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      ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients

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          Abstract

          The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematologic malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first-line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. Aspergillus guidelines now recommend the use of either voriconazole or isavuconazole for first-line treatment of invasive aspergillosis, while first-line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were made to mucormycosis recommendations.

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          Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials.

          Invasive candidiasis (IC) is an important healthcare-related infection, with increasing incidence and a crude mortality exceeding 50%. Numerous treatment options are available yet comparative studies have not identified optimal therapy. We conducted an individual patient-level quantitative review of randomized trials for treatment of IC and to assess the impact of host-, organism-, and treatment-related factors on mortality and clinical cure. Studies were identified by searching computerized databases and queries of experts in the field for randomized trials comparing the effect of ≥2 antifungals for treatment of IC. Univariate and multivariable analyses were performed to determine factors associated with patient outcomes. Data from 1915 patients were obtained from 7 trials. Overall mortality among patients in the entire data set was 31.4%, and the rate of treatment success was 67.4%. Logistic regression analysis for the aggregate data set identified increasing age (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02; P = .02), the Acute Physiology and Chronic Health Evaluation II score (OR, 1.11; 95% CI, 1.08-1.14; P = .0001), use of immunosuppressive therapy (OR, 1.69; 95% CI, 1.18-2.44; P = .001), and infection with Candida tropicalis (OR, 1.64; 95% CI, 1.11-2.39; P = .01) as predictors of mortality. Conversely, removal of a central venous catheter (CVC) (OR, 0.50; 95% CI, .35-.72; P = .0001) and treatment with an echinocandin antifungal (OR, 0.65; 95% CI, .45-.94; P = .02) were associated with decreased mortality. Similar findings were observed for the clinical success end point. Two treatment-related factors were associated with improved survival and greater clinical success: use of an echinocandin and removal of the CVC.
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            Anidulafungin versus fluconazole for invasive candidiasis.

            Anidulafungin, a new echinocandin, has potent activity against candida species. We compared anidulafungin with fluconazole in a randomized, double-blind, noninferiority trial of treatment for invasive candidiasis. Adults with invasive candidiasis were randomly assigned to receive either intravenous anidulafungin or intravenous fluconazole. All patients could receive oral fluconazole after 10 days of intravenous therapy. The primary efficacy analysis assessed the global response (clinical and microbiologic) at the end of intravenous therapy in patients who had a positive baseline culture. Efficacy was also assessed at other time points. Eighty-nine percent of the 245 patients in the primary analysis had candidemia only. Candida albicans was isolated in 62% of the 245 patients. In vitro fluconazole resistance was infrequent. Most of the patients (97%) did not have neutropenia. At the end of intravenous therapy, treatment was successful in 75.6% of patients treated with anidulafungin, as compared with 60.2% of those treated with fluconazole (difference, 15.4 percentage points; 95% confidence interval [CI], 3.9 to 27.0). The results were similar for other efficacy end points. The statistical analyses failed to show a "center effect"; when data from the site enrolling the largest number of patients were removed, success rates at the end of intravenous therapy were 73.2% in the anidulafungin group and 61.1% in the fluconazole group (difference, 12.1 percentage points; 95% CI, -1.1 to 25.3). The frequency and types of adverse events were similar in the two groups. The rate of death from all causes was 31% in the fluconazole group and 23% in the anidulafungin group (P=0.13). Anidulafungin was shown to be noninferior to fluconazole in the treatment of invasive candidiasis. (ClinicalTrials.gov number, NCT00056368 [ClinicalTrials.gov]). Copyright 2007 Massachusetts Medical Society.
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              Combination antifungal therapy for invasive aspergillosis: a randomized trial.

              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. To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA. Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479). 93 international sites. 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. The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures. 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. 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. 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. Pfizer.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                March 2017
                20 December 2016
                : 102
                : 3
                : 433-444
                Affiliations
                [1 ]Infectious Diseases Service, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland
                [2 ]Division of Haemato-Oncology, St Bartholomew’s Hospital and Blizard Institute, Queen Mary University, London, UK
                [3 ]Hematology, Catholic University of Sacred Heart, Roma, Italy
                [4 ]School of Medicine, European University Cyprus, Engomi, Cyprus
                [5 ]Infectious Disease Research Program, Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology, University Children’s Hospital, Münster, Germany
                [6 ]1st Department of Medicine, University of Athens, Greece
                [7 ]Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Austria
                [8 ]University of Genova (DISSAL), Infectious Disease Division, IRCCS San Martino-IST, Genova, Italy
                [9 ]Oncology and Hematology, Hôpitaux Universitaires de Strasbourg and Université de Strasbourg, France
                Author notes
                Article
                1020433
                10.3324/haematol.2016.152900
                5394968
                28011902
                64bed7cf-ea8a-49b7-ac1c-1b3c0f797587
                Copyright©2017 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

                History
                : 05 August 2016
                : 20 December 2016
                Categories
                Guideline Article

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