A European Organization for Research and Treatment of Cancer-International Antimicrobial Therapy Group Study of Secondary Infections in Febrile, Neutropenic Patients with Cancer

Background. Neutropenic patients with cancer may develop several episodes of fever and infection during chemotherapy-induced myeloaplasia. Methods. To identify risk factors for secondary infectious episodes among patients who responded to initial antibiotic therapy, we retrospectively analyzed 2 consecutive, prospective, randomized clinical trials performed by the International Antimicrobial Therapy Group of the European Organization for Research and Treatment of Cancer during 1991-1994. Results. Of 1720 patients with their first episode of febrile neutropenia, 836 responded to the initial antibiotic regimen and were therefore suitable for our analysis. A secondary infection was observed in 129 (15%) of 836 patients that occurred at a median of 10 days (range, 1-28 days) after the onset of the primary febrile episode. Factors at both baseline and day 4 were analyzed. Age of >16 years (odds ratio [OR], 3.46; P < .001), acute leukemia in first induction (OR, 3.17; P < .001), presence of intravenous line (OR, 1.88; P = .04), severe neutropenia (defined as an absolute granulocyte count of <100 cells/mm3) on day 4 (OR, 2.72; P < .001), and type of documentation of the primary episode (i.e., microbiologically documented cause or unexplained fever; OR, 2.56; P = .001) were found to be risk factors for secondary infection. The risk of death was higher among patients who developed a secondary infectious episode than among those who did not (5.4% vs. 1.4%; P < .01). Conclusions. The clinical parameters described above may help to identify neutropenic patients at risk of developing secondary infectio

A non-parametric Bayesian model for joint cell clustering and cluster matching: identification of anomalous sample phenotypes with random effects

BACKGROUND: Flow cytometry (FC)-based computer-aided diagnostics is an emerging technique utilizing modern multiparametric cytometry systems.The major difficulty in using machine-learning approaches for classification of FC data arises from limited access to a wide variety of anomalous samples for training. In consequence, any learning with an abundance of normal cases and a limited set of specific anomalous cases is biased towards the types of anomalies represented in the training set. Such models do not accurately identify anomalies, whether previously known or unknown, that may exist in future samples tested. Although one-class classifiers trained using only normal cases would avoid such a bias, robust sample characterization is critical for a generalizable model. Owing to sample heterogeneity and instrumental variability, arbitrary characterization of samples usually introduces feature noise that may lead to poor predictive performance. Herein, we present a non-parametric Bayesian algorithm called ASPIRE (anomalous sample phenotype identification with random effects) that identifies phenotypic differences across a batch of samples in the presence of random effects. Our approach involves simultaneous clustering of cellular measurements in individual samples and matching of discovered clusters across all samples in order to recover global clusters using probabilistic sampling techniques in a systematic way. RESULTS: We demonstrate the performance of the proposed method in identifying anomalous samples in two different FC data sets, one of which represents a set of samples including acute myeloid leukemia (AML) cases, and the other a generic 5-parameter peripheral-blood immunophenotyping. Results are evaluated in terms of the area under the receiver operating characteristics curve (AUC). ASPIRE achieved AUCs of 0.99 and 1.0 on the AML and generic blood immunophenotyping data sets, respectively. CONCLUSIONS: These results demonstrate that anomalous samples can be identified by ASPIRE with almost perfect accuracy without a priori access to samples of anomalous subtypes in the training set. The ASPIRE approach is unique in its ability to form generalizations regarding normal and anomalous states given only very weak assumptions regarding sample characteristics and origin. Thus, ASPIRE could become highly instrumental in providing unique insights about observed biological phenomena in the absence of full information about the investigated samples

Hospital-acquired bloodstream infections in critically ill cirrhotic patients: a post-hoc analysis of the EUROBACT-2 international cohort study

Bloodstream infections; Cirrhotic patientsInfecciones del torrente sanguíneo; Pacientes cirróticos críticosInfeccions del torrent sanguini; Pacients cirròtics críticsBackground: Hospital-acquired bloodstream infections are common in the intensive care unit (ICU) and have a high mortality rate. Patients with cirrhosis are especially susceptible to infections, yet there is a knowledge gap in the epidemiological distinctions in hospital-acquired bloodstream infections between cirrhotic and non-cirrhotic patients in the ICU. It has been suggested that cirrhotic patients, present a trend towards more gram-positive infections, and especially enterococcal infections. This study aims to describe epidemiological differences in hospital-acquired bloodstream infections between cirrhotic and non-cirrhotic patients hospitalized in the ICU regarding infection sources, microorganisms and mortality. Methods: Using prospective Eurobact-2 international cohort study data, we compared hospital-acquired bloodstream infections sources and microorganisms in cirrhotic and non-cirrhotic patients. The association between Enterococcus faecium and cirrhosis was studied using a multivariable mixed logistic regression. The association between cirrhosis and mortality was assessed by a multivariable frailty Cox model. Results: Among the 1059 hospital-acquired bloodstream infections patients included from 101 centers, 160 had cirrhosis. Hospital-acquired bloodstream infection source in cirrhotic patients was primarily abdominal (35.6%), while it was pulmonary (18.9%) for non-cirrhotic (p < 0.01). Gram-positive hospital-acquired bloodstream infections accounted for 42.3% in cirrhotic patients compared to 33.2% in non-cirrhotic patients (p = 0.02). Hospital-acquired bloodstream infections in cirrhotic patients were most frequently caused by Klebsiella spp (16.5%), coagulase-negative Staphylococci (13.7%) and E. faecium (11.5%). E. faecium bacteremia was more frequent in cirrhotic patients (11.5% versus 4.5%, p < 0.01). After adjusting for possible confounding factors, cirrhosis was associated with higher E. faecium hospital-acquired bloodstream infections risk (Odds ratio 2.5, 95% CI 1.3-4.5, p < 0.01). Cirrhotic patients had increased mortality compared to non-cirrhotic patients (Hazard Ratio 1.3, 95% CI 1.01-1.7, p = 0.045). Conclusions: Critically ill cirrhotic patients with hospital-acquired bloodstream infections exhibit distinct epidemiology, with more Gram-positive infections and particularly Enterococcus faecium.The Eurobact-2 database received research grants from the European Society of Intensive Care Medicine (ESICM), the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study Group for Infections in Critically Ill Patients (ESGCIP), the Norva Dahlia foundation and the Redcliffe Hospital Private Practice Trust Fund. This report was prepared with no specific funding. Open access funding provided by University of Genev

Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease

Pneumococcal disease (including community-acquired pneumonia and invasive pneumococcal disease) poses a burden to the community all year round, especially in those with chronic underlying conditions. Individuals with COPD, asthma or who smoke, and those with chronic heart disease or diabetes mellitus have been shown to be at increased risk of pneumococcal disease compared with those without these risk factors. These conditions, and smoking, can also adversely affect patient outcomes, including short-term and long-term mortality rates, following pneumonia. Community-acquired pneumonia, and in particular pneumococcal pneumonia, is associated with a significant economic burden, especially in those who are hospitalised, and also has an impact on a patient's quality of life. Therefore, physicians should target individuals with COPD, asthma, heart disease or diabetes mellitus, and those who smoke, for pneumococcal vaccination at the earliest opportunity at any time of the year

Pseudomonas aeruginosa bloodstream infections in patients with cancer: differences between patients with hematological malignancies and solid tumors

Objectives: To assess the clinical features and outcomes of Pseudomonas aeruginosa bloodstream infection (PA BSI) in neutropenic patients with hematological malignancies (HM) and with solid tumors (ST), and identify the risk factors for 30-day mortality. Methods: We performed a large multicenter, retrospective cohort study including onco-hematological neutropenic patients with PA BSI conducted across 34 centers in 12 countries (January 2006-May 2018). Episodes occurring in hematologic patients were compared to those developing in patients with ST. Risk factors associated with 30-day mortality were investigated in both groups. Results: Of 1217 episodes of PA BSI, 917 occurred in patients with HM and 300 in patients with ST. Hematological patients had more commonly profound neutropenia (0.1 × 109 cells/mm) (67% vs. 44.6%; p &lt; 0.001), and a high risk Multinational Association for Supportive Care in Cancer (MASCC) index score (32.2% vs. 26.7%; p = 0.05). Catheter-infection (10.7% vs. 4.7%; p = 0.001), mucositis (2.4% vs. 0.7%; p = 0.042), and perianal infection (3.6% vs. 0.3%; p = 0.001) predominated as BSI sources in the hematological patients, whereas pneumonia (22.9% vs. 33.7%; p &lt; 0.001) and other abdominal sites (2.8% vs. 6.3%; p = 0.006) were more common in patients with ST. Hematological patients had more frequent BSI due to multidrug-resistant P. aeruginosa (MDRPA) (23.2% vs. 7.7%; p &lt; 0.001), and were more likely to receive inadequate initial antibiotic therapy (IEAT) (20.1% vs. 12%; p &lt; 0.001). Patients with ST presented more frequently with septic shock (45.8% vs. 30%; p &lt; 0.001), and presented worse outcomes, with increased 7-day (38% vs. 24.2%; p &lt; 0.001) and 30-day (49% vs. 37.3%; p &lt; 0.001) case-fatality rates. Risk factors for 30-day mortality in hematologic patients were high risk MASCC index score, IEAT, pneumonia, infection due to MDRPA, and septic shock. Risk factors for 30-day mortality in patients with ST were high risk MASCC index score, IEAT, persistent BSI, and septic shock. Therapy with granulocyte colony-stimulating factor was associated with survival in both groups. Conclusions: The clinical features and outcomes of PA BSI in neutropenic cancer patients showed some differences depending on the underlying malignancy. Considering these differences and the risk factors for mortality may be useful to optimize their therapeutic management. Among the risk factors associated with overall mortality, IEAT and the administration of granulocyte colony-stimulating factor were the only modifiable variables.Funding: This study was supported by the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC) (CB21/13/00009; CB21/13/00079; CB21/13/00054; CB21/13/00086), Madrid, Spain. Acknowledgments: We thank the ESCMID Study Group for Bloodstream Infections, Endocarditis, and Sepsis (ESGBIES) and the ESCMID Study Group for Immunocompromised Hosts (ESGICH) for supporting the study. We thank the Centres de Recerca de Catalunya (CERCA) Program and Generalitat de Catalunya for the institutional support. We thank the Spanish Network for Research in Infectious Diseases and the Río Hortega program of the Instituto de Salud Carlos III for the financial support of pre-doctoral student J. Laporte-Amargós and A. Bergas

Clinical efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR)

Introduction: Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. Methods and analysis: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. Sample size: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. Ethics and dissemination: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH)

Pseudomonas aeruginosa Bloodstream Infections in Patients with Cancer: Differences between Patients with Hematological Malignancies and Solid Tumors

Objectives: To assess the clinical features and outcomes of Pseudomonas aeruginosa bloodstream infection (PA BSI) in neutropenic patients with hematological malignancies (HM) and with solid tumors (ST), and identify the risk factors for 30-day mortality. Methods: We performed a large multicenter, retrospective cohort study including onco-hematological neutropenic patients with PA BSI conducted across 34 centers in 12 countries (January 2006-May 2018). Episodes occurring in hematologic patients were compared to those developing in patients with ST. Risk factors associated with 30-day mortality were investigated in both groups. Results: Of 1217 episodes of PA BSI, 917 occurred in patients with HM and 300 in patients with ST. Hematological patients had more commonly profound neutropenia (0.1 x 10(9) cells/mm) (67% vs. 44.6%; p < 0.001), and a high risk Multinational Association for Supportive Care in Cancer (MASCC) index score (32.2% vs. 26.7%; p = 0.05). Catheter-infection (10.7% vs. 4.7%; p = 0.001), mucositis (2.4% vs. 0.7%; p = 0.042), and perianal infection (3.6% vs. 0.3%; p = 0.001) predominated as BSI sources in the hematological patients, whereas pneumonia (22.9% vs. 33.7%; p < 0.001) and other abdominal sites (2.8% vs. 6.3%; p = 0.006) were more common in patients with ST. Hematological patients had more frequent BSI due to multidrug-resistant P. aeruginosa (MDRPA) (23.2% vs. 7.7%; p < 0.001), and were more likely to receive inadequate initial antibiotic therapy (IEAT) (20.1% vs. 12%; p < 0.001). Patients with ST presented more frequently with septic shock (45.8% vs. 30%; p < 0.001), and presented worse outcomes, with increased 7-day (38% vs. 24.2%; p < 0.001) and 30-day (49% vs. 37.3%; p < 0.001) case-fatality rates. Risk factors for 30-day mortality in hematologic patients were high risk MASCC index score, IEAT, pneumonia, infection due to MDRPA, and septic shock. Risk factors for 30-day mortality in patients with ST were high risk MASCC index score, IEAT, persistent BSI, and septic shock. Therapy with granulocyte colony-stimulating factor was associated with survival in both groups. Conclusions: The clinical features and outcomes of PA BSI in neutropenic cancer patients showed some differences depending on the underlying malignancy. Considering these differences and the risk factors for mortality may be useful to optimize their therapeutic management. Among the risk factors associated with overall mortality, IEAT and the administration of granulocyte colony-stimulating factor were the only modifiable variables

Pseudomonas aeruginosa Bloodstream Infections Presenting with Septic Shock in Neutropenic Cancer Patients: Impact of Empirical Antibiotic Therapy

This large, multicenter, retrospective cohort study including onco-hematological neutropenic patients with Pseudomonas aeruginosa bloodstream infection (PABSI) found that among 1213 episodes, 411 (33%) presented with septic shock. The presence of solid tumors (33.3% vs. 20.2%, p < 0.001), a high-risk Multinational Association for Supportive Care in Cancer (MASCC) index score (92.6% vs. 57.4%; p < 0.001), pneumonia (38% vs. 19.2% p < 0.001), and infection due to multidrug-resistant P. aeruginosa (MDRPA) (33.8% vs. 21.1%, p < 0.001) were statistically significantly higher in patients with septic shock compared to those without. Patients with septic shock were more likely to receive inadequate empirical antibiotic therapy (IEAT) (21.7% vs. 16.2%, p = 0.020) and to present poorer outcomes, including a need for ICU admission (74% vs. 10.5%; p < 0.001), mechanical ventilation (49.1% vs. 5.6%; p < 0.001), and higher 7-day and 30-day case fatality rates (58.2% vs. 12%, p < 0.001, and 74% vs. 23.1%, p < 0.001, respectively). Risk factors for 30-day case fatality rate in patients with septic shock were orotracheal intubation, IEAT, infection due to MDRPA, and persistent PABSI. Therapy with granulocyte colony-stimulating factor and BSI from the urinary tract were associated with improved survival. Carbapenems were the most frequent IEAT in patients with septic shock, and the use of empirical combination therapy showed a tendency towards improved survival. Our findings emphasize the need for tailored management strategies in this high-risk population

VACCELERATE Site Network: Real-time definition of clinical study capacity in Europe

Background: The inconsistent European vaccine trial landscape rendered the continent of limited interest for vaccine developers. The VACCELERATE consortium created a network of capable clinical trial sites throughout Europe. VACCELERATE identifies and provides access to state-of-the-art vaccine trial sites to accelerate clinical development of vaccines. Methods: Login details for the VACCELERATE Site Network (vaccelerate.eu/site-network/) questionnaire can be obtained after sending an email to. Interested sites provide basic information, such as contact details, affiliation with infectious disease networks, main area of expertise, previous vaccine trial experience, site infrastructure and preferred vaccine trial settings. In addition, sites can recommend other clinical researchers for registration in the network. If directly requested by a sponsor or sponsor representative, the VACCELERATE Site Network pre-selects vaccine trial sites and shares basic study characteristics provided by the sponsor. Interested sites provide feedback with short surveys and feasibility questionnaires developed by VACCELERATE and are connected with the sponsor to initiate the site selection process. Results: As of April 2023, 481 sites from 39 European countries have registered in the VACCELERATE Site Network. Of these, 137 (28.5 %) sites have previous experience conducting phase I trials, 259 (53.8 %) with phase II, 340 (70.7 %) with phase III, and 205 (42.6 %) with phase IV trials, respectively. Infectious diseases were reported as main area of expertise by 274 sites (57.0 %), followed by any kind of immunosuppression by 141 (29.3 %) sites. Numbers are super additive as sites may report clinical trial experience in several indications. Two hundred and thirty-one (47.0 %) sites have the expertise and capacity to enrol paediatric populations and 391 (79.6 %) adult populations. Since its launch in October 2020, the VACCELERATE Site Network has been used 21 times for academic and industry trials, mostly interventional studies, focusing on different pathogens such as fungi, monkeypox virus, Orthomyxoviridae/influenza viruses, SARS-CoV-2, or Streptococcus pneumoniae/pneumococcus. Conclusions: The VACCELERATE Site Network enables a constantly updated Europe-wide mapping of experienced clinical sites interested in executing vaccine trials. The network is already in use as a rapid-turnaround single contact point for the identification of vaccine trials sites in Europe.The VACCELERATE Site Network has received funding from the European Union’s Horizon 2020 research and innovation pro gramme (grant agreement No 101037867) and the German Federal Ministry of Education and Research (Bundesministerium für Bil dung und Forschung [BMBF]) (grant agreement No BMBF01KX2040).S