109 results on '"Marr, Kieren A"'
Search Results
2. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America.
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Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, and Bennett JE
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- Amphotericin B therapeutic use, Aspergillosis drug therapy, Aspergillosis epidemiology, Azoles therapeutic use, Echinocandins therapeutic use, Humans, Infectious Disease Medicine organization & administration, Societies, Medical, United States, Antifungal Agents therapeutic use, Aspergillosis diagnosis
- Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
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- 2016
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3. Executive Summary: Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America.
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Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Nguyen MH, Segal BH, Steinbach WJ, Stevens DA, Walsh TJ, Wingard JR, Young JA, and Bennett JE
- Subjects
- Amphotericin B therapeutic use, Aspergillosis drug therapy, Aspergillosis epidemiology, Azoles therapeutic use, Echinocandins therapeutic use, Humans, Infectious Disease Medicine organization & administration, Societies, Medical, United States, Antifungal Agents therapeutic use, Aspergillosis diagnosis, Practice Guidelines as Topic standards
- Abstract
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
- Published
- 2016
- Full Text
- View/download PDF
4. Combination antifungal therapy for invasive aspergillosis: a randomized trial.
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Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, Heinz WJ, Jagannatha S, Koh LP, Kontoyiannis DP, Lee DG, Nucci M, Pappas PG, Slavin MA, Queiroz-Telles F, Selleslag D, Walsh TJ, Wingard JR, and Maertens JA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Anidulafungin, Antifungal Agents adverse effects, Aspergillosis complications, Aspergillosis diagnosis, Aspergillosis mortality, Double-Blind Method, Drug Therapy, Combination, Echinocandins adverse effects, Female, Galactose analogs & derivatives, Hematologic Neoplasms therapy, Humans, Karnofsky Performance Status, Male, Mannans blood, Middle Aged, Platelet Count, Treatment Outcome, Voriconazole adverse effects, Young Adult, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Echinocandins therapeutic use, Hematologic Neoplasms complications, Hematopoietic Stem Cell Transplantation, Voriconazole therapeutic use
- Abstract
Background: Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy., Objective: To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA., Design: Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479)., Setting: 93 international sites., Patients: 454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed., Measurements: The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures., Results: Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, -8.2 percentage points [95% CI, -19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, -11.5 percentage points [CI, -22.7 to -0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different., Limitations: Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability., Conclusion: Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority., Primary Funding Source: Pfizer.
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- 2015
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5. Antifungal therapy and length of hospitalization in transplant patients with invasive aspergillosis.
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Baddley JW, Andes DR, Marr KA, Kauffman CA, Kontoyiannis DP, Ito JI, Schuster MG, Brizendine KD, Patterson TF, Lyon GM, Boeckh M, Oster RA, Chiller T, and Pappas PG
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- Adult, Aged, Aspergillosis microbiology, Aspergillosis mortality, Caspofungin, Cohort Studies, Demography, Drug Therapy, Combination, Female, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Infection Control, Length of Stay, Lipopeptides, Lung microbiology, Male, Middle Aged, Severity of Illness Index, Time Factors, Voriconazole, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillus drug effects, Echinocandins therapeutic use, Pyrimidines therapeutic use, Triazoles therapeutic use
- Abstract
The impact of antifungal therapy on economic outcomes in patients with invasive aspergillosis (IA) needs further exploration. The purpose of this study was to describe antifungal therapy and factors associated with hospital length of stay (LOS) in transplant patients with IA. Patients were enrolled from March 2001 to October 2005 and IA cases identified through March 2006 from a sub-group of patients in the Transplant Associated Infection Surveillance Network (TRANSNET). Factors associated with hospital LOS were determined by logistic regression analysis. Of 361 patients, the mean age was 49 years, 60.7% were male, and 63% were hematopoietic stem cell transplantation (HSCT) recipients. Primary monotherapy was used in 233 (64.5%) patients, of which voriconazole (93/233, 39.9%) was most commonly used antifungal. Primary combination therapy was used in 128 (35.4%) of 361 patients, with voriconazole plus caspofungin (81/361, 22.4%) the most frequently employed. Mean duration of therapy was 115 days (HSCT 109.7; solid organ transplant [SOT] 125.3). Mean hospital LOS was 35.3 days (HSCT 38.7; SOT 29.7). Regression analysis identified disseminated IA, neutropenia, malnutrition and length of ICU stay as factors associated with increased hospital LOS. Initial voriconazole use was associated with decreased LOS. Further investigation on impact of antifungal therapy on economic outcomes is needed.
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- 2013
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6. Clinical epidemiology of 960 patients with invasive aspergillosis from the PATH Alliance registry.
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Steinbach WJ, Marr KA, Anaissie EJ, Azie N, Quan SP, Meier-Kriesche HU, Apewokin S, and Horn DL
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- Adolescent, Adult, Aged, Antifungal Agents therapeutic use, Aspergillosis microbiology, Aspergillosis mortality, Aspergillus classification, Aspergillus isolation & purification, Female, Hematopoietic Stem Cell Transplantation, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Organ Transplantation statistics & numerical data, Prospective Studies, Registries, Aspergillosis epidemiology, Aspergillosis therapy
- Abstract
Objectives: The study investigated the epidemiology and outcome of invasive aspergillosis (IA), an important cause of morbidity and mortality in immunocompromised patients., Methods: Cases of proven/probable IA from the Prospective Antifungal Therapy Alliance (PATH Alliance(®)) registry - a prospective surveillance network comprising 25 centers in the United States and Canada that collected data on invasive fungal infections from 2004 to 2008 - were analyzed with respect to clinical outcome., Results: Nine hundred and sixty patients with IA were enrolled, the most frequent underlying disease being hematologic malignancy (n=464 [48.3%]). Two hundred and eighty patients (29.2%) received solid organ transplant; 268 patients (27.9%) underwent hematopoietic stem cell transplantation. Identified isolates included Aspergillus fumigatus (72.6%), Aspergillus flavus (9.9%), Aspergillus niger (8.7%) and Aspergillus terreus (4.3%). The lung was most frequently affected. Following diagnosis, 47% patients received monotherapy - voriconazole (70%), an amphotericin B formulation (13.8%), or an echinocandin (10.5%) - while 279 patients (29%) received combination therapy. Twelve-week overall survival was 64.4%., Conclusions: In this series of patients with IA, the lung was the predominant focus of infection, A. fumigatus was the major species isolated, and overall survival appeared slightly improved compared with previous reports., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)
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- 2012
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7. Invasive fungal infections in solid organ transplant recipients.
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Shoham S and Marr KA
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- Aspergillosis diagnosis, Aspergillosis drug therapy, Aspergillosis pathology, Candidiasis diagnosis, Candidiasis drug therapy, Candidiasis pathology, Cryptococcosis diagnosis, Cryptococcosis drug therapy, Cryptococcosis pathology, Fungemia diagnosis, Fungemia drug therapy, Fungemia pathology, Humans, Aspergillosis epidemiology, Candidiasis epidemiology, Cryptococcosis epidemiology, Fungemia epidemiology, Immunocompromised Host, Transplants adverse effects
- Abstract
Invasive fungal infections are a major problem in solid organ transplant (SOT) recipients. Overall, the most common fungal infection in SOT is candidiasis, followed by aspergillosis and cryptococcosis, except in lung transplant recipients, where aspergillosis is most common. Development of invasive disease hinges on the interplay between host factors (e.g., integrity of anatomical barriers, innate and acquired immunity) and fungal factors (e.g., exposure, virulence and resistance to prophylaxis). In this article, we describe the epidemiology and clinical features of the most common fungal infections in organ transplantation. Within this context, we review recent advances in diagnostic modalities and antifungal chemotherapy, and their impact on evolving prophylaxis and treatment paradigms.
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- 2012
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8. Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus and resultant pulmonary inflammation.
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Chaudhary N, Datta K, Askin FB, Staab JF, and Marr KA
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- Animals, Apoptosis, Bronchi metabolism, Bronchi microbiology, Cell Line, Cystic Fibrosis genetics, Cystic Fibrosis metabolism, Cystic Fibrosis Transmembrane Conductance Regulator deficiency, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cytokines metabolism, Epithelial Cells immunology, Epithelial Cells metabolism, Flow Cytometry, Immunity, Cellular, Inflammation etiology, Lung immunology, Lung metabolism, Lung microbiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Respiratory Mucosa metabolism, Trachea metabolism, Trachea microbiology, Aspergillosis metabolism, Aspergillus fumigatus physiology, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Epithelial Cells microbiology, Host-Pathogen Interactions, Respiratory Mucosa microbiology
- Abstract
Rationale: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) alter epithelial cell (EC) interactions with multiple microbes, such that dysregulated inflammation and injury occur with airway colonization in people with cystic fibrosis (CF). Aspergillus fumigatus frequently colonizes CF airways, but it has been assumed to be an innocent saprophyte; its potential role as a cause of lung disease is controversial., Objectives: To study the interactions between Aspergillus and EC, and the role of the fungus in evoking inflammatory responses., Methods: A. fumigatus expressing green fluorescent protein was developed for in vitro and in vivo models, which used cell lines and mouse tracheal EC., Measurements and Main Results: Fungal spores (conidia) are rapidly ingested by ECs derived from bronchial cell lines and murine tracheas, supporting a role for EC in early airway clearance. Bronchial ECs harboring CFTR mutations (ΔF508) or deletion demonstrate impaired uptake and killing of conidia, and ECs with CFTR mutation undergo more conidial-induced apoptosis. Germinated (hyphal) forms of the fungus evoke secretion of inflammatory mediators, with CFTR mutation resulting in increased airway levels of macrophage inflammatory protein 2 and KC, and higher lung monocyte chemotactic protein-1. After A. fumigatus inhalation, CFTR(-/-) mice develop exaggerated lymphocytic inflammation, mucin accumulation, and lung injury., Conclusions: Data demonstrate a critical role for CFTR in mediating EC responses to A. fumigatus. Results suggest that the fungus elicits aberrant pulmonary inflammation in the setting of CFTR mutation, supporting the potential role of antifungals to halt progressive CF lung disease.
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- 2012
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9. Detection of urinary excreted fungal galactomannan-like antigens for diagnosis of invasive aspergillosis.
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Dufresne SF, Datta K, Li X, Dadachova E, Staab JF, Patterson TF, Feldmesser M, and Marr KA
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- Animals, Antibodies, Monoclonal immunology, Antibody Specificity immunology, Antigens, Fungal immunology, Aspergillosis immunology, Aspergillosis urine, Aspergillus fumigatus immunology, Cross Reactions immunology, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Galactose analogs & derivatives, Humans, Mannans immunology, Mice, Antigens, Fungal urine, Aspergillosis diagnosis, Mannans urine
- Abstract
Mortality associated with invasive aspergillosis (IA) remains high, partly because of delayed diagnosis. Detection of microbial exoantigens, released in serum and other body fluids during infection, may help timely diagnosis. In course of IA, Aspergillus galactomannan (GM), a well established polysaccharide biomarker, is released in body fluids including urine. Urine is an abundant, safely collected specimen, well-suited for point-of-care (POC) testing, which could play an increasing role in screening for early disease. Our main objective was to demonstrate GM antigenuria as a clinically relevant biological phenomenon in IA and establish proof-of-concept that it could be translated to POC diagnosis. Utilizing a novel IgM monoclonal antibody (MAb476) that recognizes GM-like antigens from Aspergillus and other molds, we demonstrated antigenuria in an experimental animal IA model (guinea pig), as well as in human patients. In addition, we investigated the chemical nature of the urinary excreted antigen in human samples, characterized antigen detection in urine by immunoassays, described a putative assay inhibitor in urine, and indicated means of alleviation of the inhibition. We also designed and used a lateral flow immunochromatographic assay to detect urinary excreted antigen in a limited number of IA patient urine samples. In this study, we establish that POC diagnosis of IA based on urinary GM detection is feasible. Prospective studies will be necessary to establish the performance characteristics of an optimized device and define its optimal clinical use.
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- 2012
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10. In vitro echinocandin susceptibility of Aspergillus isolates from patients enrolled in the Transplant-Associated Infection Surveillance Network.
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Lockhart SR, Zimbeck AJ, Baddley JW, Marr KA, Andes DR, Walsh TJ, Kauffman CA, Kontoyiannis DP, Ito JI, Pappas PG, and Chiller T
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- Anidulafungin, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillus isolation & purification, Caspofungin, Drug Resistance, Fungal, Echinocandins therapeutic use, Humans, Micafungin, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Aspergillosis microbiology, Aspergillus drug effects, Echinocandins pharmacology, Lipopeptides pharmacology, Transplantation
- Abstract
We determined the echinocandin minimum effective concentration (MEC) values for caspofungin, micafungin, and anidulafungin against 288 Aspergillus isolates prospectively collected from transplant patients with proven or probable invasive aspergillosis between 2001 and 2006 as part of the Transplant-Associated Infection Surveillance Network (TRANSNET). We demonstrated that the vast majority of Aspergillus isolates had MEC values at or below the epidemiological cutoff values for caspofungin, micafungin, and anidulafungin, including those from patients who had received caspofungin.
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- 2011
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11. Factors associated with mortality in transplant patients with invasive aspergillosis.
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Baddley JW, Andes DR, Marr KA, Kontoyiannis DP, Alexander BD, Kauffman CA, Oster RA, Anaissie EJ, Walsh TJ, Schuster MG, Wingard JR, Patterson TF, Ito JI, Williams OD, Chiller T, and Pappas PG
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- Adult, Antifungal Agents therapeutic use, Aspergillosis complications, Aspergillosis drug therapy, Cohort Studies, Female, Humans, Male, Middle Aged, Postoperative Complications mortality, Risk Factors, Aspergillosis mortality, Hematopoietic Stem Cell Transplantation mortality, Organ Transplantation mortality
- Abstract
Background: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) and solid organ transplant (SOT) recipients. The purpose of this study was to evaluate factors associated with mortality in transplant patients with IA., Methods: Transplant patients from 23 US centers were enrolled from March 2001 to October 2005 as part of the Transplant Associated Infection Surveillance Network. IA cases were identified prospectively in this cohort through March 2006, and data were collected. Factors associated with 12-week all-cause mortality were determined by logistic regression analysis and Cox proportional hazards regression., Results: Six-hundred forty-two cases of proven or probable IA were evaluated, of which 317 (49.4%) died by the study endpoint. All-cause mortality was greater in HSCT patients (239 [57.5%] of 415) than in SOT patients (78 [34.4%] of 227; P<.001). Independent poor prognostic factors in HSCT patients were neutropenia, renal insufficiency, hepatic insufficiency, early-onset IA, proven IA, and methylprednisolone use. In contrast, white race was associated with decreased risk of death. Among SOT patients, hepatic insufficiency, malnutrition, and central nervous system disease were poor prognostic indicators, whereas prednisone use was associated with decreased risk of death. Among HSCT or SOT patients who received antifungal therapy, use of an amphotericin B preparation as part of initial therapy was associated with increased risk of death., Conclusions: There are multiple variables associated with survival in transplant patients with IA. Understanding these prognostic factors may assist in the development of treatment algorithms and clinical trials.
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- 2010
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12. Geoclimatic influences on invasive aspergillosis after hematopoietic stem cell transplantation.
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Panackal AA, Li H, Kontoyiannis DP, Mori M, Perego CA, Boeckh M, and Marr KA
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- Adolescent, Adult, Air Microbiology, Aspergillus isolation & purification, Environmental Monitoring, Epidemiological Monitoring, Female, Humans, Male, Middle Aged, Seasons, Spores isolation & purification, Texas epidemiology, Washington epidemiology, Weather, Young Adult, Aspergillosis epidemiology, Hematopoietic Stem Cell Transplantation
- Abstract
Background: Aspergillus species are ubiquitous. We hypothesized that climatic variables that affect airborne mold counts affect the incidence of invasive aspergillosis (IA)., Methods: Patients who received hematopoietic stem cell transplants (HSCTs) in geographically and climatically diverse regions (Seattle, WA, and Houston, TX) were examined. Cumulative incidence function, Kaplan-Meier analysis, and Cox proportional hazards regression were performed to examine the association between IA and season. Poisson regression analysis was performed to evaluate the seasonal patterns in IA rates and association with spore counts and climate., Results: In Seattle, the 3-month incidence of IA was 4.6% (5.7% in allograft recipients and 0.8% in autograft recipients). During the 10-year study period, there was a decrease in the incidence of IA among allogeneic HSCT recipients, corresponding to decreased risks during the nonsummer months; receipt of HSCTs during the summer months was associated with an increased hazard for IA (hazard ratio, 1.87; 95% confidence interval, 1.25-2.81) after adjustment for other known risks. The person-month IA rate in Seattle was positively associated with environmental spore counts, which increased with high temperature and low precipitation. No seasonal effect on IA was observed in Houston, where total spore counts were lower and not variable by climate., Conclusions: Climatic variables differentially affect airborne spore counts and IA risk in geographically disparate centers.
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- 2010
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13. Molecular identification of Aspergillus species collected for the Transplant-Associated Infection Surveillance Network.
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Balajee SA, Kano R, Baddley JW, Moser SA, Marr KA, Alexander BD, Andes D, Kontoyiannis DP, Perrone G, Peterson S, Brandt ME, Pappas PG, and Chiller T
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- Antifungal Agents pharmacology, Aspergillus isolation & purification, DNA, Fungal chemistry, DNA, Fungal genetics, DNA, Ribosomal Spacer chemistry, DNA, Ribosomal Spacer genetics, Humans, Immunocompromised Host, Microbial Sensitivity Tests, Sequence Analysis, DNA, Tubulin genetics, Aspergillosis microbiology, Aspergillus classification, Aspergillus genetics, Transplantation adverse effects
- Abstract
A large aggregate collection of clinical isolates of aspergilli (n = 218) from transplant patients with proven or probable invasive aspergillosis was available from the Transplant-Associated Infection Surveillance Network, a 6-year prospective surveillance study. To determine the Aspergillus species distribution in this collection, isolates were subjected to comparative sequence analyses by use of the internal transcribed spacer and beta-tubulin regions. Aspergillus fumigatus was the predominant species recovered, followed by A. flavus and A. niger. Several newly described species were identified, including A. lentulus and A. calidoustus; both species had high in vitro MICs to multiple antifungal drugs. Aspergillus tubingensis, a member of the A. niger species complex, is described from clinical specimens; all A. tubingensis isolates had low in vitro MICs to antifungal drugs.
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- 2009
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14. Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network.
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Baddley JW, Marr KA, Andes DR, Walsh TJ, Kauffman CA, Kontoyiannis DP, Ito JI, Balajee SA, Pappas PG, and Moser SA
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- Aspergillosis mortality, Aspergillus isolation & purification, Drug Resistance, Fungal, Humans, Immunocompromised Host, Microbial Sensitivity Tests, Antifungal Agents pharmacology, Aspergillosis microbiology, Aspergillus drug effects, Transplantation adverse effects
- Abstract
We analyzed antifungal susceptibilities of 274 clinical Aspergillus isolates from transplant recipients with proven or probable invasive aspergillosis collected as part of the Transplant-Associated Infection Surveillance Network (TRANSNET) and examined the relationship between MIC and mortality at 6 or 12 weeks. Antifungal susceptibility testing was performed by the Clinical and Laboratory Standards Institute (CLSI) M38-A2 broth dilution method for amphotericin B (AMB), itraconazole (ITR), voriconazole (VOR), posaconazole (POS), and ravuconazole (RAV). The isolate collection included 181 Aspergillus fumigatus, 28 Aspergillus niger, 27 Aspergillus flavus, 22 Aspergillus terreus, seven Aspergillus versicolor, five Aspergillus calidoustus, and two Aspergillus nidulans isolates and two isolates identified as Aspergillus spp. Triazole susceptibilities were < or = 4 microg/ml for most isolates (POS, 97.6%; ITR, 96.3%; VOR, 95.9%; RAV, 93.5%). The triazoles were not active against the five A. calidoustus isolates, for which MICs were > or = 4 microg/ml. AMB inhibited 93.3% of isolates at an MIC of < or = 1 microg/ml. The exception was A. terreus, for which 15 (68%) of 22 isolates had MICs of >1 microg/ml. One of 181 isolates of A. fumigatus showed resistance (MIC > or = 4 microg/ml) to two of three azoles tested. Although there appeared to be a correlation of higher VOR MICs with increased mortality at 6 weeks, the relationship was not statistically significant (R2 = 0.61; P = 0.065). Significant relationships of in vitro MIC to all-cause mortality at 6 and 12 weeks for VOR or AMB were not found.
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- 2009
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15. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.
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Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, Janer M, Rodrigues SD, Li S, Hansen JA, Zhao LP, Aderem A, and Boeckh M
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- Adult, Analysis of Variance, Aspergillus fumigatus, Case-Control Studies, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Incidence, Linkage Disequilibrium, Male, Middle Aged, Proportional Hazards Models, Risk Assessment, Toll-Like Receptors genetics, Transplantation, Homologous, Aspergillosis genetics, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cell Transplantation mortality, Polymorphism, Single Nucleotide, Toll-Like Receptor 4 genetics
- Abstract
Background: Toll-like receptors (TLRs) are essential components of the immune response to fungal pathogens. We examined the role of TLR polymorphisms in conferring a risk of invasive aspergillosis among recipients of allogeneic hematopoietic-cell transplants., Methods: We analyzed 20 single-nucleotide polymorphisms (SNPs) in the toll-like receptor 2 gene (TLR2), the toll-like receptor 3 gene (TLR3), the toll-like receptor 4 gene (TLR4), and the toll-like receptor 9 gene (TLR9) in a cohort of 336 recipients of hematopoietic-cell transplants and their unrelated donors. The risk of invasive aspergillosis was assessed with the use of multivariate Cox regression analysis. The analysis was replicated in a validation study involving 103 case patients and 263 matched controls who received hematopoietic-cell transplants from related and unrelated donors., Results: In the discovery study, two donor TLR4 haplotypes (S3 and S4) increased the risk of invasive aspergillosis (adjusted hazard ratio for S3, 2.20; 95% confidence interval [CI], 1.14 to 4.25; P=0.02; adjusted hazard ratio for S4, 6.16; 95% CI, 1.97 to 19.26; P=0.002). The haplotype S4 was present in carriers of two SNPs in strong linkage disequilibrium (1063 A/G [D299G] and 1363 C/T [T399I]) that influence TLR4 function. In the validation study, donor haplotype S4 also increased the risk of invasive aspergillosis (adjusted odds ratio, 2.49; 95% CI, 1.15 to 5.41; P=0.02); the association was present in unrelated recipients of hematopoietic-cell transplants (odds ratio, 5.00; 95% CI, 1.04 to 24.01; P=0.04) but not in related recipients (odds ratio, 2.29; 95% CI, 0.93 to 5.68; P=0.07). In the discovery study, seropositivity for cytomegalovirus (CMV) in donors or recipients, donor positivity for S4, or both, as compared with negative results for CMV and S4, were associated with an increase in the 3-year probability of invasive aspergillosis (12% vs. 1%, P=0.02) and death that was not related to relapse (35% vs. 22%, P=0.02)., Conclusions: This study suggests an association between the donor TLR4 haplotype S4 and the risk of invasive aspergillosis among recipients of hematopoietic-cell transplants from unrelated donors., (2008 Massachusetts Medical Society)
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- 2008
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16. Plasminogen alleles influence susceptibility to invasive aspergillosis.
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Zaas AK, Liao G, Chien JW, Weinberg C, Shore D, Giles SS, Marr KA, Usuka J, Burch LH, Perera L, Perfect JR, Peltz G, and Schwartz DA
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- Animals, Aspergillosis mortality, Aspergillosis pathology, Aspergillus fumigatus immunology, Aspergillus fumigatus pathogenicity, Female, Humans, Lung Diseases, Fungal immunology, Lung Diseases, Fungal mortality, Mice, Mice, Inbred A, Mice, Inbred AKR, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred MRL lpr, Mice, Inbred NZB, Mice, Knockout, Plasminogen physiology, Alleles, Aspergillosis genetics, Aspergillosis microbiology, Genetic Predisposition to Disease, Lung Diseases, Fungal genetics, Lung Diseases, Fungal microbiology, Plasminogen genetics, Signal Transduction genetics
- Abstract
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection., Competing Interests: Aimee K. Zaas, MD serves on the speaker's bureau for Pfizer, Inc. John R. Perfect is a consultant for the Robert Michael Educational Institute. Guochun Liao, Jonathan Usuka and Gary Peltz are employees of Roche Biosciences. All other authors declare that no conflict of interest exists.
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- 2008
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17. Fungal infections in hematopoietic stem cell transplant recipients.
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Marr KA
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- Aspergillosis immunology, Aspergillus pathogenicity, Candidiasis immunology, Host-Pathogen Interactions, Humans, Immunity, Active, Immunity, Innate, Immunosuppression Therapy, Opportunistic Infections immunology, Treatment Outcome, Aspergillosis epidemiology, Candidiasis epidemiology, Hematopoietic Stem Cell Transplantation, Opportunistic Infections epidemiology
- Abstract
Fungal infections have historically been, and remain important causes of transplant-related morbidity in recipients of hematopoietic stem cell transplant (HSCT). However, there have been notable changes in the epidemiology and outcomes of invasive fungal infections, induced by changes in the transplant procedures as well as supportive care. This review discusses invasive fungal infections in hematopoietic stem cell transplant recipients, with a focus on the host and the two most common infections, candidiasis and those caused by moulds.
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- 2008
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18. Aspergillus galactomannan index: a surrogate end point to assess outcome of therapy?
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Marr KA
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- Aspergillosis drug therapy, Galactose analogs & derivatives, Humans, Treatment Outcome, Aspergillosis pathology, Aspergillus metabolism, Mannans blood
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- 2008
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19. MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.
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Bretz C, Gersuk G, Knoblaugh S, Chaudhary N, Randolph-Habecker J, Hackman RC, Staab J, and Marr KA
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- Animals, Aspergillosis microbiology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Colony Count, Microbial, Cytokines analysis, Inflammation pathology, Killer Cells, Natural immunology, Lung chemistry, Lung pathology, Macrophages, Alveolar immunology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88 deficiency, Necrosis pathology, Neutrophils immunology, Aspergillosis immunology, Aspergillosis pathology, Aspergillus fumigatus immunology, Lung immunology, Lung microbiology, Myeloid Differentiation Factor 88 immunology
- Abstract
Toll-like receptors and the beta-glucan receptor, dectin-1, mediate macrophage inflammatory responses to Aspergillus fumigatus through MyD88-dependent and -independent signaling mechanisms; however, pulmonary inflammatory responses in MyD88-deficient mice challenged with A. fumigatus are poorly defined. The role of MyD88 signaling in early pulmonary inflammation and fungal clearance was evaluated in C57BL/6J wild-type (WT) and MyD88-deficient (MyD88-/-) mice. Early (<48 h) after infection, MyD88-/- mice had higher fungal burdens than those of WT mice, although fungal burdens rapidly declined (>72 h) in both. MyD88-/- mice had less consolidated inflammation, with fewer NK cells, in lung tissue early (24 h) after infection than did WT mice. At the latter time point, MyD88-/- mouse lungs were characterized by a large amount of necrotic cellular debris and fibrin, while WT lungs had organized inflammation. Although there were equivalent numbers of macrophages in WT and MyD88-/- mouse lung tissues, MyD88-/- cells demonstrated delayed uptake of green fluorescent protein-expressing A. fumigatus (GFP-Af293); histologically, MyD88-/- mouse lungs had more hyphal invasion of terminal airways and vessels, the appearance of bronchiolar epithelial cell necrosis, and necrotizing vasculitis. MyD88-/- lung homogenates contained comparatively decreased amounts of interleukin-1beta (IL-1beta), IL-6, KC, and gamma interferon and paradoxically increased amounts of tumor necrosis factor alpha and macrophage inflammatory protein 1alpha. These data indicate that the MyD88-dependent pathway mediates acute pulmonary fungal clearance, inflammation, and tissue injury very early after infection. Resolution of abnormalities within a 3-day window demonstrates the importance of redundant signaling pathways in mediating pulmonary inflammatory responses to fungi.
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- 2008
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20. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America.
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Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, Morrison VA, Segal BH, Steinbach WJ, Stevens DA, van Burik JA, Wingard JR, and Patterson TF
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- Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillosis microbiology, Aspergillosis, Allergic Bronchopulmonary drug therapy, Aspergillosis, Allergic Bronchopulmonary microbiology, Humans, Lung Diseases, Fungal drug therapy, Lung Diseases, Fungal microbiology, Aspergillosis therapy, Aspergillosis, Allergic Bronchopulmonary therapy, Lung Diseases, Fungal therapy
- Published
- 2008
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21. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality.
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Upton A, Kirby KA, Carpenter P, Boeckh M, and Marr KA
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- Adolescent, Adult, Age Distribution, Aged, Aspergillosis microbiology, Aspergillosis physiopathology, Child, Child, Preschool, Cohort Studies, Female, Fungemia microbiology, Fungemia physiopathology, Hematologic Neoplasms mortality, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Hematopoietic Stem Cell Transplantation mortality, Humans, Incidence, Infant, Male, Middle Aged, Multivariate Analysis, Probability, Prognosis, Proportional Hazards Models, Retrospective Studies, Risk Factors, Severity of Illness Index, Sex Distribution, Survival Analysis, Aspergillosis mortality, Fungemia mortality, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Background: Invasive aspergillosis (IA) is a leading cause of infection-related mortality following hematopoietic cell transplantation (HCT). The aim of this study was to determine the probability of survival and prognostic factors associated with outcomes over a long period of time., Methods: Cases of proven and probable IA diagnosed in HCT recipients at the Fred Hutchinson Cancer Research Center from 1 January 1990 through 31 December 2004 were included. Patient data were collected from a prospectively maintained database and by retrospective clinical chart review. Survival was estimated using Kaplan-Meier curves, and Cox regression models were used for multivariable analyses., Results: Four hundred five cases were identified. The probability of survival at 90 days after diagnosis was higher for patients identified as having IA between 2002 and 2004 than for patients whose IA was diagnosed in preceding years (45% vs. 22%; P<.001). Risk factors independently associated with all-cause mortality include impairment in pulmonary function before HCT, receipt of human leukocyte antigen-mismatched stem cells, neutropenia, elevated bilirubin and creatinine levels, receipt of corticosteroids at > or =2 mg/kg per day, disseminated and proven IA, and IA occurring >40 days after HCT. Factors associated with a decreased risk of all-cause mortality included receipt of nonmyeloablative conditioning and peripheral blood stem cells. In a subanalysis of attributable mortality restricted to patients receiving antifungal therapy, receipt of voriconazole was independently associated with protection from IA-related death., Conclusions: There has been a significant decrease in mortality in patients with a diagnosis of IA following HCT in recent years, coinciding with multiple changes in transplantation practices, including use of nonmyeloablative conditioning regimens, receipt of peripheral blood stem cells, more prompt diagnosis of IA, and use of voriconazole.
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- 2007
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22. GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence.
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Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Kirby KA, and Keller NP
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- Animals, Apoptosis, Aspergillosis metabolism, Aspergillus fumigatus genetics, Gene Deletion, Gene Expression Regulation, Fungal, Gliotoxin analysis, Lung chemistry, Lung microbiology, Mice, Neutrophils metabolism, Transcription Factors genetics, Virulence genetics, Aspergillosis microbiology, Aspergillus fumigatus pathogenicity, Gliotoxin biosynthesis, Transcription Factors physiology
- Abstract
Gliotoxin is a nonribosomal peptide produced by Aspergillus fumigatus. This compound has been proposed as an A. fumigatus virulence factor due to its cytotoxic, genotoxic, and apoptotic properties. Recent identification of the gliotoxin gene cluster identified several genes (gli genes) likely involved in gliotoxin production, including gliZ, encoding a putative Zn(2)Cys(6) binuclear transcription factor. Replacement of gliZ with a marker gene (DeltagliZ) resulted in no detectable gliotoxin production and loss of gene expression of other gli cluster genes. Placement of multiple copies of gliZ in the genome increased gliotoxin production. Using endpoint survival data, the DeltagliZ and a multiple-copy gliZ strain were not statistically different from the wild type in a murine pulmonary model; however, both the wild-type and the multiple-copy gliZ strain were more virulent than DeltalaeA (a mutant reduced in production of gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear leukocytes (PMNs) exposed to supernatants from wild-type, DeltagliZ, complemented DeltagliZ, and DeltalaeA strains supported a role for gliotoxin in apoptotic but not necrotic PMN cell death. This may indicate that several secondary metabolites are involved in A. fumigatus virulence.
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- 2006
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23. Phenotypic and genotypic identification of human pathogenic aspergilli.
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Balajee SA and Marr KA
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- Aspergillosis diagnosis, Aspergillus classification, Aspergillus isolation & purification, Cytochromes b genetics, Genotype, Humans, Phenotype, RNA Polymerase II genetics, RNA, Ribosomal genetics, Species Specificity, Aspergillosis microbiology, Aspergillus genetics, Mycology methods
- Abstract
Human pathogenic aspergilli are identified in the clinical diagnostic laboratory predominantly by macro- and micro-morphology. Such phenotypic characteristics are largely subjective and unstable, as they are influenced by environmental factors, including media and temperature of incubation. Recent advances in molecular biology have impacted the field of mycology; multiple studies have noted new genetically distinct species that are not easily distinguished by phenotypic characteristics. Strengths of molecular typing methods include objectivity and the ability to identify nonsporulating or slowly growing fungi. As such, molecular methods provide powerful tools for the study of the epidemiology, evolution and population biology of fungal pathogens. This review focuses on current and future methods of identifying aspergilli, and implications regarding Aspergillus species/strain identification.
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- 2006
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24. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: A retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.
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Martino R, Parody R, Fukuda T, Maertens J, Theunissen K, Ho A, Mufti GJ, Kroger N, Zander AR, Heim D, Paluszewska M, Selleslag D, Steinerova K, Ljungman P, Cesaro S, Nihtinen A, Cordonnier C, Vazquez L, López-Duarte M, Lopez J, Cabrera R, Rovira M, Neuburger S, Cornely O, Hunter AE, Marr KA, Dornbusch HJ, and Einsele H
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- Adolescent, Adult, Aged, Aspergillosis epidemiology, Bone Marrow Transplantation, Child, Child, Preschool, Cytomegalovirus Infections epidemiology, Europe, Female, Humans, Male, Middle Aged, Retrospective Studies, Aspergillosis complications, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods
- Abstract
In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (> or = 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.
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- 2006
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25. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis.
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Denning DW, Marr KA, Lau WM, Facklam DP, Ratanatharathorn V, Becker C, Ullmann AJ, Seibel NL, Flynn PM, van Burik JA, Buell DN, and Patterson TF
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- Acute Disease, Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents administration & dosage, Child, Child, Preschool, Drug Therapy, Combination, Echinocandins, Female, Humans, Infant, Lipopeptides, Lipoproteins administration & dosage, Male, Micafungin, Middle Aged, Peptides, Cyclic administration & dosage, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Lipoproteins therapeutic use, Peptides, Cyclic therapeutic use
- Abstract
Background: Micafungin (FK463) is a new lipopeptide compound (echinocandin) with activity against Aspergillus and Candida species. This study evaluated the safety and efficacy of micafungin in patients with proven or probable invasive aspergillosis (IA)., Methods: A multinational, non-comparative study was conducted to examine proven or probable (pulmonary only) Aspergillus species infection in a wide variety of patient populations. The study employed an open-label design utilizing micafungin alone or in combination with another systemic antifungal agent. Criteria for IA and therapeutic responses were judged by an independent panel., Results: Of the 331 patients enrolled, only 225 met diagnostic criteria for IA as determined by the independent panel and received at least one dose of micafungin. Patients included 98/225 who had undergone hematopoietic stem cell transplantation (HSCT) (88/98 allogeneic), 48 with graft versus host disease (GVHD), and 83/225 who had received chemotherapy for hematologic malignancy. A favorable response rate at the end of therapy was seen in 35.6% (80/225) of patients. Of those only treated with micafungin, favorable responses were seen in 6/12 (50%) of the primary and 9/22 (40.9%) of the salvage therapy group, with corresponding numbers in the combination treatment groups of 5/17 (29.4%) and 60/174 (34.5%) of the primary and salvage treatment groups, respectively. Of the 326 micafungin-treated patients, 183 (56.1%) died during therapy or in the 6-week follow-up phase; 107 (58.5%) deaths were attributable to IA., Conclusions: Micafungin as primary or salvage therapy proved efficacious and safe in high-risk patients with IA, although patient numbers are small in the micafungin-only groups.
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- 2006
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26. Aspergillosis: spectrum of disease, diagnosis, and treatment.
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Barnes PD and Marr KA
- Subjects
- Humans, Antifungal Agents therapeutic use, Aspergillosis diagnosis, Aspergillosis drug therapy
- Abstract
Infections by Aspergillus species present a particular challenge. The organism, which is ubiquitous in the environment, causes allergic disease in otherwise healthy individuals and devastating disease in the immunosuppressed. This article examines the range of infections caused by Aspergillus species, the challenges of diagnosis, and current treatment options.
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- 2006
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27. Aspergillus ustus infections among transplant recipients.
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Panackal AA, Imhof A, Hanley EW, and Marr KA
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- Adult, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillosis microbiology, Aspergillus classification, Aspergillus genetics, Disease Outbreaks, Female, Humans, Male, Middle Aged, Phylogeny, Aspergillosis epidemiology, Aspergillosis etiology, Aspergillus isolation & purification, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Aspergillus ustus is a mold that rarely infects humans; only 15 systemic cases have been reported. We report the first outbreak of invasive infection caused by A. ustus among hematopoietic stem cell transplant (HSCT) recipients. Six patients with infections were identified; 3 infections each occurred in both 2001 and 2003. Molecular typing by using randomly amplified polymorphic DNA (RAPD) and antifungal drug susceptibility testing were performed on clinical and environmental isolates recovered from our hospital from 1999 to 2003. The highest overall attack rate in HSCT patients was 1.6%. The overall death rate was 50%, and death occurred within 8 days after diagnostic culture collection. Clinical isolates exhibited decreased susceptibility to antifungal drugs, especially azoles. RAPD and phylogenetic analysis showed genetic similarity between isolates from different patients. Based on the clustering of cases in space and time and molecular data, common-source acquisition of this unusual drug-resistant species is possible.
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- 2006
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28. Design issues in studies evaluating diagnostic tests for aspergillosis.
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Marr KA and Leisenring W
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- Aspergillus chemistry, Clinical Laboratory Techniques, Evaluation Studies as Topic, Galactose analogs & derivatives, Humans, Immunoenzyme Techniques, Mannans analysis, Aspergillosis diagnosis, Aspergillus isolation & purification
- Abstract
Although invasive aspergillosis is recognized as an increased concern for immunosuppressed patients, establishing an early diagnosis remains a challenge. Current methods for diagnosis, including sensitive radiography and invasive procedures to identify organisms in affected tissues, provide an early diagnosis for only a small proportion of patients infected with Aspergillus species. The availability of a standardized assay to detect circulating Aspergillus galactomannan, the BioRad Platelia Aspergillus galactomannan enzyme immunoassay, should be considered as a valuable tool. However, at present, clinical utility is hampered by controversies surrounding the performance of the test and an apparent lack of definitive data. These controversies emphasize the complexity inherent in analyzing diagnostic tests for aspergillosis. The widespread availability of a standardized assay may now allow us to address the multiple sources of variability and bias via large, cooperative studies.
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- 2005
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29. Reproducibility of low galactomannan enzyme immunoassay index values tested in multiple laboratories.
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Upton A, Gugel A, Leisenring W, Limaye A, Alexander B, Hayden R, and Marr KA
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- Aspergillosis microbiology, Enzyme-Linked Immunosorbent Assay, Galactose analogs & derivatives, Humans, Immunoenzyme Techniques, Laboratories, Reproducibility of Results, Sensitivity and Specificity, Antigens, Fungal blood, Aspergillosis diagnosis, Mannans blood, Reagent Kits, Diagnostic
- Abstract
The Platelia galactomannan enzyme immunoassay is a commercially available nonculture method for diagnosing invasive aspergillosis. Recently, steps have been taken to improve sensitivity; specifically, a low (0.5 to 0.7) galactomannan index (GMI) value to determine positivity has been validated by multiple groups. We evaluated the intra-assay and interassay reproducibility at low index levels using three different kit lots on three different days in three different microbiology laboratories. Clinical and spiked sera were blinded and sent with galactomannan enzyme immunoassay (EIA) kits to the participating laboratories. We also prospectively collected data on all galactomannan EIAs performed between 1 September 2003 and 21 July 2004 at the University of Washington Medical Center microbiology laboratory to assess reproducibility of clinical samples analyzed in "real time." From the multilaboratory study, a total of 836 results were available for evaluation. Reproducibility was excellent between laboratories and on different days. Significant variability was seen between runs/lots, which may in part be associated with different threshold control values in different kits. Among the 1,410 clinical samples that were prospectively analyzed, 168 (90%) were confirmed to be positive on repeat testing (GMI, > or =0.5). Among the 19 (10.2%) initially positive samples not confirmed on repeat testing, the majority had a GMI at the threshold of the assay (between 0.5 and 0.7). Our findings suggest that the Platelia galactomannan immunoassay has good reproducibility. However, changes in GMI levels when different kit lots are used, and single samples with low-positive (GMI of 0.5 to 0.7) indices, should be interpreted with caution.
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- 2005
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30. Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay.
- Author
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Marr KA, Laverdiere M, Gugel A, and Leisenring W
- Subjects
- Adolescent, Adult, Aged, Aspergillosis drug therapy, Aspergillus metabolism, Child, False Negative Reactions, Female, Fluconazole therapeutic use, Galactose analogs & derivatives, Humans, Itraconazole therapeutic use, Male, Mannans metabolism, Middle Aged, Sensitivity and Specificity, Antifungal Agents therapeutic use, Aspergillosis diagnosis, Aspergillus isolation & purification, Immunoenzyme Techniques methods, Mannans analysis
- Abstract
Background: Reported sensitivity of the galactomannan enzyme immunoassay as an early diagnostic test for invasive aspergillosis (IA) has been widely variable, ranging from 29% to 100% in earlier clinical studies., Methods: Studies performed to date have analyzed performance using per-patient calculations, limiting their ability to measure the impact of clinical variables that change over time, such as receipt of preventive antifungal therapy. In our study, performance of the test was calculated in per-patient and per-test analyses in a large cohort of patients at high risk for IA from 2 North American centers. A total of 272 serum samples obtained from 46 patients with IA and 3005 serum samples obtained from 269 control patients were analyzed using multiple index cutoff values to define positivity., Results: Per-patient calculations yielded sensitivities of 43% and 70% using index cutoff values of 1.5 and 0.5, respectively; specificity decreased from 93% with use of the 1.5 index cutoff to 70% with use of the 0.5 index cutoff. Per-test calculations yielded sensitivities of 31% and 59% and specificities of 99% and 92% using index cutoff values of 1.5 and 0.5, respectively. Receipt of mold-active antifungal drugs on the day of testing decreased sensitivity; samples obtained from patients not receiving prophylactic or empirical antifungal drugs yielded a sensitivity of 89% and a specificity of 92% (with use of an index cutoff value of 0.5)., Conclusions: These findings have direct implications for preventive strategies, because the diagnostic utility of the antigen assay is compromised during receipt of prophylactic or empirical antifungal therapies.
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- 2005
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31. Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid.
- Author
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Musher B, Fredricks D, Leisenring W, Balajee SA, Smith C, and Marr KA
- Subjects
- Aspergillosis microbiology, Aspergillus genetics, Galactose analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Immunoenzyme Techniques, Sensitivity and Specificity, Aspergillosis diagnosis, Aspergillus isolation & purification, Bronchoalveolar Lavage Fluid microbiology, Lung Diseases, Fungal diagnosis, Mannans analysis, Polymerase Chain Reaction methods
- Abstract
Invasive pulmonary aspergillosis (IPA) is frequent and often fatal in hematopoietic stem cell transplant patients. Diagnosis requires microbiological or histopathologic demonstration of the organism in tissues; however, cultivation of Aspergillus species from respiratory secretions has low diagnostic sensitivity. Assays to detect Aspergillus antigen or DNA in bronchoalveolar lavage (BAL) fluid could facilitate earlier diagnosis, thereby guiding optimal therapy and obviating the need for additional costly and potentially morbid diagnostic evaluation. We evaluated the performance of a galactomannan enzyme immunoassay (GM EIA; Bio-Rad) by using a range of index cutoffs to define positivity and a quantitative PCR (qPCR) assay for the detection of Aspergillus species from BAL samples of patients with proven and probable IPA (case patients; n = 49) and without IPA (control patients; n = 50). The sensitivity of the GM EIA was 61% with an index cutoff of 1.0 and 76% with an index cutoff of 0.5; the corresponding specificities were 98 and 94%, respectively. The sensitivity and specificity of qPCR assay were 67 and 100%, respectively. The sensitivity with 22 culture-negative BAL specimens from patients with IPA was 41% for GM EIA with an index cutoff of 1.0, 59% for GM EIA with an index cutoff of 0.5, and 36% for qPCR assay. GM EIA indices and DNA quantities corresponded to BAL fungal burdens, with culture-positive samples having larger amounts of antigen and DNA compared to culture-negative samples. GM EIA and qPCR assay add to the sensitivity of BAL for diagnosing IPA in high-risk patients, with excellent specificity. Adjunctive use of these tests may reduce dependence on invasive diagnostic procedures.
- Published
- 2004
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32. Combination antifungal therapy for invasive aspergillosis.
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Marr KA, Boeckh M, Carter RA, Kim HW, and Corey L
- Subjects
- Adolescent, Adult, Aged, Caspofungin, Drug Therapy, Combination, Echinocandins, Female, Humans, Lipopeptides, Male, Middle Aged, Retrospective Studies, Salvage Therapy, Survival Analysis, Treatment Outcome, Voriconazole, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Opportunistic Infections drug therapy, Peptides, Cyclic therapeutic use, Pyrimidines therapeutic use, Triazoles therapeutic use
- Abstract
Background: Aspergillosis therapy with amphotericin, azoles, or echinocandins is associated with substantial mortality, ranging from 30% to 80%, depending on the stage of infection and the host's underlying disease. The results of in vitro studies and animal models suggest that combination therapy with azoles and echinocandins may have additive activity against Aspergillus species., Methods: We evaluated the outcomes of patients with aspergillosis who experienced failure of initial therapy with amphotericin B formulations and received either voriconazole (n=31) or a combination of voriconazole and caspofungin (n=16) for salvage therapy., Results: The combination of voriconazole and caspofungin was associated with improved 3-month survival rate, compared with voriconazole alone (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.17-1.1; P=.048). In multivariable models, salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with therapy with voriconazole (HR, 0.28; 95% CI, 0.28-0.92; P=.011), independent of other prognostic variables (e.g., receipt of transplant and type of conditioning therapy). The probability of death due to aspergillosis was lowest in patients who received the combination regimen., Conclusions: Randomized trials are warranted to determine whether this combination should be used as primary therapy for aspergillosis.
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- 2004
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33. Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance.
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Marr KA, Balajee SA, McLaughlin L, Tabouret M, Bentsen C, and Walsh TJ
- Subjects
- Adolescent, Adult, Aged, Animals, Aspergillosis microbiology, Bone Marrow Transplantation adverse effects, Child, Child, Preschool, Disease Models, Animal, Female, Fungemia microbiology, Galactose analogs & derivatives, Humans, Immunoenzyme Techniques, Lung Diseases, Fungal diagnosis, Lung Diseases, Fungal microbiology, Male, Middle Aged, Rabbits, Sensitivity and Specificity, Antigens, Fungal blood, Aspergillosis diagnosis, Aspergillus isolation & purification, Fungemia diagnosis, Mannans blood
- Abstract
Invasive aspergillosis (IA) is a frequent complication of blood or marrow transplantation. Previous studies have reported that the Aspergillus galactomannan enzyme immunoassay (GM EIA) may be a useful diagnostic tool for IA, but its sensitivity is variable. We examined the performance of the GM EIA in 986 serum samples from 67 patients. Results demonstrated that decreasing the index cutoff for positivity to 0.5 increased its sensitivity, with minimal loss of specificity. The low cutoff increased the duration of test positivity before diagnosis by clinical means. Sensitivity was highest in patients who did not receive preventative mold-active antifungals (87.5%). A rabbit model demonstrated that the level of circulating antigen correlated with the tissue fungus burden. A quantifiable response to antifungal therapy in clinical samples and the rabbit model supports the development of this assay for early diagnosis and therapeutic monitoring. The 0.5 cutoff may allow for better performance as an early diagnostic test.
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- 2004
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34. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases.
- Author
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Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, Perfect JR, Lutsar I, Marr KA, Lionakis MS, Torres HA, Jafri H, and Walsh TJ
- Subjects
- Antifungal Agents therapeutic use, Aspergillosis drug therapy, Aspergillosis immunology, Aspergillosis mortality, Cohort Studies, Female, Graft vs Host Disease complications, Humans, Logistic Models, Male, Proportional Hazards Models, Pyrimidines therapeutic use, Retrospective Studies, Survival Rate, Triazoles therapeutic use, Voriconazole, Aspergillosis microbiology
- Abstract
Current in vitro and in vivo data indicate that invasive aspergillosis due to Aspergillus terreus is resistant to treatment with amphotericin B. Because little clinical data are available to guide therapy, we performed a retrospective cohort study of cases of invasive A. terreus infections from 1997-2002 to determine whether the use of voriconazole, compared with use of other antifungal therapies, led to an improved patient outcome. We analyzed a total of 83 cases of proven or probable invasive A. terreus infection (47% and 53%, respectively). A total of 66.3% of patients (55 of 83) died during management of IA, with 55.8% mortality (19 of 34 patients) in the voriconazole group and 73.4% mortality (36 of 49) in the group that received therapy with other antifungals. By use of Cox proportional hazards modeling, decreased mortality at 12 weeks was observed in those patients who received voriconazole (hazard ratio, 0.29; 95% CI, 0.15-0.56). Voriconazole is likely to be a better treatment choice for A. terreus infection than is a polyene.
- Published
- 2004
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35. Invasive aspergillosis before allogeneic hematopoietic stem cell transplantation: 10-year experience at a single transplant center.
- Author
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Fukuda T, Boeckh M, Guthrie KA, Mattson DK, Owens S, Wald A, Sandmaier BM, Corey L, Storb RF, and Marr KA
- Subjects
- Academic Medical Centers, Adolescent, Adult, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Middle Aged, Neoplasms complications, Risk Factors, Survival Analysis, Time Factors, Aspergillosis drug therapy, Aspergillosis etiology, Aspergillosis mortality, Aspergillosis pathology, Hematopoietic Stem Cell Transplantation mortality, Neoplasms therapy, Transplantation Conditioning
- Abstract
Hematopoietic stem cell transplantation (HCT) in patients with prior or active invasive aspergillosis (IA) is a frequent consideration. We reviewed outcomes of 2319 patients who underwent transplantation between 1992 and 2001 in our institution, among whom 45 patients (1.9%) had a known history of IA before HCT. Posttransplantation IA occurred in 13 of these 45 patients with a pretransplantation history (29%). Nine infections were considered recurrent by anatomic site and timing. Compared with all other patients who received allogeneic HCT during the same period, patients with histories of IA had lower overall survival (56% versus 77%; P =.0001) and higher transplant-related mortality (TRM; 38% versus 21%; P =.0001) 100 days after HCT, associated mainly with IA and other pulmonary complications. Among patients with prior IA, posttransplantation IA occurred more frequently in patients who received <1 month of antifungal therapy before HCT (4/6 versus 6/39; P =.001). The probability of posttransplantation IA and overall survival among patients who received >1 month of antifungal therapy and had resolution of radiographic abnormalities were not different from those of patients without prior IA. Patients with prior IA who received conditioning with total body irradiation (TBI) had higher TRM compared with those who received nonmyeloablative and non-total body irradiation-based regimens (16/31 versus 2/14; P =.024). Thus, the duration of antifungal therapy before transplantation, the resolution of radiographic abnormalities, and conditioning regimens are important variables to consider for minimizing the risk for IA recurrence and TRM after allogeneic HCT.
- Published
- 2004
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36. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants.
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Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA, Nichols WG, Musher B, and Corey L
- Subjects
- Adult, Antifungal Agents adverse effects, Aspergillosis mortality, Drug Resistance, Fungal, Female, Fluconazole adverse effects, Graft vs Host Disease drug therapy, Graft vs Host Disease mortality, Humans, Incidence, Itraconazole adverse effects, Male, Treatment Outcome, Antifungal Agents administration & dosage, Aspergillosis prevention & control, Fluconazole administration & dosage, Itraconazole administration & dosage, Stem Cell Transplantation adverse effects
- Abstract
Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and "on-treatment" analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P <.001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P =.46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P =.03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P =.03), but similar protection against candidiasis (3% versus 2%, P =.69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.
- Published
- 2004
- Full Text
- View/download PDF
37. Voriconazole treatment for less-common, emerging, or refractory fungal infections.
- Author
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Perfect JR, Marr KA, Walsh TJ, Greenberg RN, DuPont B, de la Torre-Cisneros J, Just-Nübling G, Schlamm HT, Lutsar I, Espinel-Ingroff A, and Johnson E
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents adverse effects, Child, Humans, Middle Aged, Pyrimidines adverse effects, Treatment Outcome, Triazoles adverse effects, Voriconazole, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Candidiasis drug therapy, Pyrimidines therapeutic use, Triazoles therapeutic use
- Abstract
Treatments for invasive fungal infections remain unsatisfactory. We evaluated the efficacy, tolerability, and safety of voriconazole as salvage treatment for 273 patients with refractory and intolerant-to-treatment fungal infections and as primary treatment for 28 patients with infections for which there is no approved therapy. Voriconazole was associated with satisfactory global responses in 50% of the overall cohort; specifically, successful outcomes were observed in 47% of patients whose infections failed to respond to previous antifungal therapy and in 68% of patients whose infections have no approved antifungal therapy. In this population at high risk for treatment failure, the efficacy rates for voriconazole were 43.7% for aspergillosis, 57.5% for candidiasis, 38.9% for cryptococcosis, 45.5% for fusariosis, and 30% for scedosporiosis. Voriconazole was well tolerated, and treatment-related discontinuations of therapy or dose reductions occurred for <10% of patients. Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections.
- Published
- 2003
- Full Text
- View/download PDF
38. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors.
- Author
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Marr KA, Carter RA, Boeckh M, Martin P, and Corey L
- Subjects
- Adolescent, Adrenal Cortex Hormones adverse effects, Adult, Age Factors, Aged, Aspergillosis etiology, Bone Marrow Transplantation adverse effects, Child, Child, Preschool, Cohort Studies, Cytomegalovirus Infections epidemiology, Cytomegalovirus Infections etiology, Female, Follow-Up Studies, Graft vs Host Disease epidemiology, Hematologic Neoplasms complications, Humans, Immunosuppression Therapy adverse effects, Immunosuppressive Agents adverse effects, Incidence, Infant, Life Tables, Male, Middle Aged, Neutropenia chemically induced, Neutropenia complications, Peripheral Blood Stem Cell Transplantation adverse effects, Respiratory Tract Infections epidemiology, Respiratory Tract Infections etiology, Risk Factors, Survival Analysis, Time Factors, Transplantation Conditioning adverse effects, Transplantation, Homologous, Aspergillosis epidemiology, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation (
6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s. - Published
- 2002
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39. Aspergillosis. Pathogenesis, clinical manifestations, and therapy.
- Author
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Marr KA, Patterson T, and Denning D
- Subjects
- Antifungal Agents therapeutic use, Aspergillosis, Allergic Bronchopulmonary complications, Aspergillosis, Allergic Bronchopulmonary diagnosis, Aspergillosis, Allergic Bronchopulmonary therapy, Aspergillus classification, Aspergillus genetics, Aspergillus pathogenicity, Aspergillus fumigatus pathogenicity, Disease Management, Humans, Immunocompromised Host, Lung Diseases, Fungal diagnosis, Lung Diseases, Fungal immunology, Lung Diseases, Fungal therapy, Aspergillosis diagnosis, Aspergillosis drug therapy, Aspergillosis etiology
- Abstract
Diseases caused by Aspergillus species are increasing in importance, especially among immunocompromised hosts. Clinical manifestations are variable, ranging from allergic to invasive disease, largely depending on the status of the host's immune system. This article focuses on the pathogenesis and clinical manifestations of diseases caused by Aspergillus species, with more detailed discussion on therapy of the most morbid manifestation, invasive aspergillosis.
- Published
- 2002
- Full Text
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40. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
- Author
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Herbrecht R, Denning DW, Patterson TF, Bennett JE, Greene RE, Oestmann JW, Kern WV, Marr KA, Ribaud P, Lortholary O, Sylvester R, Rubin RH, Wingard JR, Stark P, Durand C, Caillot D, Thiel E, Chandrasekar PH, Hodges MR, Schlamm HT, Troke PF, and de Pauw B
- Subjects
- Adolescent, Adult, Aged, Amphotericin B adverse effects, Antifungal Agents adverse effects, Aspergillosis microbiology, Aspergillosis mortality, Female, Hematologic Diseases complications, Humans, Infusions, Intravenous, Male, Middle Aged, Pyrimidines adverse effects, Survival Rate, Triazoles adverse effects, Voriconazole, Amphotericin B therapeutic use, Antifungal Agents therapeutic use, Aspergillosis drug therapy, Pyrimidines therapeutic use, Triazoles therapeutic use
- Abstract
Background: Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis., Methods: In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome., Results: A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematopoietic-cell transplantation, acute leukemia, or other hematologic diseases. At week 12, there were successful outcomes in 52.8 percent of the patients in the voriconazole group (complete responses in 20.8 percent and partial responses in 31.9 percent) and 31.6 percent of those in the amphotericin B group (complete responses in 16.5 percent and partial responses in 15.0 percent; absolute difference, 21.2 percentage points; 95 percent confidence interval, 10.4 to 32.9). The survival rate at 12 weeks was 70.8 percent in the voriconazole group and 57.9 percent in the amphotericin B group (hazard ratio, 0.59; 95 percent confidence interval, 0.40 to 0.88). Voriconazole-treated patients had significantly fewer severe drug-related adverse events, but transient visual disturbances were common with voriconazole (occurring in 44.8 percent of patients)., Conclusions: In patients with invasive aspergillosis, initial therapy with voriconazole led to better responses and improved survival and resulted in fewer severe side effects than the standard approach of initial therapy with amphotericin B., (Copyright 2002 Massachusetts Medical Society)
- Published
- 2002
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41. Diagnosis of Systemic Fungal Diseases
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Dufresne, Simon Frédéric, Marr, Kieren A., Shoham, Shmuel, and Safdar, Amar, editor
- Published
- 2019
- Full Text
- View/download PDF
42. Urine Antigen Detection as an Aid to Diagnose Invasive Aspergillosis
- Author
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Marr, Kieren A., Datta, Kausik, Mehta, Seema, Ostrander, Darin B., Rock, Michelle, Francis, Jesse, and Feldmesser, Marta
- Published
- 2018
43. Mold Infections After Hematopoietic Stem Cell Transplantation
- Author
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Marr, Kieren A., Ljungman, Per, editor, Snydman, David, editor, and Boeckh, Michael, editor
- Published
- 2016
- Full Text
- View/download PDF
44. Diagnosis of Invasive Fungal Disease
- Author
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Neofytos, Dionissios, Marr, Kieren, and Safdar, Amar, editor
- Published
- 2011
- Full Text
- View/download PDF
45. Coronavirus Disease 2019–Associated Pulmonary Aspergillosis: A Noninvasive Screening Model for Additional Diagnostics.
- Author
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Permpalung, Nitipong, Chiang, Teresa Po-Yu, Avery, Robin K, Ostrander, Darin, Datta, Kausik, Segev, Dorry L, Durand, Christine M, Zhang, Sean X, Massie, Allan B, and Marr, Kieren A
- Subjects
PULMONARY aspergillosis ,COVID-19 ,SARS-CoV-2 ,MEDICAL screening ,COVID-19 pandemic ,LUNG diseases - Published
- 2023
- Full Text
- View/download PDF
46. Combination Therapy for Invasive Aspergillosis: Controversies and Conclusions
- Author
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Schlamm, Haran T. and Marr, Kieren A.
- Published
- 2015
- Full Text
- View/download PDF
47. Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001-2006: Overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database
- Author
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Kontoyiannis, Dimitrios P., Marr, Kieren A., Park, Benjamin J., Alexander, Barbara D., Anaissie, Elias J., Walsh, Thomas J., Ito, James, Andes, David R., Baddley, John W., Brown, Janice M., Brumble, Lisa M., Freifeld, Alison G., Hadley, Susan, Herwaldt, Loreen A., Kauffman, Carol A., Knapp, Katherine, Lyon, G. Marshall, Morrison, Vicki Á., Papanicolaou, Genovefa, Patterson, Thomas F., Perl, Trish M., Schuster, Mindy G., Walker, Randall, Wannemuehler, Kathleen A., Wingard, John R., Chilier, Tom M., and Pappas, Peter G.
- Published
- 2010
48. Invasive Fungal Infections among Organ Transplant Recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET)
- Author
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Pappas, Peter G., Alexander, Barbara D., Andes, David R., Hadley, Susan, Kauffman, Carol A., Freifeld, Alison, Anaissie, Elias J., Brumble, Lisa M., Herwaldt, Loreen, Ito, James, Kontoyiannis, Dimitrios P., Lyon, G. Marshall, Marr, Kieren A., Morrison, Vicki A., Park, Benjamin J., Patterson, Thomas F., Perl, Trish M., Oster, Robert A., Schuster, Mindy G., Walker, Randall, Walsh, Thomas J., Wannemuehler, Kathleen A., and Chiller, Tom M.
- Published
- 2010
49. Empirical versus Preemptive Antifungal Therapy for Fever during Neutropenia
- Author
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Marr, Kieren A., Leisenring, Wendy, and Bow, Eric
- Published
- 2009
50. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group
- Author
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De Pauw, Ben, Walsh, Thomas J., Donnelly, J. Peter, Stevens, David A., Edwards, John E., Calandra, Thierry, Pappas, Peter G., Maertens, Johan, Lortholary, Olivier, Kauffman, Carol A., Denning, David W., Patterson, Thomas F., Maschmeyer, Georg, Bille, Jacques, Dismukes, William E., Herbrecht, Raoul, Hope, William W., Kibbler, Christopher C., Kullberg, Bart Jan, Marr, Kieren A., Muñoz, Patricia, Odds, Frank C., Perfect, John R., Restrepo, Angela, Ruhnke, Markus, Segal, Brahm H., Sobel, Jack D., Sorrell, Tania C., Viscoli, Claudio, Wingard, John R., Zaoutis, Theoklis, and Bennett, John E.
- Published
- 2008
- Full Text
- View/download PDF
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