Search

We analyzed 1,397 HIV-1 pol sequences of antiretroviral therapy-naive patients in a total of 7 university hospitals in Bonn, Cologne, Frankfurt, Hamburg, Hannover, and Munich, Germany. Phylogenetic and network analysis elucidated numerous cases of shared drug resistance mutations among genetically linked patients; K103N was the most frequently shared mutation.

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.

Reports indicate an increased mortality risk for solid organ transplant recipients with COVID-19 (1, 2), which may have been influenced by clinical decision making (triage) during the early phase of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic In Germany, relatively few transplant recipients were infected, and the capacity of the health care system was at no point in time overwhelmed Hereby, high capacity PCR-testing including all potential organ donors, symptomatic organ recipients or other patients, as well as a relatively high number of hospitals with intensive care units (1248) as well as transplant centers (40) with high capacities allowed a completely unimpaired organ procurement and transplantation situation throughout the first wave of the pandemic despite having SARS-CoV-2 infection rates of app 2200 per million persons at the end of May 2020 Our data lead to a different assessment of the risk associated with COVID-19 after organ transplantation

BACKGROUND Patients undergoing allogeneic stem cell transplantation (aSCT) are at high risk to develop an invasive fungal disease (IFD). Optimisation of antifungal prophylaxis strategies may improve patient outcomes and reduce treatment costs. OBJECTIVES To analyse the clinical and economical impact of using continuous micafungin as antifungal prophylaxis. PATIENTS/METHODS We performed a single-centre evaluation comparing patients who received either oral posaconazole with micafungin as intravenous bridging as required (POS-MIC) to patients who received only micafungin (MIC) as antifungal prophylaxis after aSCT. Epidemiological, clinical and direct treatment cost data extracted from the Cologne Cohort of Neutropenic Patients (CoCoNut) were analysed. RESULTS Three hundred and thirteen patients (97 and 216 patients in the POS-MIC and MIC groups, respectively) were included into the analysis. In the POS-MIC and MIC groups, median overall length of stay was 42 days (IQR: 35-52 days) vs 40 days (IQR: 35-49 days; p = .296), resulting in median overall costs of €42,964 (IQR: €35,040-€56,348) vs €43,291 (IQR: €37,281 vs €51,848; p = .993), respectively. Probable/proven IFD in the POS-MIC and MIC groups occurred in 5 patients (5%) vs 3 patients (1%; p = .051), respectively. The Kaplan-Meier analysis showed improved outcome of patients in the MIC group at day 100 (p = .037) and day 365 (p < .001) following aSCT. CONCLUSIONS Our study results demonstrate improved outcomes in the MIC group compared with the POS-MIC group, which can in part be explained by a tendency towards less probable/proven IFD. Higher drug acquisition costs of micafungin did not translate into higher overall costs.

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.

Objective Combination antiretroviral therapy (cART) has markedly increased survival and quality of life in people living with HIV. With the advent of new treatment options, including single-tablet regimens, durability and efficacy of first-line cART regimens are evolving. Methods We analyzed data from the prospective multicenter German Clinical Surveillance of HIV Disease (ClinSurv) cohort of the Robert-Koch Institute. Kaplan–Meier and Cox proportional hazards models were run to examine the factors associated with treatment modification. Recovery after treatment initiation was analyzed comparing pre-cART viral load and CD4+ T-cell counts with follow-up data. Results We included 8788 patients who initiated cART between 2005 and 2017. The sample population was predominantly male (n = 7040; 80.1%), of whom 4470 (63.5%) were reporting sex with men as the transmission risk factor. Overall, 4210 (47.9%) patients modified their first-line cART after a median time of 63 months (IQR 59–66). Regimens containing integrase strand transfer inhibitors (INSTI) were associated with significantly lower rates of treatment modification (adjusted hazard ratio 0.44; 95% CI 0.39–0.50) compared to protease inhibitor (PI)-based regimens. We found a decreased durability of first-line cART significantly associated with being female, a low CD4+ T-cell count, cART initiation in the later period (2011–2017), being on a multi-tablet regimen (MTR). Conclusions Drug class and MTRs are significantly associated with treatment modification. INSTI-based regimens showed to be superior compared to PI-based regimens in terms of durability.

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 The introduction of industrially produced antibiotics was a milestone in the history of medicine. Now, almost a century later, the adverse consequences of these highly effective drugs have become evident in the form of antibiotic-resistant infections, which are on the rise around the world. The search for solutions to this problem has involved both the introduction of newer types of antibiotics and, increasingly, the development of alternative strategies to prevent infections due to multidrug-resistant bacteria. In this article, we review the pathophysiological connection between the use of antibiotics and the occurrence of such infections. We also discuss some alternative strategies that are currently under development. Methods This review is based on pertinent articles that appeared from January 2000 to April 2019 and were retrieved by a selective search in the PubMed database employing the search term "(microbiota OR microbiome) AND infection." Further suggestions by our author team regarding relevant literature were considered as well. Results The spectrum of preventive strategies encompasses measures for the protection of the intestinal microbiota (antimicrobial stewardship, neutralization of antibiotic residues in the bowel, use of phages and species-specific antibiotics) as well as measures for its reconstitution (prebiotics, probiotics, and fecal microbiota transfer). Conclusion In view of the major problem that multidrug-resistant bacteria pose for the world's population and the resources now being spent on the search for a solution, derived both from public funding and from the pharmaceutical industry, we hope to see new, clinically useful approaches being developed and implemented in the near future.

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)

Rare invasive fungal diseases (IFD) are challenging for the treating physicians because of their unspecific clinical presentation, as well as the lack of standardised diagnostic and effective treatment strategies. Late onset of treatment and inappropriate medication is associated with high mortality, thus, urging the need for a better understanding of these diseases. The purpose of FungiScope™ is to continuously collect clinical information and specimens to improve the knowledge on epidemiology and eventually improve patient management of these orphan diseases. FungiScope™ was founded in 2003, and today, collaborators from 66 countries support the registry. So far, clinical data of 794 cases have been entered using a web-based approach. Within the growing network of experts, new collaborations developed, leading to several publications of comprehensive analyses of patient subgroups identified from the registry. Data extracted from FungiScope™ have also been used as the sole control group for the approval of a new antifungal drug. Due to the rarity of these diseases, a global registry is an appropriate method of pooling the scarce and scattered information. Joining efforts across medical specialities and geographical borders is key for researching rare IFD. Here, we describe the structure and management of the FungiScope™ registry.

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.

BackgroundSafety and tolerability of analytical treatment interruptions (ATIs) as a vital part of human immunodeficiency virus type 1 (HIV-1) cure studies are discussed. We analyzed current evidence for the occurrence of adverse events (AEs) during TIs.MethodsOur analysis included studies that reported on AEs in HIV-1–infected patients undergoing TIs. All interventional and observational studies were reviewed, and results were extracted based on predefined criteria. The proportion of AEs was pooled using random-effects models. Metaregression was used to explore the influence of baseline CD4+ T-cell count, viral load, study type, previous time on combined antiretroviral therapy, and follow-up interval during TIs.ResultsWe identified 1048 studies, of which 22 studies including 7104 individuals fulfilled the defined selection criteria. Included studies had sample sizes between 6 and 5472 participants, with durations of TI cycles ranging from 7 days to 27 months. The intervals of HIV-1-RNA testing varied from 2 days to 3 months during TIs. The overall proportion of AEs during TIs >4 weeks was 3% (95% confidence interval [CI], 0%–7%) and was lower in studies with follow-up intervals ≤14 days (0%; 95% CI, 0%–1%) than in studies with wider follow-up intervals (6%; 95% CI, 2%–13%; P value for interaction = .01).ConclusionsWe found moderate-quality evidence indicating that studies with narrow follow-up intervals did not show a substantial increase in AEs during TIs. Our findings indicate that ATI may be a safe strategy as part of HIV-1 cure trials by closely monitoring for HIV-1 rebound.

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.

In this article the cooperating partners of the ClinSurv HIV cohort were not listed in the acknowledgements. The correct paragraph appears below.

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

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScopeVR registry. For 208 Scedosporium spp. infections solid organ transplantation (n¼58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n¼28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n¼26, 46.4% versus n¼12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans, We thank Sabine Wrackmeyer for her private donation to support the project

Background While Germany has a long tradition in HIV research with many well-established regional cohorts, there was a lack of collaborative efforts toward harmonized data collection and biobanking, both key strategies for efficient translational research projects. Key challenges are heterogeneity of data systems and privacy concepts, of existing study and data collection protocols, and sample collection, storage, and sharing. Methods In 2013, we established the Translational Platform HIV (TP-HIV) with support of the German Centre for Infection Research (DZIF) as a collaboration between university hospitals and specialized HIV care centers throughout Germany. After assessing the individual needs of all partner sites, we have taken comprehensive action to create a common platform for collaboration in all research stages. We developed protocols, rules of operation, biobanking strategies, and privacy concepts for all collaborating partner sites. Patients infected with HIV (PLWH) who sign the informed consent for the TP-HIV are pro- and retrospectively included in the cohort. Results To date, the TP-HIV infrastructure is implemented at 27 member sites from 11 cities, potentially extending to more than 20,000 patients currently treated for HIV across Germany. Facing the special needs in the German research environment, the TP-HIV established a unique data- and biomaterial collection allowing expedited translational research and reduce project overheads, regulatory burden, and data security regulations for investigators. By active surveillance, rapid access to individual patient groups such as patients with acute HIV infection, TP-HIV is an ideal platform for early phase clinical trials with new drug candidates. Researchers with clinical, biological, epidemiological, and statistical expertise have been brought together within the TP-HIV, which enables an effective translational chain from bench to bedside and back. New collaborations have been established with currently 23 active study protocols. Conclusion The TP-HIV has demonstrated to be a powerful tool for generating and testing research hypotheses in PLWH. In the future, we will work to further expand our network and address the pressing needs in the German research environment. Disclosures All authors: No reported disclosures.

In immunocompromised patients with acute leukaemia as well as in allogeneic hematopoietic stem cell transplant patients, pulmonary lesions are commonly seen. Existing guidelines provide useful algorithms for diagnostic procedures and treatment options, but they do not give recommendations on how to evaluate early success or failure and if or when it is best to change therapy. Here, we review the diagnostic techniques currently used in association with clinical findings and propose an approach using a combination of computer tomography, clinical and all available biomarkers and inflammation parameters, especially those positive at baseline, to assess early response in invasive pulmonary aspergillosis. Computed tomography scans should be carried out at regular intervals during early and long-term follow-up. Imaging on day seven, or even earlier in clinically unstable patients, combined with an additional testing of biomarkers and inflammatory markers in between, is needed for a reliable assessment at day 14. If no improvement is seen after 2 weeks of therapy or the clinical condition is deteriorating, a change of antifungal therapy should be considered. Alleged breakthrough infections or treatment failure should undergo early diagnostic workup, including tissue biopsies when possible, to retrieve fungal cultures for resistance testing.

Author(s): Stecher, Melanie; Hoenigl, Martin; Eis-Hubinger, Anna Maria; Lehmann, Clara; Fatkenheuer, Gerd; Wasmuth, Jan-Christian; Knops, Elena; Vehreschild, Jorg Janne; Mehta, Sanjay; Chaillon, Antoine | Abstract: BackgroundGeographical allocation of interventions focusing on hotspots of human immunodeficiency virus (HIV) transmission has the potential to improve efficiency. We used phylogeographic analyses to identify hotspots of the HIV transmission in Cologne-Bonn, Germany.MethodsWe included 714 HIV-1 infected individuals, followed up at the University Hospitals Cologne and Bonn. Distance-based molecular network analyses were performed to infer putative relationships. Characteristics of genetically linked individuals and assortativity (shared characteristics) were analyzed. Geospatial diffusion (ie, viral gene flow) was evaluated using a Slatkin-Maddison approach. Geospatial dispersal was determined by calculating the average distance between the residences of linked individuals (centroids of 3-digit zip code).ResultsIn sum, 217/714 (30.4%) sequences had a putative genetic linkage, forming 77 clusters (size range: 2-8). Linked individuals were more likely to live in areas surrounding the city center (P = .043), l30 years of age (P = .009). and infected with HIV-1 subtype B (P = .002). Clustering individuals were nonassortative by area of residency (-.0026, P = .046). Geospatial analyses revealed a median distance between genetically linked individuals of 23.4 kilometers (km), lower than expected (P l .001). Slatkin-Maddison analyses revealed increased gene flow from central Cologne toward the surrounding areas (P l .001).ConclusionPhylogeographic analysis suggests that central Cologne may be a significant driver of the regional epidemic. Although clustering individuals lived closer than unlinked individuals, they were less likely to be linked to others from their same zip code. These results could help public health entities better understand transmission dynamics, facilitating allocation of resources to areas of greatest need.

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%).

Bloodstream infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are associated with treatment failure and increased mortality. Detection of CPE from blood cultures (BC) by standard methods takes 16–72 hours, which can delay the initiation of appropriate antimicrobial therapy and compromise patient outcome. In the present study, we developed and evaluated a new method for the rapid detection of carbapenemases directly from positive BC using a new multiplex immunochromatographic test (ICT). The new ICT was assessed using 170 molecularly characterized Enterobacteriaceae clinical isolates including 126 CPE (OXA-48-like (N = 79), KPC (N = 18) and NDM (N = 29)). After spiking with bacteria and incubation in a BC system, blood from positive BC bottles was hemolyzed, bacteria concentrated by centrifugation and lysed. The lysate was transferred to the RESIST-3 O.K.N. ICT (Coris BioConcept, Gembloux, Belgium), which detects OXA-48-like, KPC and NDM carbapenemases. The final results of the ICT were read when they became positive, at the latest after 15 min. All CPE isolates (126/126) were correctly detected with the new protocol (100% sensitivity, 100% specificity). There was perfect concordance between ICT results and molecular characterization. Total time to result was 20–45 min. Conclusions: This proof-of-principle study demonstrates that with the newly developed method, OXA-48-like, KPC and NDM carbapenemases can be reliably detected directly from positive BC bottles. The new method is more rapid than other currently available assays and can be performed in any routine microbiology laboratory. This can help to rapidly identify patients with CPE BSI and optimize the management of patients with these difficult-to-treat infections. Further studies are needed to assess the performance of the ICT in routine diagnostics.

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.

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.

Conducting clinical trials is costly and time consuming. Trial sites usually do not calculate site costs. Underestimating required resources slows enrollment and lowers data quality but it is currently unclear how to reliably estimate trial site costs. A group of trial staff designed and validated a tool for compiling trial tasks and calculating required expenditures prior to initiating a clinical trial. The tool was validated in two steps. Round-robin tests for accuracy compared case payments for the same trial calculated by different participants. A narrow CI was reached (22.95–715.69) demonstrating significantly similar estimates of the test participants (p = 0.039). To confirm the predictive value, the predicted and actual hours were compared and a correlation coefficient of 0.952 (p = 0.003) was found. A web-based tool, the Study Site Budgeting Tool, was developed, which allows trial sites to estimate staff costs at the site and determine the budget needed to conduct a clinical trial.

Background Rapid initiation of appropriate antimicrobial therapy is crucial in managing severe infections, including bloodstream infections. Timely availability of microbiological results is essential to enable early de-escalation of empiric therapy, which is one of the key components of an effective antimicrobial stewardship program. The Accelerate Pheno™ system (AXDX) is a novel technology for rapid identification and phenotypic antimicrobial susceptibility testing with promising results. Yet the impact of this technology on the clinical management and patient outcome still is unclear. Methods The University Hospital Cologne is a 1,464-bed tertiary care hospital. We conducted a retrospective before and after observational study and analyzed three groups with different diagnostic and therapeutic pathways following a change in the standard of care and recent integration of AXDX: conventional microbiological diagnostics with and without antimicrobial stewardship program (ASP) intervention from January 2015 to July 2015, rapid diagnostics (AXDX in addition to conventional standard) with ASP intervention from January 2017 to March 2018. Results n = 280 patients met inclusion criteria and n = 225 (conventional microbiological diagnostics n = 74/conventional diagnostics + ASP intervention n = 79/rapid diagnostics + ASP intervention n = 72) were included in the final analysis during the two study periods. There was no difference in clinical and demographic characteristics among the three groups. The use of AXDX significantly decreased time from positive blood culture to microorganism identification (ID) (median: 25 hours vs. 12.5 hours, P < 0,001) and susceptibility testing (AST) (median: 43.8 hours vs. 17.6 hours, P < 0.001) and improved time from Gram stain to optimal therapy (median: 20.1 hours vs. 7 hours, P < 0.01). ASP intervention alone without AXDX improved the proportion of patients on optimal therapy within 48 hours after Gram stain (62.2% vs. 77.2%, P < 0.05). Conclusion Use of AXDX significantly reduced time to ID and AST by 12.5/26.2 hours. In combination with ASP intervention AXDX significantly reduced time to optimal therapy by 13.1 hours, ASP intervention alone also improved the proportion of patients on optimal therapy within 48 hours. Disclosures K. Ehren, Accelerate Diagnostics Inc.: Research Contractor, Research support. A. Meißner, Accelerate Diagnostics Inc.: Research Contractor, Research support. J. Ertel, Accelerate Diagnostics Inc.: Research Contractor, Research grant. H. Seifert, Accelerate Diagnostics Inc.: Research Contractor, Research grant.

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.

Micafungin is one of three echinocandin antifungals approved by the US FDA and the European Medicines Agency (EMA). Like all echinocandin antifungals, micafungin inhibits the synthesis of 1,3-β-D-glucan, a main component of the cell wall of many medically important fungi; thus, exerting fungicidal activity against most Candida spp., as well as fungistatic activity against many Aspergillus spp. Micafungin displays linear pharmacokinetics over the therapeutic range with a long half-life, allowing once-daily intravenous administration. Steady state serum concentrations are achieved after 3 days. Since therapeutic concentrations of micafungin are achieved after the administration of a standard dose there is no need for a loading dose. Interactions of micafungin with the cytochrome P450 (CYP3A4) system are marginal; and, consequently, no severe drug–drug interactions have been reported so far. Furthermore, micafungin exhibited favorable profiles for tolerability and safety; no dose-limiting toxicity has been e...

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.

Background: Surgical site infections (SSIs) are among the most common hospital acquired infections. While the incidence of SSI in certain indicator procedures is the subject of ongoing surveillance efforts in hospitals and health care systems around the world, SSI rates vary markedly within surgical categories and are poorly represented by routinely monitored indicator procedures (eg, mastectomy or hernia surgery). Therefore, relying on indicator procedures to estimate the burden of SSI is imprecise and introduces bias as hospitals may take special precautions to achieve lower SSI rates. The most common cause of SSI is Staphylococcus aureus (S. aureus), as recently confirmed by a Europe-wide point-prevalence study conducted by the European Centre for Disease Prevention and Control (ECDC). Objective: The primary objective of this study is to determine the overall and procedure-specific incidence of S. aureus SSI in Europe. Secondary objectives are the overall and procedure-specific outcomes as well as the economic burden of S. aureus SSI in Europe. Explorative objectives are to characterize the composition of the surgical patient population and to estimate the number of patients at risk for S. aureus SSI. Methods: A retrospective, multinational, multicenter cohort study (Staphylococcus aureus Surgical Site Infection Multinational Epidemiology in Europe [SALT] study) with a nested case-control part will be conducted. The study will include all surgical procedures at a participating center in order to prevent selection bias and strengthen the understanding of SSI risk by determining the incidence for all common surgical procedures. Data will be assessed in the cohort population, including 150,000 adult patients who underwent any surgical procedure in 2016, and the case-control population. We will match patients establishing S. aureus SSI 1:1 with controls from the same center. Data on demographics, surgery, and microbiology will be exported from electronic files. More detailed data will be captured from the case-control population. The SALT study will include 13 major or academic surgical centers in Europe, comprising 3 in France, 4 in Germany, 2 in Italy, 3 in Spain, and 1 in the United Kingdom. Sites were selected using a feasibility questionnaire. Results: The SALT study is currently recruiting patients. The aim is to complete recruitment in February 2018 and to close the database in September 2018. The final results are expected by the end of 2018. Conclusions: Results of the SALT study will help to better understand the precise risk of certain procedures. They will also provide insight into the overall and procedure-specific incidence and outcome as well as the economic burden of S. aureus SSI in Europe. Findings of the study may help guide the design of clinical trials for S. aureus vaccines. Trial Registration: ClinicalTrials.gov NCT03353532; https://clinicaltrials.gov/ct2/show/NCT03353532 (Archived by WebCite at http://www.webcitation.org/6xAK3gVmO) [JMIR Res Protoc 2018;7(3):e63]

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 Blood stream infections by Candida spp. represent the majority of invasive fungal infections in intensive care patients. The high crude mortality of invasive candidiasis remained essentially unchanged during the last two decades despite new treatment options that became available. The echinocandins, the latest class of antifungals introduced since 2001, exhibit potent activity against clinically relevant fungi including most Candida spp. In several randomised multicentre phase III trials, anidulafungin, caspofungin and micafungin showed convincing efficacy when compared with standard treatment regimens. In all trials, echinocandins were at least non-inferior to standard treatments. Anidulafungin was shown to be superior to fluconazole. Echinocandins have a favourable tolerability profile and exhibit a minimal potential for drug interactions since their pharmacokinetics is independent of renal and ‐ largely ‐ hepatic function. As a result of these properties, echinocandins are appropriate drugs of choice for invasive candidiasis in intensive care where many patients experience organ failure and receive multiple drugs with complex interactions.

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.