Antifungal Prophylaxis Research Articles

Fatal invasive Aspergillus infection in an elderly patient with hepatitis E: A case report and literature review.

Elderly patients with acute liver failure are highly susceptible to severe complications, such as invasive fungal infections, due to weakened immune systems and altered gut microbiota. A thorough understanding of liver failure and opportunistic infections is crucial for effective management. An 84-year-old male with acute liver failure from hepatitis E experienced worsening jaundice despite standard treatments. He also developed respiratory symptoms, including blood-streaked sputum, raising concerns about a potential fungal infection. The patient was diagnosed with acute liver failure secondary to hepatitis E and an invasive fungal infection caused by Aspergillus fumigatus. Initial treatments included artificial liver plasma exchange and antifungal prophylaxis. Further diagnostics, including bronchoscopy and next-generation sequencing of alveolar lavage fluid, confirmed the Aspergillus infection. Elderly liver failure patients are particularly prone to opportunistic infections, underscoring the need for vigilant monitoring and early intervention. Despite aggressive treatments, including antifungal therapy and artificial liver support, prognosis remains poor, highlighting the importance of prompt diagnosis and comprehensive management to enhance patient outcomes.

Effectiveness of high efficiency particulate (HEPA) air condition combined with the antifungal prophylaxis on incidence, morbidity and mortality of invasive fungal infections in patients with acute myeloid leukemia: a retrospective single-center study

Effectiveness of high efficiency particulate (HEPA) air condition combined with the antifungal prophylaxis on incidence, morbidity and mortality of invasive fungal infections in patients with acute myeloid leukemia: a retrospective single-center study

Invasive Fungal Disease in Pediatric Heart Transplant Recipients

Abstract Background The epidemiology of IFD following pediatric heart transplantation (pHT) is poorly characterized. We sought to evaluate use of antifungal prophylaxis and describe the epidemiology of IFD in pHT at two large children’s hospitals. Methods We performed a retrospective cohort study of pediatric and young adult (≤21 years) patients undergoing heart transplantation at Cincinnati Children’s Hospital Medical Center (CCHMC) and Children’s Hospital of Philadelphia (CHOP) between 2012 and 2021. We recorded demographic, clinical, medication, and laboratory data for pHT patients through 12 months post-transplant. We identified use of topical (oral nystatin) and systemic antifungal prophylaxes in the peri-transplant period (7 days prior through 14 days following transplant) and analyzed if certain transplant variables were associated with the administration of systemic antifungals during this period using rank sum and chi squared tests. Applying published definitions, we quantified the incidence of proven and probable IFD and explored the characteristics of these cases. Results A total of 201 patients underwent heart transplant at CCHMC and CHOP. The majority were male (60.2%), White (66.7%), and not Hispanic or Latino (88.1%). Median age at time of transplant was 7.4 years (IQR 0.9-14.2). During the peri-transplant period, 143 (71.1%) patients received oral nystatin and 37 (18.4%) received systemic antifungal prophylaxis, not including PJP prophylaxis. 41 individuals (20.4%) were not on any antifungal prophylaxis throughout this period. Delayed chest closure was significantly associated with the administration of systemic antifungals (p<0.001) while several other variables (age, hospital, immunosuppression medication, ECMO/LVAD pre-transplant) were not. In total, 8 patients (4%) developed proven (n=5) or probable (n=3) IFD. In our cohort, the incidence rate of proven/probable IFD in the first year post-transplant was 44.8 per 1000 patient-years. The characteristics of these cases are shown in Table 1. Time from pHT to IFD ranged from 11 days to 196 days (median time = 25.5 days). All cases of proven IFD occurred within 28 days of transplant. In three cases of proven/probable IFD, patients were receiving a systemic antifungal or PJP prophylaxis in the seven days prior to IFD onset. Two cases met the definition of probable IFD but the infections resolved without directed therapies. Four patients with proven IFD died within 1 year following transplant, although in only 3 cases was IFD a contributing factor. The one-year all-cause mortality rate among pHT patients with proven/probable IFD (50%) was higher than that in pHT patients without IFD (10.3%; Fisher’s exact p=0.008). Conclusion Over a 10-year period at CCHMC and CHOP, 4% of pHT patients developed proven or probable IFD within one-year post-transplant. All proven IFD cases occurred within a month of transplant while probable cases occurred more than 100 days post-transplant. Delayed chest closure was significantly associated with the administration of systemic antifungal prophylaxis. Patients with proven IFD had poor outcomes despite receipt of appropriate antifungal treatment. Given the low incidence of IFD at these two centers, we were unable to evaluate risk factors for IFD in this population and so larger studies would be needed.

Clinical insights into Invasive Aspergillosis in Mexican children with cancer

Abstract Background In the last years Invasive Aspergillosis (IA) has become the most frequent invasive fungal infection (IFI) affecting children with hematological malignancies. This complication results in the delay of cancer treatment and/or poor prognosis mainly due to late diagnosis and late start of antifungal treatment. Therefore, antifungal prophylaxis and preemptive approaches have been proposed for these patients based on risk factors and local epidemiological data. For this reason, we performed a unicenter, descriptive and prospective study to determine the frequency and clinical course of IA in hospitalized cancer patients with fever and neutropenia. Methods we included events of fever and neutropenia of hospitalized patients with cancer and either with persistent febrile neutropenia (PFN: fever for >96h with total neutrophil count of <500cells/mm3) or profound prolonged neutropenia (PPN: total neutrophil count of <500cells/mm3 for >7 days). Informed consent was requested prior inclusion and follow up of these events was performed with weekly measurement of serum galactomannan antigen (until the recovery of neutrophil count), lung computed tomography (CT) and/or sinus and/or central nervous system (CNS) imaging, depending on clinical findings, and if feasible bronchoscopy to obtain bronchioalveolar lavage (BAL) samples. Clinical and laboratory data were obtained; with this information diagnosis of IA was classified as possible, probable, and proven, according to the EORTC/MSG guidelines. This protocol was approved by the hospital’s research and ethics committees (INP 041/2021). For data analysis categorical variables were presented as frequencies and numerical variables as median and range. Statistical analysis was made with X2 and U Mann Whitney tests. Results Seventy events were included, 14 (20%) had IA diagnosis; 2 possible, 11 probable and 1 proved. Median of age was 10.2y (5.5 – 17) and 64.3% were male. Acute lymphoblastic leukemia was the main oncologic diagnosis (71.4%), 35.7% during induction phase; followed by acute myeloblastic leukemia (21.4%). 92.9% of events with IA presented as PFN (p=0.001) with a fever duration of 3.5 days (1-8) (p=0.004). Pulmonary disease was evident in all events with IA, two had disseminated infection. In 5/14 events serum galactomannan antigen was positive in the first measurement. Only 8 events underwent bronchoscopy: BAL was positive in 6 and 4 had positive culture with Aspergillus spp. Lung CT scan showed different findings, lobar/segmental consolidation and nodule with halo sign were the most common; 85.7% of cases presented with more than one radiological sign (p=0.003). Voriconazole monotherapy was given to 78.5% of IA cases and 21.4% required combined antifungal therapy (added caspofungine or liposomal amphotericin B) due to disseminated disease or severe clinical course. Intensive care admission resulted with statistical significance for the events with diagnosis of IA (64.3% p= 0.019). Within the IA events survival at 60 days was of 78.6%. Conclusion Frequency of IA was high among our high risk cancer patients. This study demonstrates the importance of a complete work up for invasive fungal infection in high-risk patients with persistent febrile neutropenia. The information obtained is of great use for the implementation of pre-emptive approaches and antifungal prophylaxis in this patient population.

Invasive fungal disease in patients with cancer in a tertiary care pediatric hospital

Abstract Background In the last two decades, the raise in invasive fungal diseases (IFD) has been associated with increased morbidity and mortality in immunosuppressed hosts. Its incidence varies between 2 to 21% and depends on the host´s underlying disease, the intensity of immunosuppressive treatment and the presence of comorbidities. The aim of this study is to describe the epidemiological, clinical and microbiological characteristics of IFD in patients with hematology-oncology disease. Methods Retrospective, descriptive study. Patients under 18 years of age with acute leukemias, lymphomas and solid tumors with a diagnosis of proven IFD (according to EORTC-MSG 2019 criteria) were included during the period from January 2020 to November 2023 in a tertiary care pediatric hospital. Results During the study period, 304 patients were under follow-up. 14 episodes of proven IFD were identified in 13 patients.The median age was 120 months. Male sex predominated (69.2%). The recognized factors associated were neutropenia (69.2%), use of corticosteroids in the last 3 months (61.5%) and use of previous antibiotics (92.3%). The most common underlying disease was Acute Lymphoblastic Leukemia (ALL) in 11 cases (78.5%), of which 3 were in relapse. The 21.4% of the episodes occurred in solid tumors (1 osteosarcoma of the tibia, 1 abdominal germ cell tumor, 1 neuroblastoma). Patients receiving primary prophylaxis for filamentous fungi were 3/14 (21.4%), according to the European Conference on Infections in Leukemia (ECIL-8). All received voriconazole. The fungal isolates identified were: 1 Rhizopus spp. (eye biopsy, paranasal sinuses) 1 Penicillum spp. (lung biopsy), 1 Exserohilum rostratum (skin biopsy), 1 Trichophyton asahii (blood cultures), 1 Purpuracillum lilacinus (skin biopsy), 1 Aspergillus fumigatus (Bronchoalveolar lavage, BAL),: 3 Candida parapsilosis (blood cultures), 1 Candida tropicalis (blood cultures), 1 Candida spp (blood cultures), 1 Malassezia (BAL). The patients with invasive molds infections were six, all of them with pathological chest tomography. Galactomannans (GM) were positive in 66% (4/6). BAL with positive GM was performed in 2 of them. The primary focus were: cutaneous (3/6), pulmonary (2/6) and orbital-rhinosinusal (1/6). Regarding IFD due to yeast fungi: all Candida infections were associated with central venous catheters fungemia. Malassezia infection presented with pulmonary involvement. Fungal co-infection was observed in 1 patient with documentation of Aspergillus fumigatus in BAL and Candida tropicalis in blood and urine cultures. Empirical antifungal therapy was liposomal amphotericin in 76.9 % of the patients. Two patients died (15.4%) at 30 days of follow-up. Conclusion Early diagnosis and timely antifungal therapy represent the main strategies to increase the survival of patients with IFD. Antifungal prophylaxis is postulated as an effective prevention measure and its indication should be defined according to the patient’s characteristics and the incidence of IFD at the treating center. We consider that patients with suspected IFD and clinical focus should undergo the corresponding tissue biopsy for culture, histological evaluation, and molecular biology, to direct the appropriate treatment. Candida species represent the most frequent isolates, however, Aspergillus and Rhizopus infections are associated with higher morbidity and mortality.

Chronic Disseminated Candidiasis among Pediatric Cancer Patients: The Hidden Threat

Abstract Background Chronic disseminated Candidiasis (CDC) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukemia treated with intensive chemotherapy. Clinical manifestations include persistent fever under broad-spectrum antibiotics and abdominal discomfort. HSC is characterized by the presence of nodular lesions in the liver, spleen, and other organs (lungs, kidneys, and skin) on radiological imaging. Methods The retrospective study was conducted from 2013 - 2022 including all pediatric hematological patients diagnosed with chronic disseminated candidiasis admitted and treated in Children’s Cancer Hospital Egypt (CCHE). Data included primary diagnosis, clinical presentation, microbiological, radiological, and treatment data. Results Three hundred fifty (350) pediatric cancer patients were diagnosed with candidemia. The median age was four years (4 months- 18 years). Chronic dissemination candidiasis (CDC) was reported in 30(9%) of our patients. The most affected organs were Liver (19 patients), spleen (13), renal (13), cautelous (13), brain (2) and retina (2). Candida tropicalis was the most common isolated spp. from blood/tissue culture (24 patients) followed by C. parapsilosis (3 patients). The primary diagnosis in patients with CDC was ALL (24 Patients) while (4 patients) has AML. CDC was developed on top of antifungal prophylaxis in 7 patients (24%): liposomal-amho B (3 patients), Micafungin (3 patients) and voriconazole (1 patient). Candida tropicalis was the most common isolated spp. from blood/tissue culture (80%). Steroid as treatment for CDC immune reconstitution syndrome done in around 50% of patients (Persistent fever with neutrophil recovery, absent progressive clinical/radiological findings). PET-CT was done in 10 patients with positive uptake in all cases, was helpful in resuming intensive chemotherapy in six patients despite persistent lesions in CT and was used to stop antifungal treatment despite positive radiological lesions in CT in three patients. The first line of treatment was echinocandin (53%) and liposomal ampho-B (46%) with overall mortality among CDC patients were 30%. Conclusion CDC is still a hidden threat among pediatric patients with still high mortality rate. Antifungal stewardship through screening and Rapid diagnosis using non-culture diagnostics are needed. PET scan is a helpful tool for diagnosis and response assessment and can add to treatment decision. Figure 1. Chronic Disseminated Candidiasis among Pediatric Cancer patients.

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

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

Clinical Characteristics and Risk Factors for Cryptococcal Meningitis in Diverse Patient Populations in New York City.

Cryptococcal meningitis (CM) is responsible for 15%-20% of human immunodeficiency virus (HIV)-associated mortalities. CM prevalence has also increased in other immunocompromised populations of transplant recipients, patients with cancer, and individuals on immunomodulatory medication. This retrospective review included 51 definitive patients with CM hospitalized at a tertiary academic medical center in New York City between 2010 and 2023. We assessed clinical features and outcomes of CM, with additional analysis of factors related to antiretroviral therapy (ART) adherence in HIV-infected cases and immunomodulatory medication history of HIV-negative cases. The cohort had a mean (standard deviation) age of 47.1 ± 15.1 years, and was predominantly male (37, 72.5%). Of 32 patients with HIV, 3 (9.4%) were newly diagnosed with HIV at the time of CM hospitalization, 5 (15.6%) had recurrent CM, and 2 (6.3%) had a CM relapse. The majority (30, 93.8%) of patients with HIV were ART nonadherent. Of 19 HIV-negative patients, 8 (42.1%) were solid-organ transplant recipients, 5 (26.3%) had autoimmune conditions of sarcoidosis or systemic lupus erythematosus, and 3 (15.8%) had chronic lymphocytic leukemia. Six (11.8%) patients died during hospitalization, 4 of whom had HIV. The burden of CM in people with HIV and immunocompromised patients continues even in settings with accessible standard antifungal treatment though interventions of increased ART adherence for those with HIV and antifungal prophylaxis may improve morbidity and mortality.

Diagnostic Value of Serum Biomarkers for Invasive Aspergillosis in Haematologic Patients.

Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancies. Accurate diagnosis of IA is challenging due to non-specific symptoms and the impact of antifungal prophylaxis on biomarker sensitivity. This retrospective study evaluated the diagnostic performance of three serum biomarkers: Aspergillus Galactomannan Ag VirClia Monotest® (VirClia), Wako β-D-Glucan Test® (Wako BDG), and MycoGENIE Real-Time PCR® (MycoGENIE PCR). True positives were defined as patients with proven or probable IA (n = 14), with a positive Platelia Aspergillus Antigen® (Platelia) serving as a mycological criterion. True negatives were identified as patients with a positive Platelia assay but classified as non-probable IA (n = 10) and outpatients who consistently tested negative with the Platelia test throughout the study period (n = 20). Most patients diagnosed with proven or probable IA were acute myeloid leukaemia or myelodysplastic syndrome patients receiving mould-active antifungal prophylaxis or treatment (71%). VirClia demonstrated high sensitivity (100%) for detecting IA, with a specificity of 83%. Wako BDG and MycoGENIE PCR showed lower sensitivities for IA (57% and 64%, respectively). MycoGENIE PCR detected Aspergillus spp. and Mucorales in two patients. Accurate diagnosis of IA remains challenging, especially in patients who have received mould-active antifungal treatment. VirClia showed comparable performance to Platelia, suggesting its potential for routine use. However, Wako BDG and MycoGENIE PCR results were less favourable in our study cohort. Nevertheless, MycoGENIE PCR detected two probable co-infections with Aspergillus spp. and Mucorales.

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

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

Bridging Echinocandin With Azole Antifungal Therapy on Prevention of Invasive Candidiasis Post-Lung Transplantation.

Invasive candidiasis (IC) is a significant factor for lung transplant recipient (LTR) mortality, especially in the immediate postoperative phase. Receipt of antifungal prophylaxis has demonstrated lower all-cause mortality. This was a single-center, retrospective cohort study of LTRs between August 2017 and August 2020. Included patients were adult LTRs with positive Candida cultures preoperatively (donor or recipient) or within 6 weeks postoperatively. Patients were divided into 2 cohorts-bridged and unbridged. The bridged cohort received micafungin in the postoperative period until therapeutic azole concentrations were achieved or up to 2 weeks, whichever was sooner. The primary outcome was a composite of proven or probable invasive candidiasis. A total of 117 patients were included in the study, with 68 in the unbridged cohort and 49 in the bridged cohort. There were more cases of IC in the bridged cohort than in the unbridged cohort (P = .011). In combination with an azole antifungal, micafungin did not prevent IC in postoperative LTRs with cultures positive for Candida species in this cohort. Larger prospective studies are needed to determine the ideal combination and duration of antifungal prophylaxis.

The Road Ahead: Advancing Antifungal Vaccines and Addressing Fungal Infections in the Post-COVID World.

In impoverished nations, the COVID-19 pandemic has led to a widespread occurrence of deadly fungal diseases like mucormycosis. The limited availability of effective antifungal treatments and the emergence of drug-resistant fungal strains further exacerbate the situation. Factors such as systemic steroid use, intravenous drug misuse, and overutilization of broad-spectrum antimicrobials contribute to the prevalence of hospital-acquired infections caused by drug-resistant fungi. Fungal infections exploit compromised immune status and employ intricate mechanisms to evade immune surveillance. The immune response involves the innate and adaptive immune systems, leading to phagocytic and complement-mediated elimination of fungi. However, resistance to antifungals poses a challenge, highlighting the importance of antifungal prophylaxis and therapeutic vaccination. Understanding the host-fungal immunological interactions and developing vaccines are vital in combating fungal infections. Further research is needed to address the high mortality and morbidity associated with multidrug-resistant fungal pathogens and to develop innovative treatment drugs and vaccines. This review focuses on the global epidemiological burden of fungal infections, host-fungal immunological interactions, recent advancements in vaccine development and the road ahead.

Diagnostic and Therapeutic Challenge Caused by Candida albicans and Aspergillus spp. Infections in a Pediatric Patient as a Complication of Acute Lymphoblastic Leukemia Treatment: A Case Report and Literature Review.

Fungal infections constitute a significant challenge and continue to be a predominant cause of treatment failure in pediatric leukemia cases. Despite the implementation of antifungal prophylaxis, these infections contribute to approximately 20% of cases in children undergoing treatment for acute lymphoblastic leukemia (ALL). The aim of this study is to highlight the diagnostic and therapeutic challenges associated with invasive fungal infections (IFIs). We also present a review of the epidemiology, risk factors, treatment, and a clinical presentation of IFI in patients with ALL. This case report details the clinical course of confirmed Candida albicans (C. albicans) and Aspergillus spp. infections during the consolidation phase of ALL treatment in a 5-year-old pediatric patient. This male patient did not experience any complications until Day 28 of protocol II. Then, the patient's condition deteriorated. Blood culture detected the growth of C. albicans. Despite the implementation of targeted therapy, the boy's condition did not show improvement. The appearance of respiratory symptoms necessitated a computed tomography (CT) of the chest, which revealed multiple nodular densities atypical for C. albicans etiology. In spite of ongoing antifungal treatment, the lesions depicted in the CT scans showed no regression. A lung biopsy ultimately identified Aspergillus species as the source of the infection. Overcoming fungal infections poses a considerable challenge; therefore, an accurate diagnosis and the prompt initiation of targeted therapy are crucial in managing these infections in patients with leukemia.

Inborn errors of immunity and invasive fungal infections: presentation and management.

We review the clinical presentations of invasive fungal infections in a selection of inborn errors of immunity. In addition, we review the particularities of their management, including antifungal therapy, prophylaxis, and immunomodulatory treatments. Patients with chronic granulomatous disease and with signal transducer and activator of transcription 3 (STAT3) deficiency are particularly prone to aspergillosis. Mold-active antifungal prophylaxis should be prescribed to all patients with chronic granulomatous disease, and in patients with STAT3 deficiency and underlying parenchymal lung disease. Invasive fungal infections are rare in patients with STAT1 gain-of-function mutations, while the clinical phenotype of caspase-associated recruitment domain-containing protein 9 deficiency encompasses a wide range of superficial and invasive fungal infections. Most patients with inborn errors of immunity and invasive fungal infections require prolonged durations of antifungals. Hematopoietic stem cell transplantation should be considered early for patients with chronic granulomatous disease, but results have been more mixed for other inborn errors of immunity with active invasive fungal infections. Inborn errors of immunity can confer increased susceptibility to a variety of invasive fungal infections, which can present with specific clinical and radiological features. Management of fungal infections in these patients is often challenging, and relies on a combination of antimicrobial prophylaxis, antifungal treatments, and immunomodulation.

Primary antifungal prophylaxis after haematopoietic stem cell transplantation: will the search for perfection become the enemy of good?

Primary antifungal prophylaxis after haematopoietic stem cell transplantation: will the search for perfection become the enemy of good?

Risk Factors and Outcomes of Mucorales Infection in a Modern Cohort of Solid Organ Transplant, Hematopoietic Cell Transplant, and Chimeric Antigen Receptor T-cell Therapy Recipients

Mucorales infections continue to cause significant morbidity and mortality in immunocompromised hosts despite the advent of new approaches for diagnosis and treatment of fungal infections. We aimed to evaluate risk factors and outcomes of Mucorales infection in solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell therapy recipients. This single-center retrospective study included solid organ transplant, hematopoietic cell transplant, and chimeric antigen receptor T-cell patients with cultures positive for Mucorales. Forty-three patients were included for analysis; 34 solid organ transplant (79%) and 9 hematopoietic stem cell transplant or chimeric antigen receptor T-cell (21%). Infection with Mucorales occurred a median of 184 days after transplant. At the time of diagnosis, 36 patients were on antifungal prophylaxis with the majority receiving posaconazole (53%). Thirty-three had clinically significant disease; 30 received definitive anti-Mucorales therapy and 3 empiric antifungal therapy. Isavuconazole was the most common azole used for treatment in monotherapy recipients. All-cause mortality was 64% and, of these deaths, 18 (75%) were directly related to Mucormycosis. The highest mortality was seen in disseminated and intra-abdominal disease (100%), followed by pulmonary disease (50%). There was no significant association with mortality and transplant type or number of immunosuppressive agents. Mucormycosis is an important cause of morbidity and mortality in immunocompromised patients. Breakthrough infection was not uncommon in this study. Data regarding the incidence of infection at approximately 6 months after transplantation can inform prophylaxis and treatment regimens. The spectrum of antifungal regimens used reflects the lack of consensus on ideal regimens for these organisms and a need for more studies.

Concurrent versus sequential or no triazole anti-fungal therapy in patients undergoing 7 + 3 plus midostaurin induction for FLT-3 acute myelogenous leukemia.

Midostaurin is a multikinase inhibitor approved for the treatment of adult patients with newly diagnosed FMS-like tyrosine kinase 3 mutated (FLT3m) acute myeloid leukemia (AML). Azole antifungal medications are commonly used in AML and are known to interact with anti-cancer drugs such as midostaurin through the CYP3A pathway. However, there are no midostaurin related dose modifications recommended with strong CYP3A inhibitors. We retrospectively reviewed 40 patients between 2017-2022 and compared efficacy and safety outcomes in patients who received azole antifungals concurrently to those who did not receive an azole or received it sequentially to midostaurin for treatment of FLT3m AML. Median age of both groups was approximately 55 years and 70% of patients harbored FLT-3 internal tandem duplication mutations. Most patients in the concurrent arm were on either posaconazole (33%) or isavuconazole (50%) for antifungal prophylaxis and micafungin (72%) for the sequential/no azole arm. Overall CR/CRi rate with concurrent versus sequential/no azole were 72% and 77%, and non-hematologic grade 3 toxicities were 22% and 40% (p = 0.21), respectively. Rates of dose reductions (6% vs. 0%, p = 0.26) and held doses (17% vs. 14%, p = 0.79) were not different between concurrent and sequential/no azole. There were no differences in the rates of new fungal infection during induction between the two groups. Azoles given concurrently or sequentially with midostaurin were found to be equally safe and effective in the treatment of newly diagnosed FLT3 AML. Additional confirmatory studies are needed due to our limited sample size.

A Retrospective Evaluation of the Treatment Effects of Rituximab in Patients with Progressive and Symptomatic Fibrosing Mediastinitis.

Fibrosing mediastinitis is an uncommon fibro-inflammatory condition without established or effective medical therapies. Infiltrating B-lymphocytes are commonly present, and progressive fibrosis compromises mediastinal structures including blood vessels and airways resulting in significant morbidity and mortality. To evaluate the benefits and side effects of Rituximab in patients with progressive and symptomatic fibrosing mediastinitis. We treated 22 patients (median age 35 years, range: 15-68 years, 45% female) with metabolically active, progressive fibrosing mediastinitis with off-label rituximab. Additionally, patients were put on pneumocystis and antifungal prophylaxis when immunosuppressed with rituximab. Modeling of longitudinal treatment response based on changes in relative lesion volume from baseline was performed retrospectively using functional data analysis; time-to-event modeling was performed to estimate treatment response rates based on a >30% reduction in pre-treatment volume. The primary end points were lack of disease progression and change in mediastinal lesion volume by CT (evaluated retrospectively). No patient experienced disease progression after rituximab therapy. Median clinical follow-up was 42 months (range: 7 to 94) and imaging follow-up 21 months (range: 7 to 62). 82% of patients had confirmed histoplasmosis-associated fibrosing mediastinitis. After rituximab treatment a 49.6% (95% CI = [17.5%, 64.4%]) mean estimated decrease in pre-treatment lesion volume was observed at 24 months. The estimated objective treatment response rate was 47.9% (95% CI = [26.7%, 70.3%]). This observational study suggests that Rituximab is well tolerated and potentially effective therapy in a cohort of patients with symptomatic and progressive FM.

Invasive Candida Infections in Neonatal Intensive Care Units: Risk Factors and New Insights in Prevention.

Invasive Candida infections represent a significant cause of morbidity and mortality in neonatal intensive care units (NICUs), with a particular impact on preterm and low-birth-weight neonates. In addition to prematurity, several predisposing factors for Candida colonization and dissemination during NICU hospitalization have been identified, including prolonged exposure to broad-spectrum antibiotics, central venous catheters, parenteral nutrition, corticosteroids, H2 antagonist administration, and poor adherence to infection control measures. According to the literature, the implementation of antifungal prophylaxis, mainly fluconazole, in high-risk populations has proven to be an effective strategy in reducing the incidence of fungal infections. This review aims to provide an overview of risk factors for invasive Candida infections and current perspectives regarding antifungal prophylaxis use. Recognizing and reducing people's exposure to these modifiable risk factors, in conjunction with the administration of antifungal prophylaxis, has been demonstrated to be an effective method for preventing invasive candidiasis in susceptible neonatal populations.

Antifungal heteroresistance causes prophylaxis failure and facilitates breakthrough Candida parapsilosis infections.

Breakthrough fungal infections in patients on antimicrobial prophylaxis during allogeneic hematopoietic cell transplantation (allo-HCT) represent a major and often unexplained cause of morbidity and mortality. Candida parapsilosis is a common cause of invasive candidiasis and has been classified as a high-priority fungal pathogen by the World Health Organization. In high-risk allo-HCT recipients on micafungin prophylaxis, we show that heteroresistance (the presence of a phenotypically unstable, low-frequency subpopulation of resistant cells (~1 in 10,000)) underlies breakthrough bloodstream infections by C. parapsilosis. By analyzing 219 clinical isolates from North America, Europe and Asia, we demonstrate widespread micafungin heteroresistance in C. parapsilosis. Standard antimicrobial susceptibility tests, such as broth microdilution or gradient diffusion assays, which guide drug selection for invasive infections, fail to detect micafungin heteroresistance in C. parapsilosis. To facilitate rapid detection of micafungin heteroresistance in C. parapsilosis, we constructed a predictive machine learning framework that classifies isolates as heteroresistant or susceptible using a maximum of ten genomic features. These results connect heteroresistance to unexplained antifungal prophylaxis failure in allo-HCT recipients and demonstrate a proof-of-principle diagnostic approach with the potential to guide clinical decisions and improve patient care.