomized controlled trials (RCTs) to investigate the prophylactic role of oral nystatin in the prevention of fungal colonization in very low birth weight (VLBW) infants compared with placebo or no treatment intervention. From inception until June 2022, we screened four major databases for pertinent RCTs and examined their risk of bias. The main outcomes were the rate of fungal colonization, rate of invasive fungal infection, rate of mortality, mean length of stay in the neonatal intensive care unit (NICU), and mean duration of antibiotic treatment. We summarized data as risk ratio (RR) or mean difference (MD) with 95% confidence interval (CI), using the fixed-effects model. Five RCTs met our inclusion criteria. One RCT was evaluated as having "high risk," one RCT was evaluated as having "some concerns," and three RCTs were evaluated as having "low risk" of bias. Compared with the control group, oral nystatin prophylaxis was correlated with substantial decrease in the frequency of fungal colonization (n=4 RCTs, RR=0.34, 95% CI {0.24, 0.48}, p<0.0001), the rate of invasive fungal infection (n=4 RCTs, RR=0.15, 95% CI {0.12, 0.19}, p<0.0001), and the mean duration of antibiotic treatment (n=3 RCTs, MD=-2.79 days, 95% CI {-5.01, -0.56}, p=0.01). However, there was no significant difference between both groups regarding the rate of mortality (n=4 RCTs, RR=0.87, 95% CI {0.64, 1.18}, p=0.37) and mean length of stay in NICU (n=3 RCTs, MD=-2.85 days, 95% CI {-6.52, 0.82}, p=0.13). In conclusion, among VLBW infants, the prophylactic use of oral nystatin was correlated with favorable antifungal benefits compared with placebo or no treatment intervention.