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Rituximab (RTX) has been classified as a drug associated with a high risk for hepatitis B virus (HBV) reactivation in HbsAg-negative/anti-HBc-positive patients. However, data on frequency of HBV reactivation are limited especially for RTX monotherapy. Several new recommendations for screening, monitoring and prophylactic antiviral treatment have been published recently. Here, we report the real-life experience in the management and reactivation rate of HbsAg-negative/anti-HBc-positive patients treated with RTX with or without chemotherapy from a large cohort and discuss our results in the light of updated recommendations.

Background Weight gain effects of individual antiretroviral drugs are not fully understood. We investigated associations between a prespecified clinically significant increase (>7%) in body-mass index (BMI) and contemporary antiretroviral use. Methods The International Cohort Consortium of Infectious Diseases (RESPOND) is a prospective, multicohort collaboration, including data from 17 well established cohorts and over 29 000 people living with HIV. People with HIV under prospective follow-up from Jan 1, 2012, and older than 18 years were eligible for inclusion. Each cohort contributed a predefined minimum number of participants related to the size of the specific cohort (with a minimum of 1000 participants). Participants were required to have CD4 cell counts and HIV viral load measurement in the 12 months before or within 3 months after baseline. For all antiretroviral drugs received at or after RESPOND entry, changes from pre-antiretroviral BMI levels (baseline) were considered at each BMI measurement during antiretroviral treatment. We used logistic regression to identify individual antiretrovirals that were associated with first occurrence of a more than 7% increase in BMI from pre-antiretroviral BMI. We adjusted analyses for time on antiretrovirals, pre-antiretroviral BMI, demographics, geographical region, CD4 cell count, viral load, smoking status, and AIDS at baseline. Findings 14 703 people were included in this study, of whom 7863 (53middot5%) had a more than 7% increase in BMI. Compared with lamivudine, use of dolutegravir (odds ratio [OR] 1middot27, 95% CI 1middot17-1middot38), raltegravir (1middot37, 1middot20-1middot56), and tenofovir alafenamide (1middot38, 1middot22-1middot35) was significantly associated with a more than 7% BMI increase, as was low pre-antiretroviral BMI (2middot10, 1middot91-2middot31 for underweight vs healthy weight) and Black ethnicity (1middot61, 1middot47-1middot76 vs White ethnicity). Higher CD4 count was associated with a reduced risk of BMI increase (0middot97, 0middot96-0middot98 per 100 cells per mu L increase). Relative to lamivudine, dolutegravir without tenofovir alafenamide (OR 1middot21, 95% CI 1middot19-1middot32) and tenofovir alafenamide without dolutegravir (1middot33, 1middot15-1middot53) remained independently associated with a more than 7% increase in BMI; the associations were higher when dolutegravir and tenofovir alafenamide were used concomitantly (1middot79, 1middot52-2middot11, and 1middot70, 1middot44-2middot01, respectively). Interpretation Clinicians and people with HIV should be aware of associations between weight gain and use of dolutegravir, tenofovir alafenamide, and raltegravir, particularly given the potential consequences of weight gain, such as insulin resistance, dyslipidaemia, and hypertension. Funding The CHU St Pierre Brussels HIV Cohort, The Austrian HIV Cohort Study, The Australian HIV Observational Database, The AIDS Therapy Evaluation in the Netherlands national observational HIV cohort, The EuroSIDA cohort, The Frankfurt HIV Cohort Study, The Georgian National AIDS Health Information System, The Nice HIV Cohort, The ICONA Foundation, The Modena HIV Cohort, The PISCIS Cohort Study, The Swiss HIV Cohort Study, The Swedish InfCare HIV Cohort, The Royal Free HIV Cohort Study, The San Raffaele Scientific Institute, The University Hospital Bonn HIV Cohort and The University of Cologne HIV Cohorts, ViiV Healthcare, and Gilead Sciences. Copyright (c) 2021 Elsevier Ltd. All rights reserved.

Objectives: Although outcomes of antiretroviral therapy (ART) have been evaluated in randomized controlled trials, experiences from subpopulations defined by age, CD4 count or viral load (VL) in heterogeneous real-world settings are limited. Methods: The study design was an international multicohort collaboration. Logistic regression was used to compare virological and immunological outcomes at 12±3months after starting ART with an integrase strand transfer inhibitor (INSTI), contemporary nonnucleoside reverse transcriptase inhibitor (NNRTI) or boosted protease inhibitor (PI/b) with two nucleos(t)ides after 1 January 2012. The composite treatment outcome (cTO) defined success as VL'200 HIV-1 RNA copies/mL with no regimen change and no AIDS/death events. Immunological success was defined as a CD4count '750cells/μL or a 33% increase where the baseline CD4 count was ≥500 cells/μL. Poisson regression compared clinical failures (AIDS/death≥14days after starting ART). Interactions between ART class and age, CD4 count, and VL were determined for each endpoint. Results: Of 5198 ART-naïve persons in the International Cohort Consortium of Infectious Diseases (RESPOND), 45.4% started INSTIs, 26.0% PI/b and 28.7% NNRTIs; 880 (17.4%) were aged ' 50years, 2539 (49.4%) had CD4 counts '350 cells/μL and 1891 (36.8%) had VL'100000 copies/mL. Differences in virological and immunological success and clinical failure among ART classes were similar across age groups (≤ 40, 40–50 and '50 years), CD4 count categories (≤ 350 vs. '350 cells/μL) and VL categories at ART initiation (≤ 100000 vs. '100000copies/mL), with all investigated interactions being nonsignificant (P'0.05). Conclusions: Differences among ART classes in virological, immunological and clinical outcomes in ART-naïve participants were consistent irrespective of age, immune suppression or VL at ART initiation. While confounding by indication cannot be excluded, this provides reassuring evidence that such subpopulations will equally benefit from contemporary ART.

Summary Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection., Graphical Abstract, Highlights • Identification of 1-18, a highly broad and potent VH1-46-derived CD4bs antibody • 2.5-Å cryo-EM structure of 1-18-Env complex reveals inter-protomer contacts • 1-18 overcomes VRC01-class resistance and restricts development of HIV-1 escape • Monotherapy with 1-18 maintains viral suppression in HIV-1YU2-infected humanized mice, Broadly neutralizing antibodies targeting the HIV-1 envelope protein are a promising option for prevention and treatment of HIV-1 infection. However, development of viral resistance can limit clinical efficacy. Schommers et al. identify a highly broad and potent antibody that targets the CD4 binding site of HIV-1. Compared with other potent CD4 binding site antibodies, it restricts the development of viral escape and effectively suppresses HIV-1 in vivo.

Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions.

Background Advances in the survival of patients with invasive aspergillosis (IA) are jeopardized by the emergence of azole resistance in Aspergillus fumigatus, which has been associated with high probability of azole treatment failure. The clinical implications of azole-resistant IA compared to azole-susceptible IA remain unclear. Thus, we seek to describe the epidemiology and to determine the efficacy of antifungal therapy in patients with documented azole-resistant IA compared to azole-susceptible IA in patients with hematological malignancy. Methods For proven and probable IA (EORTC/MSG 2019) caused by A. fumigatus in patients with hematological malignancies retrospective data were documented, comprising demographics, diagnosis, treatment, response, and outcome. Sites provided susceptibility results or respective isolates for analysis in a central laboratory. Results Sites in 16 countries worldwide enrolled 187 cases diagnosed with IA between 2010 and 2019; 31 (16.6%) were resistant to at least one of the clinical azoles. Fungal isolates were available from 42 cases. A mixed fungal infection was reported for 32 patients (17.1%), most were related to non-fumigatus Aspergillus and non-Aspergillus molds (n=22, 69%). Most patients were male (66.8%) and overall the majority of patients were in the age groups between 50 and 89 years (71%). Amphotericin B was used for treatment in 24 (77%) patients with azole-resistant IA, compared to 76 (49%) in the azole-susceptible group (lipid-based formulation in 98%); only five (16%) patients with azole-resistant IA were treated with an azole alone vs. 57 (36%) of those with azole-susceptible IA. Overall, all-cause mortality rate was higher for patients with azole-resistant compared to azole-susceptible IA (74.2% vs. 53.8%, log rank P=0.004), the 8 patients with an azole-resistant IA treated in the intensive care unit died within 1 month (Figure 1). Details on underlying disease and survival are given in Table 1. Table 1. Underlying hematological malignancy and clinical outcome of patients with azole-resistant and azole-susceptible invasive aspergillosis Figure 1. Intensive care unit 1-year survival probability for patients with azole-resistant and azole-susceptible invasive aspergillosis Conclusion Azole-resistance in IA is associated with worse outcome, especially in critically ill patients. Susceptibility testing should be considered in patients with a suspected azole-resistant IA to support treatment decisions. Disclosures Danila Seidel, PhD, Basilea (Other Financial or Material Support, travel grant) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Philipp Koehler, MD, Akademie für Infektionsmedizin e.V., (Other Financial or Material Support, Personal fees)Astellas Pharma GmbH (Other Financial or Material Support, Personal fees)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany (Other Financial or Material Support, Other)Gilead Sciences GmbH (Other Financial or Material Support, Personal fees)GPR Academy Ruesselsheim (Speaker’s Bureau)Miltenyi Biotec GmbH (Other Financial or Material Support, Non-financial support)MSD Sharp & Dohme GmbH (Other Financial or Material Support, Personal fees)Noxxon N.V. (Speaker’s Bureau)University Hospital, LMU Munich (Other Financial or Material Support, Personal fees) Katrien Lagrou, n/a, FUJIFILM WAKO (Speaker’s Bureau)Gilead (Consultant, Speaker’s Bureau)MSD (Consultant, Speaker’s Bureau, Other Financial or Material Support, travel grant)Pfizer (Speaker’s Bureau, travel grant)SMB Laboratoires Brussels (Consultant) Zdenek Racil, n/a, Astellas (Grant/Research Support, Speaker’s Bureau, travel grant) Blandine Rammaert, n/a, Gilead (Speaker’s Bureau, Other Financial or Material Support, travel grant)Merck/MSD (Speaker’s Bureau)Pfizer (Other Financial or Material Support, travel grant) Nikolay Klimko, n/a, Astellas (Speaker’s Bureau)Gilead (Speaker’s Bureau)Merck/MSD (Speaker’s Bureau)Pfizer (Speaker’s Bureau) Sung-Yeon Cho, MD, Gilead (Grant/Research Support, Speaker’s Bureau)Merck Sharp & Dohme (Grant/Research Support, Speaker’s Bureau)Pfizer (Grant/Research Support, Speaker’s Bureau)

Background We conduct a retrospective, multinational cohort study with a nested case–control (NCT03353532). Data from all patients undergoing any surgical procedure in 2016 are collected within the cohort, comprising more than 150,000 procedures. S. aureus SSI cases are documented in an electronic database and matched 1:1 to controls within each center. Criteria for matching include epidemiological data and type of procedure. Participating sites are 14 major surgical centers in France, Germany, Italy, Spain, and the UK. We here present preliminary data from the interim analysis. Methods We conduct a retrospective, multinational cohort study with a nested case–control (NCT03353532). Data from all patients undergoing any surgical procedure in 2016 are collected within the cohort, comprising more than 150,000 procedures. S. aureus SSI cases are documented in an electronic database and matched 1:1 to controls within each center. Criteria for matching include epidemiological data and type of procedure. Participating sites are 14 major surgical centers in France, Germany, Italy, Spain, and the UK. We here present preliminary data from the interim analysis. Results We determine overall and procedure-specific incidence of S. aureus SSI. To date, 619 cases have been documented with a mean age of 59.0 years, 50,7% male and 49.3% female. Chronic cardiovascular disease (23%), diabetes (22%), and solid tumors (18%) are the most frequent comorbidities. Overall length of hospitalization is 19 days. A total of 20% SSI cases were treated at the intensive care unit, 49% were readmitted to the hospital, and 47% patients needed revision surgery. Conclusion The study includes all surgical procedures at participating centers allowing us to determine the incidence for all common surgical procedures aiming to better understand the risk of certain procedures. Furthermore, the study will analyze the risk composition of the surgical patient population to enable the calculation of the number of patients at risk in the overall surgical population in Europe. Predictive factors for S. aureus SSIwill be analyzed and thus allow future investigation into targeted prophylactic strategies such as S. aureus vaccines. Disclosures All authors: No reported disclosures.

Background Timely availability of microbiological results from positive blood cultures is essential to enable early pathogen-directed therapy. The Accelerate Pheno system (ADX) is a novel technology using fluorescence in situ hybridization for rapid species identification (ID) and morphokinetic bacterial analysis for phenotypic antimicrobial susceptibility testing (AST), with promising results. Yet the impact of this technology on clinical management and patient outcome remains unclear. Methods We conducted a quasiexperimental before-and-after observational study and analyzed 3 groups with different diagnostic and therapeutic pathways following recent integration of ADX: conventional microbiological diagnostics with and without antimicrobial stewardship program (ASP) intervention, and rapid diagnostics (ADX in addition to conventional standard) with ASP intervention. Primary endpoints were time to adequate, to optimal and to step-down antimicrobial therapy. Secondary endpoints were antimicrobial consumption, in-hospital mortality, length of stay (LOS), and the incidence of Clostridioidesdifficile infection (CDI). Results Two hundred four patients (conventional diagnostics, n = 64; conventional diagnostics + ASP, n = 68; rapid diagnostics + ASP; n = 72) were evaluated. The use of ADX significantly decreased time from Gram stain to ID (median, 23 vs 2.2 hours, P < .001) and AST (median, 23 vs 7.4 hours, P < .001), from Gram stain to optimal therapy (median, 11 vs 7 hours, P = .024) and to step-down antimicrobial therapy (median, 27.8 vs 12 hours, P = .019). However, groups did not differ in antimicrobial consumption, duration of antimicrobial therapy, mortality, LOS, or incidence of CDI. Conclusions Use of ADX significantly reduced time to ID and AST as well as time to optimal antimicrobial therapy but did not affect antimicrobial consumption and clinical outcome.

Objectives: Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness. Methods: We set up a web-based registry on www.ClinicalSurveys.net for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively. Results: Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD. Conclusions: Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species. Keywords: Invasive fungal infection, Neutropenia, Posaconazole serum level, Clinical effectiveness, High-risk patient

Background Healthcare-associated infections (HAIs) are a leading cause for morbidity and mortality in neutropenic patients. Methods The Cologne Cohort of Neutropenic Patients (CoCoNut) is an ongoing, prospective, longitudinal cohort, collecting inpatient data for analysis of epidemiology, risk factors, and outcome of neutropenic patients (at least one day of absolute neutrophil count < 500/µL) at risk for HAIs. The CoCoNut contains comprehensive data, i.e. patient characteristics, medication, chemotherapy, clinical data (e.g., diarrhea, body temperature), as well as laboratory, microbiological, virologic, and radiological results. The purpose of this cohort is to improve the knowledge on HAIs and management of anti-infective prophylaxis and therapy. Results To date, the CoCoNut includes 8,176 inpatient stays from 3,354 neutropenic patients treated at the hematology/oncology department of the University Hospital of Cologne between January 2009 and December 2018. Hodgkin and Non-Hodgkin lymphoma (32%), acute leukemia (28%), and chronic leukemia (10%) were the predominant underlying diseases; comprising 843/8,176 (10%) inpatient stays with allogenic stem cell transplantation. The overall number of neutropenic days and fever days (body temperature ≥ 38 °C) was 56,824 and 25,347, respectively. Blood stream infections (occurrence of fever and positive blood culture) occurred in 1,283/8,176 (16%) inpatient stays, and the overall mortality rate was 9% (n = 716/8,176). By now, 17 peer-reviewed articles analyzing epidemiology, treatment, and outcome of HAIs were published based on data from the CoCoNut. Conclusion Data extracted from the CoCoNut underlines the important role of evaluating innovative treatment strategies. Considering the remaining high infection rate for HAIs of neutropenic patients, the growing development of antimicrobial drug resistance, and the existing powerful methods for data processing (e.g., artificial intelligence), we will continue to utilizing and expanding the CoCoNut in the future. Disclosures All authors: No reported disclosures.

Background Current first-line (first) antifungal treatment for invasive mucormycosis (IM) consists of liposomal amphotericin B (AMB). Salvage (SAL) treatment options are limited and often based on posaconazole oral suspension (POSsusp). However, with the approval of posaconazole new formulations (POSnew), patients could benefit from improved pharmacokinetics, safety and tolerability. Our aim was to assess the effectiveness of POSnew as first-line and SAL treatments for IM. Methods We performed a case-matched analysis with proven or probable IM patients from the FungiScope® Registry. 1st-POSnew and 1st-AMB+POSnew cases were matched with 1st-AMB-based treatment controls, and SAL-POSnew cases were matched with SAL-POSsusp controls. Each case was matched with up to three controls based on severity, hematological/oncological malignancy, surgery and/or renal dysfunction. Results Five patients receiving first-line POSnew alone, 18 receiving first-line POSnew combined with AMB, and 22 receiving salvage POSnew were identified. By day 42, favorable response was reported for 80.0% (n = 4/5) of patients receiving first-line POSnew, for 27.8% (n = 5/18) receiving first-line POSnew plus AMB, and for 50.0% (n = 11/22) receiving salvage POSnew. Day-42 all-cause mortality of patients receiving POSnew was lower compared with mortality in their respective controls (20.0% (n = 1/5) in 1st-POSnew vs. 53.3% (n = 8/15) in 1st-AMB; 33.3% (n = 6/18) in 1st-AMB+POSnew vs. 52.0% (n = 26/50) in 1st-AMB; 0.0% (n = 0/22) in SAL-POSnew vs. 4.4% (n = 2/45) in SAL-POSsusp). Conclusion In the observed patients, POSnew was effective in terms of treatment response and-associated mortality of IM. POSnew may be an alternative for the treatment of IM. Disclosures All authors: No reported disclosures.

Background Clinical management of prolonged febrile neutropenia despite broad-spectrum empirical antibacterial treatment is a clinical challenge, as standard empirical treatment has failed and a broad spectrum of differential diagnoses has to be considered. Growing prevalence of multi-resistant bacteria and fungi has made a balanced choice of effective anti-infective treatment more difficult. A reliable prediction of complications could indicate options for treatment optimization. Methods We implemented a supervised machine learning approach to predict death or admission to intensive care unit within 28 days in cancer patients with prolonged febrile neutropenia (neutrophils < 500/mm3 and body temperature ≥ 38°C longer than 3 days). We analyzed highly granular retrospective medical data of the Cologne Cohort of Neutropenic Patients (CoCoNut) between 2008 and 2014. Random forest and 10-fold cross-validation were used for classification. The neutropenic episodes from 2014 were used for evaluation of prediction. Results In total, 927 episodes of prolonged febrile neutropenia (median age 52 years, interquartile range 42–62; 562/927 [61%] male; 390/927 [42%] acute myeloid leukemia; 297/927 [32%] lymphoma) with 211/927 (23%) adverse outcomes were processed. We computed 226 features including patient characteristics, medication, clinical signs, as well as laboratory results describing changes of state and interactions of medical parameters. Feature selection revealed 65 features with an area under the receiver operating characteristic curve (AUC) of 0.75. In the validation data set the optimized model had a sensitivity/specificity of 36% and 99% (AUC: 0.68; misclassification error: 0.12) and positive/negative predictive values of 89% and 88%, respectively. The most important features were albumin, age, and procalcitonin. Conclusion Structured granular medical data and machine learning approaches are an innovative tool that can be used in a retrospective setting for prediction of adverse outcomes in patients with prolonged febrile neutropenia. This study is the first important step toward clinical decision support based on predictive models in high-risk cancer patients. Disclosures All authors: No reported disclosures.

Background Due to severe immunosuppression, patients undergoing allogeneic hematopoietic stem cell transplantation (aSCT) are at increased risk of infection and especially bloodstream infections (BSI) remain a major cause of death. Knowledge of the specific epidemiology of pathogens and resistances is of utmost importance to optimize antimicrobial treatment strategies. Methods Based on the Cologne Cohort of Neutropenic Patients (CoCoNut) database, we conducted a retrospective analysis of blood cultures collected within 100 days following transplantation of patients undergoing aSCT between January 2009 and December 2018 at the University Hospital of Cologne, Germany. Contamination of coagulase-negative Staphylococci (CoNS) isolates (single positive isolate within 5 days) was considered within the analysis. Results In total, 843 aSCT patients were available for analysis (484/843 [57%] male). The median age was 53 (interquartile range [IQR] 43–62) years, predominant underlying diseases were acute myeloid leukemia (47%, 397/843), lymphoma (14%, 117/843), and acute lymphoblastic leukemia (11%, 89/843). Median inpatient stay was 39 (IQR 34–50) days, while 67/843 (8%) patients died. Antibacterial prophylaxis was administered in 289/843 (34%) and antifungal prophylaxis in 738/843 (88%) patients. BSI was diagnosed in 233/843 (28%) patients. In total, 5,489 pairs of blood cultures were taken (median 4 per patient, IQR 2–8), while a pathogen could only be detected in 922/5,489 (17%). Most frequent pathogens were CoNS (259/922, 28%), Enterococcus spp. (219/922, 24%), E. coli (132/922, 14%), Klebsiella spp. (44/922, 5%), P. aeruginosa (39/922, 4%), S. aureus (37/922, 4%), and Candida spp. (42/922, 5%). Polymicrobial infection was detected in 58/922 (6%) cases. Within Enterococci isolates, 24/219 (11%) were VRE. None of the Klebsiella, but 9/132 (7%) of E. coli isolates were ESBL positive. In 4/37 (11%) cases S. aureus isolates were MRSA. Conclusion Patients in the early phase after aSCT are at high risk of BSI with a predominantly gram-positive spectrum. Empirical antimicrobial treatment must consider pathogen epidemiology and resistance patterns while waiting for blood culture results. Disclosures All authors: No reported disclosures.

Background In recent years, survival of patients with invasive aspergillosis (IA) has improved mainly due to availability of extended spectrum triazoles. These advances are jeopardized by the emergence of azole resistance in Aspergillus fumigatus, the most common causative pathogen of IA. Despite several studies suggesting high probability of azole treatment failure in patients with azole-resistant isolates, the clinical implications of azole-resistant IA compared with azole-susceptible IA remain unclear. Methods In patients with hematological malignancies, cases of proven or probable IA (EORTC/MSG 2008) caused by A. fumigatus are registered. Retrospective data are documented, comprising demographics, diagnosis, treatment, response and outcome. Participating sites provided susceptibility results or isolates. Provided isolates were analyzed in a central laboratory. Results Since January 2018, 51 sites in 15 countries worldwide enrolled 154 cases diagnosed with IA between 2010 and 2019, of which 23 (14.9%) had azole-resistant IA. Of 44 cases, the respective clinical fungal isolate was analyzed in the central laboratory. A mixed fungal infection was reported for 34 patients (22.1%), 1 (2.9%) in the azole-resistant group; most were related to non-fumigatus Aspergillus species (n = 12, 35.3%) and non-Aspergillus molds (n = 10, 29.4). Most patients were male (n = 98, 63.6%); 19 (82.6%) in the azole-resistant group, 79 (60.3%) in the azole-susceptible group. Age was documented in categories instead of the exact age. Median age group was 50–69 years in both groups (ranging from 7–11 to 70–89 years for azole-resistant cases, 1–12 months to 70–89 years for azole-susceptible cases). Underlying disease and survival are shown in the table. Conclusion A worldwide network of investigators contributes to the CLARITY registry study. Completion of recruitment and subsequent data analysis are planned for 2019. Further sites may be added if azole-resistant cases are encountered. Disclosures All authors: No reported disclosures.

In patients with hematological malignancies, bronchoalveolar lavage fluid (BALF) specimens are commonly used for the diagnosis of mold infections. However, it is not clear whether the cell pellet (P) or the supernatant fraction (S) of the BALF specimen is optimal for molecular diagnostic testing. Thus, 99 BALF specimens were collected from 96 hematology patients with or without allogeneic hematopoietic stem cell transplant. The cell pellets and supernatants were processed alone and in combination (S/P) for testing by two fungus-specific real-time PCR assays compliant with international recommendations. The results achieved with S/P were revealed to be superior in comparison to those achieved with S and P alone, with the use of each single fraction showing a reduced sensitivity for the detection of Aspergillus DNA (82% and 43% for S and P, respectively). In 57% of the samples, testing of the combination of S and P generated a lower quantification cycle value than testing of S or P alone. Molds would have been missed in 5 and 16 out of 28 samples if only S or P, respectively, was analyzed. No sample was positive by testing of S or P only. Similar results were obtained for the detection of Mucorales DNA in BALF specimens (reduced sensitivity of 67% and 50% for S and P, respectively). Study patients were categorized according to the current European Organization for the Research and Treatment of Cancer/Mycoses Study Group classification for invasive fungal disease (IFD), revealing that 35 patients had proven/probable IFD (36%), 47 patients had possible IFD (49%), and 14 patients had undetermined IFD (15%).

Summary Overall survival (OS) of patients with acquired immunodeficiency syndrome (AIDS)-related Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) and plasmablastic lymphoma (PBL) was analysed in the German AIDS-related-Lymphoma-Cohort-Study. Of 291 patients prospectively included between January 2005 and December 2012, 154 had DLBCL, 103 BL and 34 PBL. Two-year OS rates were similar between BL (69%) and DLBCL patients (63%) but lower for PBL patients (43%). Intermediate (Hazard ratio [HR] 4·1 95% confidence interval [CI] 1·98–8·49) or high (HR 4·92 95% CI 2·1–11·61) International Prognostic Index, bone marrow involvement (HR 1·69 95% CI 1·00–2·84) and PBL histology (HR 2·24 95% CI 1·24–4·03) were independent predictors of mortality.

Received 20 March 2014; returned 4 June 2014; revised 9 July 2014; accepted 15 July 2014Background: Bloodstream infections (BSIs) caused by enterobacteria remain a leading cause of mortality inpatients with chemotherapy-induced neutropenia. The rate and type of colonization and infection with ESBL-producing Enterobacteriaceae (ESBL-E) and their mode of transmission in German cancer centres is largelyunknown.Methods: We performed a prospective, observational study at five German university-based haematologydepartments. Participating sites screened for intestinal ESBL-E colonization within 72 h of admission, every10+2 days thereafter and before discharge. Three of the five centres performed contact isolation for patientscolonized or infected with ESBL-E. Molecular characterization of resistance mechanisms and epidemiologicaltyping of isolates by repetitive extragenic palindromic PCR (rep-PCR) and PFGE was performed to assess straintransmission between patients.Results: Between October 2011 and December 2012, 719 hospitalizations of 497 haematological high-riskpatients comprising 20143 patient-days were analysed. Mean duration of in-hospital stay was 36.6 days(range: 2–159 days). ESBL-E were identified from screening samples (82.8%Escherichia coliand 14.6%Klebsiella pneumoniae) in 55/497 patients (11.1%; range by centre: 5.8%–23.1%). PFGE and rep-PCR revealedonlyasinglecaseofpotentialcross-transmissionamongtwopatientscolonizedwithK.pneumoniae.Sixepisodesof BSI with ESBL-E were observed. Multivariate analysis revealed previous colonization with ESBL-E as the mostimportant risk factor for BSI with ESBL-E (OR 52.00; 95% CI 5.71–473.89).Conclusions: Even though BSI with ESBL-E is still rare in this high-risk population, colonization rates are substan-tial and vary considerably between centres. In-hospital transmission of ESBL-E as assessed by molecular typingwas the exception.Keywords: febrile neutropenia, bacteraemia, bloodstream infections, intestinal colonization, infection control, contact isolation

Introduction Invasive fungal diseases (IFDs) are an important cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (SCT). Methods To compare the effectiveness of two prophylactic antifungal regimens used as standard of care (SOC) in the setting of SCT during the periods of May 2006 – September 2009 (oral posaconazole, POS) and October 2009 – July 2011 (oral posaconazole with intravenous micafungin bridging, POS-MIC), data from the Cologne Cohort of Neutropenic Patients (CoCoNut) study were analyzed after nearest-neighbor matching. Endpoints were occurrence of breakthrough probable/proven IFD under prophylaxis, incidence and duration of persistent febrile neutropenia, incidence of unspecific pneumonic infiltrates, possible IFD, positive galactomannan tests, as well as fungal-free and overall survival. Results Of 291 patients with 307 SCTs observed during the study period, 212 fulfilled the inclusion criteria and were included into the analysis. Patients receiving POS-MIC were less likely to develop a pneumonic infiltrate (RR 0.71, 95% CI 0.51–1.00) or possible IFD (RR 0.36, 95% 0.15–0.87). They also demonstrated improved fungal-free survival at day 100 (P = 0.009). No significant differences were observed for the incidence of probable or proven IFD, positive galactomannan tests, persistent febrile neutropenia, duration of hospitalization and overall mortality. There was no grade III or IV CTCAE (Common Terminology Criteria for Adverse Events) toxicity related to antifungal prophylaxis. Conclusion Our results suggest that both prophylactic regimens, POS and POS-MIC are feasible, safe and effective. Our data suggest that bridging with intravenous micafungin could indeed improve exposure to antifungal prophylaxis, which may explain the reduced incidence of pneumonia and IFD in the bridging group.

Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined. Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis. One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08–15.31) and lesion volume (OR 3.14, 95%CI: 0.73–13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42–282.00 and OR 15.97, 95%CI: 1.62–157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94–24.05 and OR 40.69, 95%CI: 2.55–649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates. Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value. • CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis. • Predictive capability exceeds galactomannan, blood counts, and lesion count. • Any progression between day 7 and day 14 constitutes a high-risk scenario.

Objectives Antifungal prophylaxis is recommended for haematological patients at high risk of invasive fungal infections (IFIs). Incidence, optimal therapeutic management and outcome of breakthrough IFIs (bIFIs) are largely unknown. Methods To assess bIFI incidence, treatment and outcomes, data on patients undergoing AML remission-induction and consolidation chemotherapy and from allogeneic HSCT recipients on antifungal prophylaxis with itraconazole, micafungin or posaconazole were extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut). bIFIs were classified according to revised EORTC/MSG criteria. Results From January 2004 to April 2013, 250 AML patients with 329 hospitalizations and 409 HSCT patients with 496 hospitalizations were identified. In AML patients, there were 16 (6.4%) proven or probable bIFIs and 44 (17.6%) possible bIFIs. In HSCT patients, there were 14 (3.4%) proven or probable bIFIs and 37 (9.0%) possible bIFIs. Proven cases included five candidaemias, two mucormycoses, three aspergilloses and one fusariosis. The most frequent choice for bIFI treatment was liposomal amphotericin B in AML patients (21/60; 35.0%) and continuation of posaconazole prophylaxis in HSCT patients (16/51; 31.4%). In HSCT recipients, survival on day 365 was significantly lower in bIFI patients (AML, 63.3% versus 70.0%; P = 0.297; HSCT, 49.0% versus 66.8%; P = 0.012). Comparison of continuation of prophylaxis versus switch of antifungal class as first-line treatment showed no significant difference regarding response to treatment and survival. Conclusions Rates of bIFIs observed in our population were comparable to previous data. There was no clear shift towards rare species, as previously reported. A high variety of treatment approaches was observed.

Patients receiving high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) are at high risk of infections, especially bacteraemia. A prospective, double-blind, randomised, placebo-controlled, single-centre, pilot study was performed on oral moxifloxacin 400mg versus placebo for preventing bacteraemia in PBSCT recipients. Patients received moxifloxacin or placebo for the duration of neutropenia or until emergence of fever or other infections necessitating intravenous antibiotic treatment. Of 68 patients included in the trial, 2 were excluded from the trial before taking their first dose. The remaining 66 patients were eligible for evaluation in the intention-to-treat analysis set. Neutropenia with an absolute neutrophil count of

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

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.

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.Fifteen patients with Hodgkin's or non-Hodgkin's lymphoma receiving HD conditioning chemotherapy and autologous SCT were assessed with respect to oral pain and severity of stomatitis on day -6, 0, +5 to +7, +13 to +15, and +100. On the same dates, IL-1 and TNF-α were quantified in saliva and screening for a wide range of viral pathogens was carried out by cell culture and PCR and complemented by serological analyses. t Tests were used to assess potential associations between these variables.All but one patient had a positive HSV IgG titer at baseline. Reactivation as confirmed by HSV PCR was observed in seven patients (50%). There was a significant association between the presence of HSV in saliva samples and severity of stomatitis (t test, p = 0.015). The highest concentration of TNF-α and IL-1 coincided with the maximum intensity of stomatitis, but the association was not significant.We found a significant association between the presence of HSV in saliva samples and severity of stomatitis in patients receiving HD chemotherapy and subsequent autologous SCT. While acyclovir prophylaxis has become standard for patients undergoing allogeneic SCT, this issue has not been sufficiently explored for other chemotherapy regimens. Based on our findings, conduction of a well-powered controlled randomized trial may be warranted.

In this review, we aim to compare different early treatment strategies of invasive fungal diseases in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Three treatment approaches – prophylactic, empiric, and pre-emptive treatment – are subject to continuous discussion among physicians treating patients at risk. Considering the available clinical basis of evidence, we opt for antifungal prophylaxis with posaconazole 200 mg tid po as our primary prophylactic strategy, while the employment of pre-emptive treatment should be delayed until more accurate diagnostic tools become available. In addition to antifungal prophylaxis, empiric treatment with caspofungin or L-AmB may be administered to patients with fever resistant to broad-spectrum antibiotic treatment and without radiographic findings typical of invasive fungal disease.

Invasive fungal diseases (IFD) are severe complications in patients receiving immunosuppression after solid organ or allogeneic stem cell transplantation. Extensive study has been conducted on therapeutic strategies for IFD in neutropenic patients, mostly those with hematological malignancy. There is an ongoing discussion on whether these studies may be applied to transplant patients as well.We have reviewed relevant literature on transplantation and clinical mycology of the last 20 years and selected articles relevant for today's treatment decisions. This article reports on the epidemiology of IFD in transplant recipients and current antifungal drugs in the context of tansplantation medicine. For invasive aspergillosis and invasive candidiasis, we give a detailed report of current clinical evidence.This review is intended as a quick-start for clinicians and other care providers new to transplant care and as an update for experienced transplant physicians. In a field in which evidence is scarce and conflicting, we provide evidence-based strategies for diagnosing and treating the most relevant IFD in transplant recipients.Physicians treating transplant patients should maintain a high level of awareness towards IFD. They should know the local epidemiology of IFD to make the optimal decision between current diagnostic and therapeutic strategies. Prophylaxis or early treatment should be considered given the high mortality of IFD.

Patients surviving invasive fungal disease (IFD) and needing further antineoplastic chemotherapy are at high risk of recurrent fungal infection. In the absence of randomised controlled trials in this area, secondary prophylactic regimens are diverse. From 448 patients registered with the Multinational Case Registry of Secondary Antifungal Prophylaxis, we performed an analysis of patients receiving caspofungin (CAS) or itraconazole (ITC). All patients had an underlying haematological malignancy and had been diagnosed with an episode of IFD earlier in their course of treatment. Data collected comprised demographics, underlying disease, first episode of IFD, antifungal prophylaxis, incidence and outcome of breakthrough IFD and survival. A total of 75 patients were evaluated, comprising 28 receiving CAS and 47 receiving ITC. Patients in the CAS group were more likely to have had progression of underlying disease (32.1% vs. 8.5%; P = 0.028) as well as incomplete response of initial IFD at baseline (85.7% vs. 57.4%; P = 0.005). Allogeneic stem cell transplantation was more prevalent in patients receiving CAS (46.4% vs. 14.9%; P = 0.010). There was no difference in the occurrence of breakthrough IFD between both groups (32.1% vs. 31.9%). Treatment outcomes for recurrent IFD and overall mortality did not differ between groups. Both ITC and CAS were equally effective in preventing second episodes of IFD. Patients with uncontrolled first IFD, uncontrolled underlying disease or those receiving stem cell transplantation were more likely to have received CAS prophylaxis. Despite antifungal prophylaxis, risk of breakthrough IFD was high in both groups. (C) 2009 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Summary Background Novel respiratory viruses were discovered in the last years predominantly in children. Until now information on newly identified respiratory viruses in immunosuppressed adult patients is limited. Here we investigated immunocompromised adults with suspected Pneumocystis jirovecii pneumonia (PCP) for new respiratory viruses. Methods Bronchoalveolar lavage (BAL) samples of 128 patients with atypical pneumonia (HIV-infected n =50, hematological malignancy n =51, immunosuppressive treatment n =27) were prospectively evaluated for P. jirovecii and retrospectively for new respiratory viruses (HMPV, HBoV, HCoV-NL63/SARS/HKU1). Results P. jirovecii was detected in 26/128, bacteria in 10, fungi in four, Influenza A in two patients. Novel respiratory viruses were found in only two/128 patients with hematological malignancy, of those one patient with HBoV-infection and one with HMPV-infection, respectively. No pathogens were detected in 82/128 patients. The one patient with detection of hMPV and clinical diagnosis of atypical pneumonia died of pulmonary failure. Conclusion Human bocavirus and human metapneumovirus are rarely involved in atypical pneumonia in immunocompromised adult patients with suspected PCP, but may contribute to severe respiratory failure.

Anidulafungin is the most recently approved compound of the echinocandin antifungal class. Its mode of action is the noncompetitive inhibition of β-(1,3)-D-glucan synthesis. Potent fungicidal activity has been demonstrated against many Candida spp., including non-albicansCandida spp. and fluconazole-resistant strains, as well as fungistatic activity against Aspergillus spp. Owing to low oral bioavailability, it can only be administered intravenously. Anidulafungin is not metabolized by the liver and renal clearance is negligible, thus rendering dosage adjustments in patients with impaired hepatic or renal function unnecessary. Due to lack of interference with the cytochrome P450 pathway, it displays minimal drug-drug interaction. Anidulafungin has been approved by the US FDA for the treatment of esophageal and invasive candidiasis after clinical trials demonstrated its noninferiority to fluconazole. In September 2007, anidulafungin gained EMEA approval for the treatment of invasive candidiasis in adult non-neutropenic patients. For those with invasive or noninvasive candidiasis with resistance or intolerance to fluconazole in particular, as well as those requiring antifungal medication, that anidulafungin does not interact with concomitant medication means it may be regarded as a safe and efficacious treatment option. Promising results from animal models and experience with the other echinocandins indicate several potential lines of investigation: invasive aspergillosis, prophylaxis and treatment of transplant patients, and empirical treatment in patients with febrile neutropenia. Significant differences in clinical efficacy or safety favoring anidulafungin over the other echinocandins are yet to be discovered.

Summary Anidulafungin is the most recent development in the echinocandin class antifungals. Like other echinocandins, it inhibits 1,3-β-d-glucan synthesis, thus achieving fungicidal activity against many Candida spp. including those resistant to fluconazole as well as fungistatic activity against some clinically important filamentous fungi, especially Aspergillus spp. The drug is well tolerated, even in patients with renal or hepatic impairment. It has a low drug–drug interaction profile as it does not significantly interfere with the cytochrome P450 pathway. Anidulafungin has been approved for treatment of candidaemia, intra-abdominal abscesses, peritonitis and oesophageal candidiasis. Trials have shown non-inferiority of anidulafungin to fluconazole in the treatment of invasive and non-invasive candidiasis. After promising results from animal models, the role of anidulafungin in the treatment of invasive aspergillosis and other filamentous fungi is yet to be cleared. Currently, anidulafungin offers another alternative in the treatment of Candida infections, especially in patients where avoidance of drug–drug interactions is needed. Future investigations may elucidate how anidulafungin performs clinically in comparison with the other echinocandins.

Zygomycoses are very rare invasive fungal infections (IFI). They primarily occur in the immunocompromised patients and are associated with a high mortality. During the last years, a rising incidence of zygomycosis in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) has been reported, which is probably a part of the trend in the incidence of mould infections that has been going on for decades. Difficulty in diagnosis, especially concerning the differentiation of zygomycosis from the far more common aspergillosis, additionally hampers a reliable assessment of the incidence of zygomycosis. In patients undergoing allogeneic HSCT, changes in the frequency, severity and management of Graft-versus-Host-Disease (GvHD) also favour mould infections, among them zygomycosis. In centres employing voriconazole for prophylaxis of IFI since its approval for treatment in 2001, incidence of aspergillosis has markedly dropped. The assumption that the frequency of zygomycosis has increased since the introduction of voriconazole is not found in prospective trials and therefore needs verification, especially when considering the long ongoing trends in fungal incidence. Currently recruiting multicentre trials on primary prophylaxis of IFI will have to show the preventive effectiveness of antifungals with mould activity and the incidence of zygomycosis under prospectively controlled conditions.

Causes of death in human immunodeficiency virus (HIV)-infected subjects have changed in countries with high resources over the last several years. Acquired immunodeficiency syndrome (AIDS)-related diseases have become less prevalent, whereas deaths due to non-AIDS causes are increasing. The aim of the present study was to analyse causes of death in the Cologne-Bonn cohort.Causes of death from the Cologne-Bonn cohort between 2004 and 2010 were systematically recorded using the CoDe algorithm (The Coding Causes of Death in HIV Project).In 3,165 patients followed from 2004 to 2010, 182 deaths occurred (5.7 %, 153 males, 29 females). The median age at the time of death was 47 years (range 24-85 years). The most frequent causes of death were AIDS-defining events (n = 60, 33 %), with non-Hodgkin lymphoma (NHL) (n = 29, 16 %) and infections (n = 20, 11 %) being the leading entities in this category. Non-AIDS malignancies accounted for 16 % (n = 29), non-HIV-related infections for 10 % (n = 18), cardiovascular diseases for 7 % (n = 14), suicide or accident for 4 % (n = 7) and liver diseases for 3 % (n = 5) of deaths (unknown n = 47, 26 %). Although the majority of patients (92.5 %) was on antiretroviral therapy (ART), only 50 % were virologically suppressed (HIV-RNA50 copies/mL) and 44 % had a decreased CD4+ count (200/μL) at their last visit before death.One-third of the causes of death in our cohort between 2004 and 2010 was AIDS-related. Since most of these deaths occur with severe immune suppression, they can possibly be prevented by the early diagnosis and treatment of HIV infection. Care providers must be aware of an increased risk for a broad range of diseases in HIV-infected patients and should apply appropriate preventive measures.

Invasive mucormycosis (IM) in patients with acute leukemia and allogeneic stem cell transplant (allo-SCT) recipients treated with antifungal monotherapy is associated with high mortality rates of 44–49%.[1][1]–[3][2] Among the available antifungals, amphotericin B (AmB) formulations and

OBJECTIVES Invasive aspergillosis (IA) is a life-threatening infection in severely immunocompromised patients, especially those receiving intensive chemotherapy or undergoing haematopoietic stem cell transplantation. As the clinical diagnosis of IA is mostly based on biomarkers (galactomannan, β-d-glucan, PCR assays) indicating Aspergillus as the underlying pathogen, the effect of antifungal treatment on the performance of these parameters is still controversial. We evaluated the effect of antifungal treatment on the performance of an Aspergillus-specific PCR assay in bronchoalveolar lavage (BAL) samples. PATIENTS AND METHODS Two-hundred-and-twenty-six BAL samples from 226 patients with haematological malignancies at high risk for IA classified according to the 2008 European Organization for the Research and Treatment of Cancer criteria were analysed retrospectively for the diagnostic performance of a nested Aspergillus PCR assay in relation to the number and type of mould-active antifungals received prior to BAL sampling. RESULTS Sensitivity of BAL PCR for patients without antifungal treatment prior to BAL sampling was 0.69, whereas specificity was 0.87. While no significant change in diagnostic performance by the addition of one antifungal was observed, receiving two or more antifungals prior to BAL sampling led to a significant decrease in the diagnostic performance of BAL PCR testing (P

Invasive fungal diseases are a source of significant morbidity and mortality in patients with haematological malignancies, particularly those with prolonged and severe neutropenia. In view of the poor prognosis associated with tardy treatment initiation, antifungal prophylaxis has become increasingly popular. Until recently, fluconazole – a drug with no Aspergillus activity – and itraconazole, which has absorption-associated problems and is often poorly tolerated, used to be the preferred choices for antifungal prophylaxis. Clinical trials have now assessed the prophylactic use of posaconazole, a new-generation triazole with broad spectrum antifungal activity against Candida, Aspergillus and Fusarium spp., as well as the Zygomycetes. Results have further strengthened the evidence base for antifungal prophylaxis, showing a significant reduction of invasive fungal diseases and significantly improved overall survival in patients with acute myelogenous leukaemia and myelodysplastic syndrome. Moreover, improved attributable survival in patients with severe graft versus host disease on immunosuppressive therapy was documented. For patients undergoing allogeneic haematopoietic stem cell transplantation, fluconazole prophylaxis is still considered current standard. Considering the extended spectrum of posaconazole and its good tolerability, it seems warranted to replace fluconazole by posaconazole for this indication.

Posaconazole is a new drug in the triazole class that has recently been investigated in pivotal Phase III clinical trials. Its antifungal activity is based on the inhibition of the fungal ergosterol synthesis. As demonstrated in vitro, posaconazole exhibits fungicidal activity against Aspergillus spp., Candida spp. and zygomycetes. Currently, posaconazole is only available as an oral suspension. Food consumption affects the bioavailability of posaconazole, while the exposure to posaconazole increases in a dose-proportional manner with a saturation of absorption occurring with a daily dose over 800 mg. Posaconazole is well tolerated without an increase in risk of any treatment-related adverse events during prolonged treatment for 6 or more months (n = 108). Posaconazole has been recently approved by the US FDA and other regulatory bodies for the treatment of oropharyngeal candidiasis, and the prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients. As demonstrated in two pivotal Phase III trials, posaconazole prophylaxis of invasive fungal infection in patients severely immunocompromised by graft–versus–host disease (n = 600) or neutropenia (n = 602) is superior to fluconazole and/or itraconazole prophylaxis. Significantly more patients who received posaconazole, instead of fluconazole, as treatment for oropharyngeal candidiasis sustained clinical success after the treatment was stopped. Preliminary data from a subgroup analysis (n = 24) of two salvage therapy trials for invasive fungal infections, as well as single case reports and series and in vitro studies, suggest that posaconazole might be an attractive oral treatment alternative for zygomycosis.

Micafungin is a new drug in the echinocandin class and is currently being investigated in Phase III clinical trials. Like other echinocandins, it inhibits 1,3-β-D-glucan synthesis, thus achieving fungicidal activity against virtually all Candida spp., including those resistant to fluconazole, and fungistatic activity against Aspergillus spp. Micafungin sodium is available for intravenous administration only. It has a favorable safety and drug–drug interaction profile. Micafungin has been approved by the US FDA for treatment of esophageal candidiasis and for antifungal prophylaxis during the pre-engraftment phase in patients undergoing hematopoietic stem cell transplantation. Considering the competitive pricing as well as the good tolerability and efficacy, at present micafungin seems to be another choice for both of these indications. Current research has proven micafungin sodium to add a rational and effective option to the antifungal armamentarium, especially in esophageal candidiasis refractory to fluconazole treatment, in those intolerant to triazoles or in patients needing concomitant therapy interacting with triazoles. In addition to the current indications, recent uncontrolled clinical trials have demonstrated a marked success in the treatment of candidemia and invasive candidiasis. Results from in vitro studies, animal models, small clinical trials, as well as the obvious comparison with the more established caspofungin, hint at possible future indications such as invasive aspergillosis and empirical antifungal therapy. However, preclinical data on micafungin is inconsistent and published well-designed clinical studies are scarce. More controlled and sufficiently scaled trials are imperative in order to establish micafungin as a reliable and safe option in clinical practice.

Background: Invasive fungal diseases (IFD) are on the rise due to the increasing numbers of immunosuppressed patients including those undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation. Isavuconazole (ISA) is a novel, broad-spectrum antifungal triazole, available as a water-soluble prodrug in IV and oral formulations. IM is a life-threatening IFD with significant mortality and limited treatment options. Methods: The VITAL study was a Phase III, multicenter, open-label, single arm, trial conducted to evaluate efficacy and safety of ISA treatment in patients with rare IFD, including IM. Eligibility criteria and evaluated outcomes are outlined in clinicaltrials.gov, NCT00634049. Patients received IV or PO ISA 200 mg TID for 2 days followed by 200 mg/day. FungiScope™ – Global Emerging Fungal Infection Registry maintains a global web-based database on rare IFD, including IM. Entrance criteria are outlined in clinicaltrials.gov, NCT01731353. 21 patients from the VITAL study who received ISA for the primary treatment of proven/probable IM were matched (blinded to mortality status) to up-to 3 proven/probable patients with IM who received a formulation of amphotericin B entered in FungiScope™ based on 3 dichotomous risk factors: severe disease (i.e. CNS/disseminated), surgical debridement, and hematologic malignancy. All-cause mortality through day 42 was summarized. Results: 33 FungiScope™ matched controls were identified; 14 VITAL cases were matched to a single control each (n=14), 2 VITAL cases were matched to 2 controls each (n=4), and 5 VITAL cases were matched to 3 controls each (n=15). Demographics, treatments, matching criteria and mortality outcomes are shown in Table 1. The crude mortality rate (33.3%) through day 42 from the VITAL cases was similar to the mortality rate (39.4% crude; 41.3% weighted) from the matched controls of FungiScope™. Table 1 Parameter Isavuconazole VITAL Cases (n=21) FungiScopeTM Amphotericin B Matched Controls (n=33) Treatment, n (%) Isavuconazole Deoxycholate amphotericin B Liposomal amphotericin B Amphotericin B Lipid Complex 21 (100) 0 0 0 0 7 (21) 22 (67) 4 (12) Case year, range 2008–2013 2005–2013 Age, median (range) 51 (25–77) 57 (22–81) Male, n (%) 17 (81) 22 (67) Race, n (%) White Black/African American Asian 12 (57) 1 (5) 8 (38) 31 (94) 0 2 (6) Severe Disease,1 n (%) 12 (57) 13 (39) Surgical Debridement,2 n (%) 9 (43) 13 (39) Hematologic Malignancy, n (%) 11 (52) 18 (55) Crude Mortality, n (%) 7 (33.3) 13 (39.4) Weighted Mortality3 (%) Not Applicable 41.3 1 – CNS Involvement and/or Disseminated Disease 2 – Surgery performed +/– 7 days of the initiation of isavuconazole or amphotericin. 3 – Weights were applied according to the ratio of the number of controls matched to each VITAL case. Conclusions: Isavuconazole was as effective as amphotericin B formulations in the primary treatment of invasive mucormycosis based on this matched case comparison of mortality rates from the VITAL study and FungiScope™. Disclosures Vehreschild: MJGTV has served at the speakers' bureau of Pfizer, Merck, Gilead Sciences and Astellas Pharma, received research funding from 3M and Gilead Sciences and is a consultant to Berlin Chemie.: Consultancy, Research Funding, Speakers Bureau. Vehreschild:Astellas, Gilead, Infectopharm, MSD/Merck, Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Marty:Astellas Pharma US, Merck, WHISCON: Honoraria, Research Funding. Perfect:Astellas, Pfizer, Merck, F26, Scynexis, Viarret: Consultancy, Research Funding. Ostrosky-Zeichner:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rahav:Astellas: Research Funding. Zeiher:Astellas Pharma Global Development: Employment. Lee:Astellas: Employment. Maher:Astellas: Employment. Lovell:Astellas Pharma Inc: Consultancy. Engelhardt:Basilea Pharmaceutica International Ltd: Employment. Cornely:Astellas: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Invasive fungal infections are frequent and often deadly complications in patients with malignant hematological diseases. Voriconazole is a third generation triazole antifungal with broad activity against most clinically relevant fungal pathogens. Clinical practice often deviates from insights gained from controlled randomized trials. We conducted a multi-centre survey to evaluate efficacy, safety, treatment indications and dosing of voriconazole outside clinical trials. Patients receiving voriconazole were documented via electronic data capturing. An analysis was conducted after submission of 100 episodes from September 2004 to November 2005. Voriconazole was administered for suspected or proven invasive fungal infection (IFI) (57%), as empirical treatment in patients with fever of unknown origin (21%) and secondary (19%) as well as primary (3%) prophylaxis of IFI. Investigators’ assessment of fungal infection often diverted from EORTC/MSG 2002 criteria. A favorable response was reported in 61.4% for suspected or proven IFI and 52.4% for empirical treatment. Mortality was 15%, 26.7% of which was attributable to IFI. Breakthrough fungal infections occurred in four (21.1%) patients with voriconazole as secondary prophylaxis. Toxicity and adverse events comprised elevated liver enzymes and visual disturbances. Although indications frequently deviated from clinical evidence and legal approval, voriconazole showed efficacy and safety, comparable to major controlled clinical trials. Data from this survey demonstrate the difficulty of putting drugs to their approved use in IFI.