scholarly journals 1585. Isavuconazonium Sulfate plus Micafungin Improves Survival in an Immunocompromised Murine Model of Disseminated Fusariosis

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S578-S579
Author(s):  
Eleftheria Mavridou ◽  
Nura Al-Saddah ◽  
Konstantinos Mouskas ◽  
Ethan Naing ◽  
Rinat Abzalimov ◽  
...  
Keyword(s):  
Murine Model ◽  
Hematological Malignancies ◽  
Fusarium Spp ◽  
Successful Management ◽  
Antifungal Effect ◽  
Fungal Burden ◽  
Kaplan Meier ◽  
Invasive Mycosis ◽  
Excellent Safety Profile ◽  
High Doses

Abstract Background Disseminated fusariosis in patients with hematological malignancies is a frequently fatal and emerging invasive mycosis. Fusarium spp. are often resistant to safely achievable concentrations of mould active triazoles and amphotericin B. We aimed to determine the efficacy of isavuconazonium sulfate (ISA) alone or in combination with micafungin (MICA) in a murine model of disseminated fusariosis caused by Fusarium solani. Methods Groups of five 5-week-old Swiss Webster female mice, 20–22 g, were rendered neutropenic by intraperitoneal (IP) injection of cyclophosphamide at 200 mg/kg on day −2 and 150 mg/kg on day +3. Mice were infected with 5 × 10E5 CFU F. solani intravenously (IV) via the lateral tail vein on day 0. To prevent bacterial infection, ceftazidime was administered 50 mg/kg/day IP. Therapy began 18 h post-challenge for 6 days. MICA was given at dosages of 10, 5, 2.5 and 1.25 mg/kg IP Q12h combined with ISA 14 mg/kg/day IP. Six groups of mice received ISA orogastrically (OG) Q8h, Q12h and Q24h at 224 mg/kg alone or combined with MICA at 10 mg/kg Q12h IP. Kaplan–Meier survival analysis was performed. Results ISA at 14 mg/kg Q12h combined with 10 mg/kg MICA doses resulted in improved survival but with no significant reduction of residual fungal burden compared with monotherapy or other ISA/MICA dose combinations. Improved survival with dose-escalated oral monotherapy was observed at ISA 224 mg/kg Q12h (50% survival) and Q8h OG (60%) compared with other monotherapy or combination, or untreated groups (18–20%). The residual fungal burden in kidney between monotherapy and combination therapy groups was 5.81 10Log (untreated), 4.03 10Log (ISA 224 mg/kg, OG Q12h), 5.19 10Log (ISA 224 mg/kg Q12h + MICA 10 mg/kg, Q12h), 4.67 10Log (ISA 224 mg/kg, Q24h), and 4.82 10Log (ISA 224 mg/kg Q24h + MICA 10 mg/kg, Q12h). Conclusion High doses of isavuconazole (exceeding currently approved human dosages) in combination with micafungin improved survival in experimental murine disseminated fusariosis. Given the excellent safety profile of ISA, exploration of higher dosages that are necessary to achieve this antifungal effect is warranted for successful management of disseminated fusariosis. Disclosures All authors: No reported disclosures.

Impact of serial systemic infection on Candida albicans virulence factors

2020 ◽  
Vol 15 (13) ◽  
pp. 1249-1263
Author(s):  
Glaucia S Arita ◽  
Daniella R Faria ◽  
Karina M Sakita ◽  
Franciele AV Rodrigues-Vendramini ◽  
Isis RG Capoci ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Virulence Factors ◽  
Murine Model ◽  
Systemic Infection ◽  
Systemic Candidiasis ◽  
Fungal Burden ◽  
Histopathological Findings ◽  
Phenotypic Profile ◽  
Proteomic Data ◽  
Repeated Contact

Aim: To evaluate changes in virulence and pathogenicity approaches from Candida albicans after successive passages in a murine model of systemic candidiasis. Materials & methods: Phenotypic assays were performed using colonies recovered from animals infected serially, totalizing five passages. Results: A progressive infection was observed along the passages, with increased fungal burden and the presence of greater inflammatory areas in the histopathological findings. Recovered strains exhibited increased filamentation and biofilm abilities, along with modulation of phospholipase and proteinase activities. Conclusion: Repeated contact between yeast and host increased the expression of virulence factors. Furthermore, a correspondence between phenotypic profile and proteomic data obtained previously was observed.

scholarly journals 1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S411-S412
Author(s):  
Edward P Garvey ◽  
Andrew Sharp ◽  
Peter Warn ◽  
Christopher M Yates ◽  
Robert J Schotzinger
Keyword(s):  
Antifungal Activity ◽  
Invasive Aspergillosis ◽  
Murine Model ◽  
Pathogenic Fungi ◽  
Rational Drug Design ◽  
Fungal Burden ◽  
Delayed Treatment ◽  
Rational Drug

Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.

Perioperative dilemma: Challenges of the management of a patient on mega doses of morphine and methadone

2014 ◽  
Vol 10 (1) ◽  
pp. 69 ◽  
Author(s):  
Alan David Kaye, MD, PhD, DABA, DABPM, DABIPP ◽  
Aymen A. Alian, MD ◽  
Nalini Vadivelu, MD ◽  
Keun Sam Chung, MD
Keyword(s):  
Back Pain ◽  
Case Report ◽  
High Dose ◽  
Successful Management ◽  
Present Case Report ◽  
Opioid Induced Hyperalgesia ◽  
History Of ◽  
High Doses

High doses of opioids are often needed in the management of cancer-related pain. A discussion of a patient’s perioperative opioid management and mechanisms contributing to opioid-induced hyperalgesia (OIH) are presented. In the present case report, a patient on high doses of opioids, including morphine and methadone, with severe worsening back pain and a history of increasing opioid requirements for the last 2 months due to metastatic leiomyosarcoma to the femur, spine, and neck is described. Use of high dose opioids is associated with numerous challenges, including tolerance. The successful management of this patient was multimodal and included the use of potent analgesics, N-methyl-D-aspartatereceptor antagonists, and the α-2 agonist clonidine.

Effect of Epoetin beta on Survival, Tumor Progression and Thromboembolic Events in Patients with Lymphoid Malignancies Receiving Chemotherapy: A Meta-Analysis of Controlled Clinical Studies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3149-3149 ◽  
Author(s):  
Bertrand Coiffier ◽  
Marc Boogaerts ◽  
Anders Österborg ◽  
Hans-Ulrich Burger
Keyword(s):  
Tumor Progression ◽  
Disease Progression ◽  
Hematological Malignancies ◽  
Cox Regression ◽  
Meta Analysis ◽  
Control Group ◽  
Thromboembolic Events ◽  
Treatment Groups ◽  
Epoetin Beta ◽  
Kaplan Meier

Abstract BACKGROUND: Epoetin beta (NeoRecormon®) 30 000 IU/week raises hemoglobin levels, reduces transfusion need and improves quality of life in patients with cancer. Recent studies have also suggested that epoetin therapy may impact upon outcomes in these patients. A meta-analysis was performed to investigate the effects of epoetin beta on survival, tumor progression and thromboembolic events in patients with hematological malignancies receiving chemotherapy. METHODS: Data were pooled from all five randomized, controlled (placebo or standard care) clinical trials of epoetin beta that included anemic patients with hematological malignancies receiving chemotherapy. The study that showed epoetin beta once weekly to be as effective with the same safety profile as a three times weekly regimen was excluded from this analysis because of the lack of a non-epoetin-treated group. These studies were not designed to assess duration of survival and in all except one there was no follow-up beyond the duration of study treatment plus an additional 4-week period. Deaths reported during the study plus 4 weeks were therefore recorded in this analysis. All adverse event reports were assessed for evidence of disease progression or thromboembolism. Data were analyzed by standard Kaplan-Meier methods, Cox regression and log-rank tests. RESULTS: A total of 791 patients with hematological malignancies were included (epoetin beta, n=461; control, n=330) (the difference in number was due to two of the five studies containing multiple epoetin beta treatment groups versus one control group). The majority was diagnosed with lymphoma (56%) or multiple myeloma (42%); the remaining patients (2%) were diagnosed with acute myeloid leukemia. Treatment groups were well balanced with regard to baseline demographic characteristics. There were no obvious differences in baseline tumor stage between treatment groups, although these data were not consistently collected across studies. The median weekly dose of epoetin beta was 30 000 IU. Death rates were similar in both the epoetin beta and control groups (0.39 vs 0.37 deaths/patient year). There was no indication of a difference in survival with epoetin beta compared with control (relative risk 1.04, 95% CIs 0.69, 1.55, p=0.86). The rate of disease progression was lower in the epoetin beta group compared with the control group (0.69 vs 0.81 events/patient year). The results from Kaplan-Meier estimates and Cox regression did not indicate an increased risk of disease progression with epoetin beta compared with control (relative risk 0.84, 95% CIs 0.62, 1.13, p=0.25). In fact, the hazard rate of 0.84 indicated a 16% reduction in the risk of an event when treated with epoetin beta. Thromboembolic event rates were also similar in the epoetin beta and control groups (0.17 vs 0.14 events/patient year), corresponding to crude rates of 5.4% and 4.8% (observation times: 147 and 112 patient years). These event rates are well within the range of those reported in the literature. CONCLUSIONS: Epoetin beta has no effect on short-term survival, tumor progression or thromboembolic events when used to treat anemic patients with hematological malignancies, and the risk-to-benefit ratio of epoetin beta therapy remains favorable.

Methylation Analysis of the Wnt Antagonist in Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5048-5048
Author(s):  
Hongyan Tong ◽  
Chen Mei ◽  
Kongfei Li ◽  
Jie Jin
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Methylation Status ◽  
Wnt Signaling Pathway ◽  
Aberrant Methylation ◽  
Methylation Frequency ◽  
Kaplan Meier ◽  
Close Relationship

Abstract Abstract 5048 Background and Objectives: Myelodysplastic syndrome (MDS) is one of the most threatening hematological malignancies. Recently, the epigenetic changes have been recognized in the MDS, and some research found that the aberrant DNA methylation had close relationship with the MDS. Meanwhile, some studies showed that the activation of the Wnt signaling pathway and abnormal methylation of the Wnt antagonists had close relationship with hematological malignancies, such as AML AALL Aand CLL, but less is known in MDS. In our research, we studied the methylation status of Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) in the patients with MDS and evaluated the role of them in the pathogenesis and progression of MDS, with providing a new theory support for clarifying the complicated pathogenesis and progression of MDS. Methods: The methylation status of Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) in pretreatment bone marrow samples from 53 patients with MDS was measured by methylation-specific polymerase chain reaction (MSP). On the other hand, we collected the clinical materials of the patients with MDS and follow up the patients. Then the correlation between methylation and clinical features as well as prognosis of MDS patients was analyzed byχ2 test and Kaplan-Meier method. Results: In 53 bone marrow samples, the methylation frequencies of the Wnt antagonists were as follows: SFRP4 for 62.3 % (33/53), DKK1 for 45.3 % (24/53), HDPR1 for 34.0 % (18/53), SFRP1 for 15.1 % (8/53), DKK3 for 9.4 % (5/53), and WIF-1 for 5.7 % (3/53). After analyzing individual tumor suppressor gene, clinical parameters and prognostic information, it was found that the patients with the percentage of BM blast above 5% had higher methylation frequency of HDPR1 than the patients with the percentage of BM blast bellow 5% (44.4%∼a13.3%, P=0.034); besides, the methylation frequency of HDPR1 exhibited significant differences in the MDS subtypes (P=0.019), and was significantly correlated with the WPSS (P=0.037); In addition, Kaplan-Meier survival curve indicated that the mean overall survival of patients with methylation was significantly shorter than that of patients without HDPR1 methylation (457.3 days vs. 919.6 days, P=0.037) (Fig.1). Conclusion: The methylation of the Wnt antagonists (DKK1, DKK3, HDPR1, WIF-1, SFRP1 and SFRP4) were observed in patients with MDS and their methylation frequencies were different. The aberrant methylation of HDPR1 may play an important role in the progression and prognosis of MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Efficacies of Fluconazole, Caspofungin, and Amphotericin B in Candida glabrata-Infected p47phox−/− Knockout Mice

2002 ◽  
Vol 46 (5) ◽  
pp. 1240-1245 ◽  
Author(s):  
Justina Y. Ju ◽  
Cynthia Polhamus ◽  
Kieren A. Marr ◽  
Steven M. Holland ◽  
John E. Bennett
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Murine Model ◽  
Knockout Mice ◽  
Candida Glabrata ◽  
Drug Efficacy ◽  
Fungal Burden ◽  
Lethal Infection

ABSTRACT Candida glabrata is the second leading cause of adult candidemia, resulting in high mortality. Amphotericin B is considered the treatment of choice, while the efficacy of fluconazole is controversial and caspofungin efficacy is unknown. To ascertain drug efficacy in vivo, the utility of a murine model of C. glabrata infection was investigated. C. glabrata was found to cause progressive, lethal infection when injected intravenously into C57BL/6 mice with reduced oxidative microbicidal capacity due to knockout of the p47phox gene. Spleen and kidney organ CFU counts were determined in groups of mice 2 days after the mice completed 6 days of daily intraperitoneal drug treatment, which began on the day of infection. Daily injections of fluconazole at 80 mg/kg did not reduce spleen or kidney CFU counts after infection with C. glabrata strains having in vitro fluconazole MICs of 2, 32, or 256 μg/ml compared to saline-treated controls. However, this fluconazole regimen reduced spleen CFU counts in mice infected with Candida albicans, an infection that is known to be responsive to fluconazole. Caspofungin at 5 mg/kg and amphotericin B at 5 mg/kg were both effective in reducing fungal burden in spleens and kidneys of C. glabrata-infected mice. Ten mice treated for 6 days with caspofungin at 1 mg/kg survived for 15 days, though all 10 saline-injected mice died or were so ill that they had to be sacrificed by 96 h postinfection. This murine model provided evidence of the efficacy of amphotericin B and caspofungin but not of fluconazole against C. glabrata infection.

SURVIVAL TRENDS IN CHILDHOOD HEMATOLOGICAL MALIGNANCIES

2012 ◽  
Vol 05 (06) ◽  
pp. 1250053
Author(s):  
STEPHANIE RICH ◽  
SHIHAB ALI ◽  
GEOFFREY W. CALKINS ◽  
JAMES S. MICHAELSON
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Hematological Malignancies ◽  
Lymphoblastic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Medical Progress ◽  
Risk Of Death ◽  
The Past ◽  
Kaplan Meier ◽  
Time Period ◽  
Cause Specific Survival

Survival of patients with childhood hematological malignancies has increased markedly in the past decades. To examine the fine-scale details of how this progress has occurred, we carried out Kaplan–Meier cause-specific survival analysis using the Surveillance Epidemiology and End Results (SEER) dataset for patients with childhood hematological malignancies — Hodgkin's Lymphoma, Non-Hodgkin's Lymphoma, Lymphoblastic Leukemia and Myeloid Leukemia — diagnosed in five eras: 1983–1987; 1988–1992; 1993–1997; 1998–2002 and 2003–2007. We generated Kaplan–Meier estimates of survival for each of the first 24 years after diagnosis. These figures agree with previously reported five- and ten-year values and attest to the remarkable increase in survival that has occurred over the past three decades of medical progress. The trend towards progressively increasing survival shows no sign of slowing, suggesting that we may expect further increases in survival in the years ahead. Most of the increase in survival for childhood hematological malignancies has occurred by reducing the risk of death in the first two years after diagnosis. This may be largely explained by the fact that this is the time period when patients are at highest risk of death.

scholarly journals Anidulafungin Treatment of Candidal Central Nervous System Infection in a Murine Model

2009 ◽  
Vol 53 (8) ◽  
pp. 3576-3578 ◽  
Author(s):  
Cheol-In Kang ◽  
Mark S. Rouse ◽  
Jayawant N. Mandrekar ◽  
James M. Steckelberg ◽  
Robin Patel
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Candida Albicans ◽  
Brain Tissue ◽  
Amphotericin B ◽  
Murine Model ◽  
Potential Role ◽  
Central Nervous System Infection ◽  
Cns Infection ◽  
Fungal Burden

ABSTRACT We established a murine model of Candida albicans central nervous system (CNS) infection and evaluated the efficacy of anidulafungin. Ten milligrams/kg/day anidulafungin, amphotericin B, or voriconazole significantly reduced mortality and fungal burden in brain tissue, although amphotericin B and 10 mg/kg/day anidulafungin reduced fungal burden in brain tissue to a greater extent than did voriconazole. This suggests a potential role for anidulafungin in the treatment of candidal CNS infection.

scholarly journals 984. Diagnostic Utility of Bronchoalveolar Lavage Pneumocystis jirovecii DNA Polymerase Chain Reaction Assay in Patients with Hematological Malignancies and Hematopoietic Cell Transplantation

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S583-S583
Author(s):  
Deepa Nanayakkara ◽  
Bernard Tegtmeier ◽  
Justine Abella Ross ◽  
Jana Dickter ◽  
Alfredo Puing ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Bronchoalveolar Lavage ◽  
Cell Transplantation ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Pneumocystis Jirovecii ◽  
Chain Reaction ◽  
Fungal Burden ◽  
Polymerase Chain

Abstract Background Pneumocystis jirovecii, an ubiquitous fungus, can lead to opportunistic pneumonia (PJP) in patients with hematological malignancies (HM) and hematopoietic cell transplantation (HCT) with mild to severe presentation. Unlike patients with HIV, diagnosis of PJP pneumonia is often challenging in patients with HM/HCT possibly related to lower fungal burden versus atypical presentation. The gold standard for diagnosis of PJP from bronchoalveolar lavage fluid (BALF) is cytology, followed by direct fluorescent antigen (DFA), however, in the context of lower fungal burden, quantitative polymerase chain reaction (PCR) is increasingly used. PCR DNA load cut-off for diagnosis of PJP is not established. The objective of this study is to assess the correlation between three tests (cytology, DFA and PCR) and diagnosis of PJP (colonization, possible, probable or proven infection). Methods In this retrospective study at City of Hope, HM/HCT patients with BALF performed to investigate pneumonia who tested positive for any of the 3 tests were included. The study period is from July 2014 to July 2020. All patients had a clinical and radiographic diagnosis of pneumonia. Results Eighty-five patients were identified to have at least one positive diagnostic test for PJP. Twenty (23.5%) patients had a PCR with less than 84 copies/mL, and colonization was suspected in these patients. Of the remaining 65 patients, 46 had all 3 tests done. Twenty seven (58.7%) patients only had positive PCR ranging from 106 to 588,000 copies/mL with negative DFA and cytology. Twelve (26.1%) patients had either DFA or cytology positive with a positive PCR, and in 6 patients (13%) all 3 tests were positive. All of these 18 patients had clinical presentation and radiographic findings consistent with PJP. Quantitative or qualitative serum beta-D-glucan (BDG) level was available in 28 patients and 17 had a positive test with a level >80 pg/ml. Conclusion PJP PCR is a very sensitive test that can lead to early detection of PJP pneumonia in HM/HCT with lower sensitivity of DFA/cytology unless the fungal burden is high. However, the optimal cut off PCR value associated with disease needs to be clinically validated in our patient population and a concurrent serum BDG level can increase diagnostic yield. Disclosures All Authors: No reported disclosures

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