scholarly journals Efficacy of Rezafungin in Prophylactic Mouse Models of Invasive Candidiasis, Aspergillosis, and Pneumocystis Pneumonia

2020 ◽  
pp. AAC.01992-20
Author(s):  
Lynn Miesel ◽  
Melanie T. Cushion ◽  
Alan Ashbaugh ◽  
Santiago R. Lopez ◽  
Voon Ong
Keyword(s):  
Mouse Models ◽  
Invasive Candidiasis ◽  
Opportunistic Infections ◽  
Single Agent ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Pneumocystis Jirovecii ◽  
Drug Concentrations

Antifungal prophylaxis is recommended to prevent invasive fungal disease caused by Candida spp., Aspergillus spp., and Pneumocystis jirovecii in patients at risk for opportunistic infections, such as allogeneic blood or marrow transplant recipients, patients with hematological disease undergoing chemotherapy, or patients on immunosuppressive therapies. Current approaches to antifungal prophylaxis require multiple agents to cover these key fungi. Rezafungin, a novel echinocandin designed for next-generation properties (e.g., greater stability and long-acting pharmacokinetics for once-weekly dosing), has demonstrated in vitro activity against Candida and Aspergillus spp. and efficacy against Pneumocystis spp. biofilms. Rezafungin was evaluated in in vivo studies of prophylactic efficacy using immunosuppressed mouse models of invasive candidiasis, aspergillosis, and Pneumocystis pneumonia. Rezafungin reduction of Candida CFU burden was generally greater with increasing drug concentrations (5, 10, or 20 mg/kg) and when rezafungin was administered closer to the time of fungal challenge (Days –1,–3, or–5). Similarly, in the aspergillosis model, survival rates increased with drug concentrations and when rezafungin was administered closer to the time of fungal challenge. Against P. murina, rezafungin significantly reduced trophic nuclei and asci counts at all doses tested. Rezafungin prevented infection at the 2 higher doses when compared with vehicle and had comparable activity to the active control trimethoprim-sulfamethoxazole at human equivalent doses for prevention. These findings support Phase 3 development of rezafungin and the potential for single-agent prophylaxis against invasive fungal disease caused by Candida spp., Aspergillus spp., and Pneumocystis jirovecii.

scholarly journals A National Strategy to Diagnose Coronavirus Disease 2019–Associated Invasive Fungal Disease in the Intensive Care Unit

2020 ◽  
Author(s):  
P Lewis White ◽  
Rishi Dhillon ◽  
Alan Cordey ◽  
Harriet Hughes ◽  
Federica Faggian ◽  
...  
Keyword(s):  
Risk Factors ◽  
Intensive Care ◽  
Mortality Rate ◽  
Respiratory Distress ◽  
Antifungal Therapy ◽  
Invasive Fungal Disease ◽  
Chronic Respiratory Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Severe Respiratory Distress

Abstract Background Fungal coinfection is a recognized complication of respiratory virus infections, increasing morbidity and mortality, but can be readily treated if diagnosed early. An increasing number of small studies describing aspergillosis in coronavirus disease 2019 (COVID-19) patients with severe respiratory distress are being reported, but comprehensive data are lacking. The aim of this study was to determine the incidence, risk factors, and impact of invasive fungal disease in adult COVID-19 patients with severe respiratory distress. Methods An evaluation of a national, multicenter, prospective cohort evaluation of an enhanced testing strategy to diagnose invasive fungal disease in COVID-19 intensive care patients. Results were used to generate a mechanism to define aspergillosis in future COVID-19 patients. Results One-hundred and thirty-five adults (median age: 57, M/F: 2.2/1) were screened. The incidence was 26.7% (14.1% aspergillosis, 12.6% yeast infections). The overall mortality rate was 38%; 53% and 31% in patients with and without fungal disease, respectively (P = .0387). The mortality rate was reduced by the use of antifungal therapy (mortality: 38.5% in patients receiving therapy vs 90% in patients not receiving therapy (P = .008). The use of corticosteroids (P = .007) and history of chronic respiratory disease (P = .05) increased the likelihood of aspergillosis. Conclusions Fungal disease occurs frequently in critically ill, mechanically ventilated COVID-19 patients. The survival benefit observed in patients receiving antifungal therapy implies that the proposed diagnostic and defining criteria are appropriate. Screening using a strategic diagnostic approach and antifungal prophylaxis of patients with risk factors will likely enhance the management of COVID-19 patients.

scholarly journals Invasive Fungal Disease in Patients with Newly Diagnosed Acute Myeloid Leukemia

2021 ◽  
Vol 7 (9) ◽  
pp. 761
Author(s):  
Anastasia I. Wasylyshyn ◽  
Kathleen A. Linder ◽  
Carol A. Kauffman ◽  
Blair J. Richards ◽  
Stephen M. Maurer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Proportional Hazards ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

This single-center retrospective study of invasive fungal disease (IFD) enrolled 251 adult patients undergoing induction chemotherapy for newly diagnosed acute myeloid leukemia (AML) from 2014–2019. Patients had primary AML (n = 148, 59%); antecedent myelodysplastic syndrome (n = 76, 30%), or secondary AML (n = 27, 11%). Seventy-five patients (30%) received an allogeneic hematopoietic cell transplant within the first year after induction chemotherapy. Proven/probable IFD occurred in 17 patients (7%). Twelve of the 17 (71%) were mold infections, including aspergillosis (n = 6), fusariosis (n = 3), and mucomycosis (n = 3). Eight breakthrough IFD (B-IFD), seven of which were due to molds, occurred in patients taking antifungal prophylaxis. Patients with proven/probable IFD had a significantly greater number of cumulative neutropenic days than those without an IFD, HR = 1.038 (95% CI 1.018–1.059), p = 0.0001. By cause-specific proportional hazards regression, the risk for IFD increased by 3.8% for each day of neutropenia per 100 days of follow up. Relapsed/refractory AML significantly increased the risk for IFD, HR = 7.562 (2.585–22.123), p = 0.0002, and Kaplan-Meier analysis showed significantly higher mortality at 1 year in patients who developed a proven/probable IFD, p = 0.02. IFD remains an important problem among patients with AML despite the use of antifungal prophylaxis, and development of IFD is associated with increased mortality in these patients.

DDRE-28. IDENTIFICATION OF SYNERGISTIC DRUG COMBINATIONS FOR THE THERAPY OF IDHmut GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi80-vi80
Author(s):  
Rolf Warta ◽  
Florian Stammler ◽  
Andreas Unterberg ◽  
Christel Herold-Mende
Keyword(s):  
Single Agent ◽  
Therapy Response ◽  
Drug Combinations ◽  
Drug Concentrations ◽  
Brain Barrier Permeability ◽  
Approved Drugs ◽  
Fda Approved Drugs ◽  
Biological Differences ◽  
Synergistic Drug Combinations

Abstract OBJECTIVE Isocitrate Dehydrogenase (IDH) mutation in glioma results in a multitude of biological differences with consequences for survival and therapy response. Therefore, IDH mutated (IDHmut) and wildtype (IDHwt) tumors are regarded as separate entities with the need for adjusted therapy like the combination of procarbazine, CCNU and vincristine (PCV). However, as vincristine has often severe side effects like neuropathy new effective therapy options are required. Therefore, we searched for combinations of FDA-approved drugs which effectively inhibit the growth of IDHmut cells in vitro. METHODS We tested different drug combinations of a drug library consisting of 146 FDA-approved drugs on two established IDHmut GSC lines. Based on a previous single agent drug screen, six drugs were selected (Idarubicin, Ixazumib, Ponatinib, Neratinib, Romidepsin) to be combined with all 146 drugs of the library. Cell viability was assessed by the CellTiterGlo 3D assay (Promega) in 96 well plates, while Caspase-Glo 3/7 3D assay was used to measure induction of apoptosis. RESULTS Out of 1460 drug combinations tested altogether 21 synergistic drug combinations could be identified and validated. The combination with the highest blood-brain-barrier permeability score was further investigated. Finally, drug-concentrations elucidating the highest synergistic effect on proliferation was further studied in a 8-point dose-response matrix followed by validation in additional four IDHmut GSC lines. CONCLUSION This work can lay the foundation for future improvements of the therapy of patients suffering from LGGs.

Fungal infections in neonates

2017 ◽  
Author(s):  
Adilia Warris
Keyword(s):  
Invasive Candidiasis ◽  
Neonatal Intensive Care ◽  
Fungal Infections ◽  
Invasive Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Extremely Low Birth Weight ◽  
Neonatal Intensive Care Units ◽  
Low Birth Weight Infants ◽  
Optimal Dosing ◽  
Neurodevelopmental Impairment

Fungal infections in the neonatal population are caused predominantly by Candida species and invasive fungal disease mainly affects extremely low birth weight infants. The vast majority of Candida infections are due to C. albicans and C. parapsilosis, while the more fluconazole-resistant Candida species are only sporadically observed. Invasive candidiasis typically occurs during the first month of life and presents with non-specific signs of sepsis. Despite antifungal treatment, 20% of neonates developing invasive candidiasis die and neurodevelopmental impairment occurs in nearly 60% of survivors. Antifungal prophylaxis reduces the incidence in neonatal intensive care units with high rates of invasive candidiasis (>10%). Amphotericin B, fluconazole, micafungin, and caspofungin can be used to treat neonatal candidiasis, although optimal dosing for fluconazole and the two echinocandins has not yet been established.

Rapamycin Enhances the Cytotoxicity of Bortezomib and Rituximab on Mantle Cell Lymphoma (MCL) Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2411-2411 ◽  
Author(s):  
Laila K. Ismail ◽  
Michael Timm ◽  
Anne Novak ◽  
Mary Stenson ◽  
Stephen M. Ansell ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Combination Index ◽  
Single Agent ◽  
In Vitro Studies ◽  
Fixed Dose ◽  
Effect Analysis ◽  
Bortezomib Treatment ◽  
Drug Concentrations

Abstract [Background]: MCL is an aggressive non-Hodgkin lymphoma (NHL) with a median survival of 3-4 years. New agents with mechanisms of action different than standard chemotherapy are needed to improve the outcome of MCL. Recent studies have documented single agent activity of bortezomib and rituximab in MCL. Analogs of rapamycin (temsirolimus) have also shown single agent activity in MCL (J Clin Oncol, June 27, 2005 epub). In order to provide rationale for a clinical trial combining rapamycin analogs with bortezomib or rituximab, we performed in vitro studies of the effect of combinations of these drugs on human MCL cell lines. [Methods]: Two human lymphoma cell lines - Granta 519 and M0258 - were incubated with various concentrations of rapamycin, bortezomib, and rituximab to determine the LD50 of each drug alone. For the experiments with rituximab a secondary goat anti-human (GAH) IgG Fc antibody was used to crosslink cell bound rituximab and induce cell killing. Percent viability was assessed after 48 hours using annexin/propidium iodide staining and flow cytometry. Tests for drug synergy used combinations of rapamycin and bortezomib and the Granta 519 cell line. Fixed ratios of the two drugs were tested and the results were evaluated for synergism (combination index <1 in median effect analysis) in inducing cell death. The drug concentrations used spanned the LD50 of each drug determined from the single-agent studies. In the studies combining rituximab with bortezomib or rapamycin, a single fixed dose of rituximab and GAH Fc was tested with various concentrations of the other drugs to detect additive anti-tumor effects. Studies were performed at least in triplicate. [Results]: All three drugs exhibited single-agent activity in vitro against the two cell lines. The LD50 for rapamycin ranged from 17.5 – 25 micromolar for the Granta 519 cell line and 7.5–10 micromolar for M0258. The LD50 for bortezomib ranged from 2–5 ng/ml in both cell lines. Incubation of the cells with various concentrations of rituximab and GAH Fc had mild cytotoxic activity (reduced viability to 50–70% compared to GAH Fc control). This activity was not concentration dependent indicating saturation of CD20 by rituximab; therefore, a fixed concentration of rituximab was used for the combination experiments. When rituximab was added to bortezemib the % viability decreased by up to 37% (compared to bortezomib alone), and the bortezomib LD50 typically decreased to <1–2 ng/ml (LD50 was 2–5 ng/ml with bortezomib alone). The addition of rapamycin to rituximab increased the cytotoxicity by 23% compared to either drug alone and decreased the rapamycin LD50. When rapamycin and bortezomib were combined as treatment of Granta 519 cells, rapamycin was synergistic with bortezomib with a combination index <1. Sequencing the rapamycin either before or after the bortezomib treatment did not effect synergy in either direction. [Conclusion]: In vitro, rapamycin synergizes with bortezomib to enhance its cytotoxicity in MCL lines. Rituximab enhances the cytotoxicity of both of rapamycin and bortezomib. These in vitro studies provide the rationale to test combinations of these active agents in patients with MCL.

scholarly journals Secondary Antifungal Prophylaxis in Hematological Malignancy Patients with Previous Invasive Fungal Disease: A Retrospective Analysis

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e115461 ◽  
Author(s):  
Mingjuan Liu ◽  
Yan Li ◽  
Yongqing Zhang ◽  
Xiaoli Zhao ◽  
Bing Zhai ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Hematological Malignancy ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis

scholarly journals Micafungin twice weekly as antifungal prophylaxis in paediatric patients at high risk for invasive fungal disease

2015 ◽  
Vol 70 (5) ◽  
pp. 1527-1530 ◽  
Author(s):  
K. Bochennek ◽  
A. Balan ◽  
L. Müller-Scholden ◽  
M. Becker ◽  
F. Farowski ◽  
...  
Keyword(s):  
High Risk ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Paediatric Patients

Incidence and outcome of invasive fungal disease after front-line intensive chemotherapy in patients with acute myeloid leukemia: impact of antifungal prophylaxis

2019 ◽  
Vol 98 (9) ◽  
pp. 2081-2088 ◽  
Author(s):  
Rebeca Rodríguez-Veiga ◽  
Pau Montesinos ◽  
Blanca Boluda ◽  
Ignacio Lorenzo ◽  
David Martínez-Cuadrón ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Intensive Chemotherapy ◽  
Front Line ◽  
Acute Myeloid

scholarly journals Invasive Fungal Disease Following Myeloablative Cord Blood Transplantation for Patients with Hematological Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5653-5653
Author(s):  
Duihong Li ◽  
Huang Jiafu ◽  
Xiaofan Li ◽  
Zheng Jing ◽  
Haiying Fu ◽  
...  
Keyword(s):  
Cord Blood ◽  
Incidence Rate ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Cord Blood Transplantation ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Antifungal Prophylaxis ◽  
Hematopoietic Stem ◽  
Blood Transplantation

Objective: Invasive fungal disease (IFD) is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited data is available on its clinical features after cord blood transplantation (CBT) for patients with hematological malignancies. Method: We retrospectively reviewed 63 patients who underwent myeloablative CBT at our institution between July 2013 and June 2019 with a median follow-up of 14 months. Micafungin, Voriconzole or Posaconazole was used for IFD prophylaxis. Results: Eight patients were identified as having an IFD, including 2 with proven IFD, 1 with probable IFD, and 5 with possible IFD. The most common prophylaxis regimen is micafungin (68.2%, 43/63). The incidence rate of IFD in the primary antifungal prophylaxis (PAP) and secondary antifungal prophylaxis (SAP) groups were 11.3% and 25% (P=0.488). The OS of day at +100, six months and +200 in the IFD and No IFD groups were 62.5% vs. 86.9% (P=0.1), 50 % vs.78.2% (P=0.07), and 50% vs.75.9% (P=0.094), respectively. The 3-year probabilities of overall survival (OS) in the IFD and No IFD groups were 50% and 60.5%, respectively (p=0.316). The incidence rate of Non-relapse Mortality in the IFD and No IFD groups were 42.9% and 30%, respectively (p=0.319). Conclusion: Antifungal prophylaxis could help to reduce the incidence of IFD after CBT for patients with hematological malignancies. Figure Disclosures No relevant conflicts of interest to declare.

A phase II study (NCI9775) of sapanisertib (MLN0128/TAK-228) in relapsed and/or refractory acute lymphoblastic leukemia (ALL): Interim analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18506-e18506 ◽  
Author(s):  
Aref Al-Kali ◽  
Ibrahim Aldoss ◽  
Carrie Strand ◽  
Bijal D. Shah ◽  
Jonathan Allen Webster ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Lymphoid Cells ◽  
Ecog Performance Status ◽  
Drug Concentrations ◽  
Treatment Naïve

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.

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