Showing papers by "Oliver A. Cornely published in 2011"

European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3—2009 Update

Abstract: In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.

Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia

Abstract: Background Targeted therapies to stabilize the clinical manifestations and prolong pregnancy in preeclampsia do not exist. Soluble fms-like tyrosine kinase 1 (sFlt-1), an alternatively spliced variant of the vascular endothelial growth factor receptor 1, induces a preeclampsia-like phenotype in experimental models and circulates at elevated levels in human preeclampsia. Removing sFlt-1 may benefit women with very preterm ( Methods and results We first show that negatively charged dextran sulfate cellulose columns adsorb sFlt-1 in vitro. In 5 women with very preterm preeclampsia and elevated circulating sFlt-1 levels, we next demonstrate that a single dextran sulfate cellulose apheresis treatment reduces circulating sFlt-1 levels in a dose-dependent fashion. Finally, we performed multiple apheresis treatments in 3 additional women with very preterm (gestational age at admission 28, 30, and 27+4 weeks) preeclampsia and elevated circulating sFlt-1 levels. Dextran sulfate apheresis lowered circulating sFlt-1, reduced proteinuria, and stabilized blood pressure without apparent adverse events to mother and fetus. Pregnancy lasted for 15 and 19 days in women treated twice and 23 days in a woman treated 4 times. In each, there was evidence of fetal growth. Conclusions This pilot study supports the hypothesis that extracorporeal apheresis can lower circulating sFlt-1 in very preterm preeclampsia. Further studies are warranted to determine whether this intervention safely and effectively prolongs pregnancy and improves maternal and fetal outcomes in this setting.

Diagnosis and therapy of Candida infections: joint recommendations of the German Speaking Mycological Society and the Paul‐Ehrlich‐Society for Chemotherapy

Abstract: Summary Invasive Candida infections are important causes of morbidity and mortality in immunocompromised and hospitalised patients. This article provides the joint recommendations of the German-speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMyKG) and the Paul-Ehrlich-Society for Chemotherapy (PEG) for diagnosis and treatment of invasive and superficial Candida infections. The recommendations are based on published results of clinical trials, case-series and expert opinion using the evidence criteria set forth by the Infectious Diseases Society of America (IDSA). Key recommendations are summarised here: The cornerstone of diagnosis remains the detection of the organism by culture with identification of the isolate at the species level; in vitro susceptibility testing is mandatory for invasive isolates. Options for initial therapy of candidaemia and other invasive Candida infections in non-granulocytopenic patients include fluconazole or one of the three approved echinocandin compounds; liposomal amphotericin B and voriconazole are secondary alternatives because of their less favourable pharmacological properties. In granulocytopenic patients, an echinocandin or liposomal amphotericin B is recommended as initial therapy based on the fungicidal mode of action. Indwelling central venous catheters serve as a main source of infection independent of the pathogenesis of candidaemia in the individual patients and should be removed whenever feasible. Pre-existing immunosuppressive treatment, particularly by glucocorticosteroids, ought to be discontinued, if feasible, or reduced. The duration of treatment for uncomplicated candidaemia is 14 days following the first negative blood culture and resolution of all associated symptoms and findings. Ophthalmoscopy is recommended prior to the discontinuation of antifungal chemotherapy to rule out endophthalmitis or chorioretinitis. Beyond these key recommendations, this article provides detailed recommendations for specific disease entities, for antifungal treatment in paediatric patients as well as a comprehensive discussion of epidemiology, clinical presentation and emerging diagnostic options of invasive and superficial Candida infections.

Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

Abstract: Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

Therapeutic Drug Monitoring of Voriconazole and Posaconazole

Abstract: Despite the availability of newer antifungal agents, invasive fungal diseases remain a leading cause of morbidity and mortality in immunocompromised patients. Voriconazole and posaconazole are two extended-spectrum triazoles indicated for treatment and prophylaxis of invasive fungal diseases. Recently, there has been increased interest in the utility of therapeutic drug monitoring to optimize safety and efficacy of antifungals in an attempt to improve patient outcomes. We reviewed the pharmacokinetic and pharmacodynamic characteristics of voriconazole and posaconazole in the context of clinical indications for therapeutic drug monitoring. In addition, the most recent evidence examining the relationship between serum concentrations of voriconazole and posaconazole and their efficacy or toxicities was evaluated. This information was then integrated to formulate recommendations for use of therapeutic drug monitoring in clinical settings.

Efficacy outcomes in a randomised trial of liposomal amphotericin B based on revised EORTC/MSG 2008 definitions of invasive mould disease

Abstract: In 2008, the European Organisation for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) published revised definitions for diagnosing invasive fungal disease. A previous prospective trial of liposomal amphotericin B for invasive mould disease (AmBiLoad) used modified EORTC/MSG 2002 criteria. We wished to re-evaluate the response and survival based on the revised definitions to compare the outcomes of early vs. late treatment. Patients who had received an allogeneic haematopoietic stem cell transplant or who were neutropaenic (absolute neutrophil count <500 μl(-1) within 14 days of study entry) had been recruited on the basis of a halo or air crescent sign on chest computerised tomography. Originally classified as probable invasive mould disease, they were categorised as possible invasive mould disease using 2008 criteria. Patients had received liposomal amphotericin B at either 3 or 10 mg kg(-1) QD for 14 days, followed by 3 mg kg(-1) QD. Response at end of treatment and the 12-week survival were re-calculated according to 2008 definitions. Six-week survival was estimated by Kaplan-Meier analysis. Of 201 patients with invasive mould disease, 118 (59%) had a diagnosis based on halo signs (possible cases). Mycological evidence was present in 83 (41%) cases (probable/proven cases). Survival rates at 12 weeks for possible vs. probable/proven cases in the 3 mg kg(-1) QD group were 82% vs. 58% (P = 0.006), and 65% vs. 50% (P = 0.15) in the 10 mg kg(-1) QD group. At 6 weeks, rates were 87% vs. 69% in the 3 mg kg(-1) QD group (P = 0.009), and 75% vs. 61% in the 10 mg kg(-1) QD group (P = 0.01). Patients with possible invasive mould disease based on EORTC/MSG 2008 criteria had improved survival rates compared with those treated for probable/proven invasive mould disease. As possible invasive mould disease probably reflects an early-stage of disease, a better outcome might be expected when treatment with liposomal amphotericin B is started preemptively.

Evaluating the role of prophylaxis in the management of invasive fungal infections in patients with hematologic malignancy

Abstract: Invasive fungal infection (IFI) is a persistent problem among critically ill and immunocompromised patients, especially hematopoietic stem cell transplant or solid organ transplant recipients, or patients on intensive chemotherapy for acute leukemia. Although numerous antifungal agents are available, IFI remains a serious problem because of obstacles to timely diagnosis and high morbidity and mortality rates associated with such infection. Improvements in treatment of underlying diseases have rapidly expanded the patient populations at risk for IFI with increased use of immunosuppressants, aggressive chemotherapy, broad-spectrum antibiotics, and narrow-spectrum antifungal prophylaxis. There are various treatment strategies that can be used to manage IFI: prophylaxis, empiric, preemptive, and directed. As the infection progresses, the prospect of successfully treating an infection diminishes; conversely, the earlier the intervention, the greater the possibility of unnecessary treatment. This article discusses the epidemiology of the most important fungal pathogens, identifies high-risk patient groups and risk factors associated with IFI, and critically evaluates the advantages and disadvantages of available diagnostic tests and treatment strategies and the rationale for antifungal prophylaxis. For patients at high risk for IFI, antifungal prophylaxis is an attractive strategy, and numerous randomized, controlled clinical studies have documented the benefit of such prophylaxis as well as the most efficacious of currently available agents.

Accumulated safety data of micafungin in therapy and prophylaxis in fungal diseases

Abstract: Objective: To define better the safety profile of micafungin, an analysis of micafungin clinical trial safety data was undertaken. Research design and methods: Adverse event data were pooled worldwide from 17 clinical efficacy and safety studies. Adverse events were coded using the Medical Dictionary for Regulatory Activities version 5.0. Results: In the pooled clinical trial data set, 3028 patients received at least one dose of micafungin. The mean age of patients was 41.4 years; with 296 (9.8%) children (< 16 years) and 387 (12.8%) elderly patients (≥ 65 years). Common underlying conditions were hematopoietic stem cell and other transplantations (26.1%), malignancies (20.8%) and HIV (32.9%). Mean exposure was 18 days for adults and 29 days for children. The most frequently reported treatment-related adverse events were nausea (2.8%), vomiting (2.5%), phlebitis (2.5%), hypokalemia (2.1%), fever/pyrexia (2.1%) and diarrhea (2%), as well as increases in alkaline phosphatase (2.7%), aspartate aminotransfera...

Current issues in the clinical management of invasive aspergillosis – the AGIHO, DMykG, ÖGMM and PEG web-based survey and expert consensus conference 2009

Abstract: The objectives of this study were to identify unsolved issues in the management of invasive aspergillosis, identify controversies and achieve consensus. The German Speaking Mycological Society (Deutschsprachige Mykologische Gesellschaft, DMykG) invited other German infectious diseases (ID) and mycological societies to submit unsolved issues concerning the diagnosis and treatment of invasive aspergillosis. Based on these contributions, a digital web-based questionnaire of 12 questions on Aspergillus spp. was designed to be completed by experts of the participating societies. Controversial results were identified by a mathematical model and were discussed at a consensus conference during the 43rd Annual Meeting of the DMykG in Cologne, Germany. Forty-two individuals completed the questionnaire. Analysis showed a strong consensus on effective preventive measures, choice of antifungal agents for pre-emptive, empiric and targeted treatment, as well as the evaluation of early chest CT control scans as a measure of treatment response assessment. Opinions on the indication for a pulmonary biopsy of a halo sign in high-risk neutropenic patients and on the role of Aspergillus spp. PCR as well as galactomannan from serum in the assessment of treatment duration diverged in spite of discussion such that a consensus could not be reached. Using a recently published two-step approach - web-based survey plus classical panel discussion - expert consensus was achieved on 10 of 12 questions concerning the diagnosis and treatment of invasive aspergillosis.

Clinically defined chemotherapy-associated bowel syndrome predicts severe complications and death in cancer patients

Abstract: Background Neutropenic patients are at risk of abdominal complications and yet the incidence and impact of these complications on patients’ morbidity and mortality have not been sufficiently evaluated. We aimed to assess a clinical rule for early detection of abdominal complications leading to death or transfer to intensive care in patients with chemotherapy-associated neutropenia. Design and Methods This observational multicenter study was carried out in seven German hematology-oncology departments. For inclusion, neutropenia of at least 5 consecutive days was required. Risk factors for “transfer to intensive care” and “death” were assessed by backward-stepwise binary logistic regression analyses. Chemotherapy-associated bowel syndrome was defined as a combination of fever (T ≥37.8 °C) and abdominal pain and/or lack of bowel movement for 72 hours or more. Five hundred and twenty-one neutropenic episodes were documented in 359 patients. Results The incidence of chemotherapy-associated bowel syndrome was 126/359 (35%) in first episodes of neutropenia. Transfer to intensive care occurred in 41/359 (11%) and death occurred in 17/359 (5%) first episodes. Chemotherapy-associated bowel syndrome and duration of neutropenia were identified as risk factors for transfer to intensive care ( P <0.001; OR 4.753; 95% CI 2.297–9.833, and P =0.003; OR 1.061/d; 95% CI 1.021–1.103). Chemotherapy-associated bowel syndrome and mitoxantrone administration were identified as risk factors for death ( P =0.005; OR 4.611; 95% CI 1.573–13.515 and P =0.026; OR 3.628; 95% CI 1.169–11.256). Conclusions The occurrence of chemotherapy-associated bowel syndrome has a significant impact on patients’ outcome. In future interventional clinical trials, this definition might be used as a selection criterion for early treatment of patients at risk of severe complications.

Efficacy and safety of micafungin for treatment of serious Candida infections in patients with or without malignant disease.

Abstract: The aim of this study was to evaluate micafungin efficacy for treatment of invasive candidiasis/candidaemia in patients with cancer. Modified intent-to-treat populations were analysed from two trials: one, in adults and children with confirmed Candida infection, compared micafungin (adults 100 mg day(-1); children 2 mg kg(-1) day(-1)) with liposomal amphotericin B (L-AmB 3 mg kg(-1) day(-1)); and the other, in adults only, compared micafungin (100 or 150 mg day(-1)) with caspofungin (50 mg day(-1); 70 mg loading dose). Primary efficacy endpoint in both trials was treatment success, defined as both clinical and mycological response at end of therapy. In the micafungin/L-AmB trial, 183/489 patients had malignancy (37% neutropenic). In the micafungin/caspofungin trial, 176/572 patients had malignancy (26% neutropenic). Micafungin treatment success rates were generally similar in patients with/without malignancy and to rates observed with L-AmB and caspofungin. Most patients with malignancy and neutropenia were successfully treated by all three drugs. For all drugs, incidence of discontinuations because of treatment-related adverse events was similar for patients with malignancy (≤7.7%) vs. no malignancy (≤8.0%). These results suggest that compared with L-AmB and caspofungin, micafungin was effective and well tolerated in patients with candidiasis/candidaemia with/without malignancy. Further prospective trials are recommended to evaluate comparative outcomes with a primary focus on patients with malignancies and invasive candidiasis.

Making Moulds Meet Information retrieval as a basis for understanding Pseudallescheria and Scedosporium

Abstract: G. S. de Hoog, V. Robert, M. Lackner, M. J. G. T. Vehreschild, J. J. Vehreschild, F. Symoens, E. Gottlich-Fligg, D. Garcia-Hermoso, A. Harun, W. Meyer, S. C. A. Chen, A. Hamprecht, G. Fischer, W. Buzina, O. A. Cornely, J. Guarro, J. Cano and R. Horre* CBS-KNAW Fungal Biodiversity Centre, Utrecht, The Netherlands, Institute for Biodiversity and Ecosystem Dynamics, University of Amsterdam, The Netherlands, Peking University Health Science Center, Research Center for Medical Mycology, Beijing, China, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China, Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria, 1st Department of Internal Medicine, University of Cologne, Cologne, Germany, Scientific Institute of Public Health, Brussels, Belgium, BZH Deutsches Beratungszentrum fur Hygiene des Universitatsklinikums Freiburg, Freiburg, Germany, Institut Pasteur, Unite de Mycologie Moleculaire, Centre National de Reference Mycologie et Antifongiques, Paris, France, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia, Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Westmead Millennium Institute, Sydney Medical School Westmead Hospital, Sydney, The University of Sydney, Australia, Landesgesundheitsamt Baden-Wurttemberg, Stuttgart, Germany, Institute of Hygiene, Microbiology and Environmental Medicine, Medical University Graz, Graz, Austria, Clinical Trials Centre Cologne, ZKS Koln, University of Cologne, Cologne, Germany, Center for Integrated Oncology CIO Koln-Bonn, University of Cologne, Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany, Facultad de Medicina, Universitat Rovira i Virgili, Reus, Spain, Institute for Medical Microbiology, Immunology and Parasitology, University of Bonn, Bonn, Germany and Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany

Voriconazole as secondary antifungal prophylaxis in stem cell transplant recipients.

Abstract: A recently published editorial by Dr. Girmenia addressed the difficult issue of preventing invasive fungal disease in hematology patients. [1][1] The author concluded that several questions remained unanswered concerning the use of secondary antifungal prophylaxis in this setting. We agree with Dr.

Association of HSV reactivation and pro-inflammatory cytokine levels with the severity of stomatitis after BEAM chemotherapy and autologous SCT.

Abstract: Background Stomatitis, including oral mucositis and ulcerations induced by HSV-reactivation are major sources of morbidity after high-dose (HD) chemotherapy and subsequent autologous hematopoietic stem cell transplantation (SCT). While increased synthesis of pro-inflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α)—as well as reactivation of viral infections have frequently been observed in this setting, data on their association with the severity of mucositis is limited.

Voriconazole serum concentrations in prophylactically treated acute myelogenous leukaemia patients.

Abstract: Summary Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9‐21). The mean voriconazole concentration was 486 l gl )1 and ranged from 136 l gl )1 to 1257 l gl )1 . Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis.

Acceptance and tolerability of an adjuvanted nH1N1 vaccine in HIV-infected patients in the Cologne-Bonn cohort

Abstract: Objective To evaluate the acceptance and tolerability of the nH1N1 2009 vaccine in HIV-positive individuals.