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Abstract Objective To evaluate the acceptance and tolerability of the nH1N1 2009 vaccine in HIV-positive individuals. Method 758 patients were included in this prospective study. Different study populations were formed: The Tolerability Study Group consists of HIV-infected patients who visited three outpatient clinics (Cologne, Bonn, Freiburg) during a predefined time period. Patients were offered nH1N1 vaccination. Those accepting were administered a standard dose AS03 adjuvant nH1N1 vaccine. Questionnaires to report side effects occurring within 7 days after immunization were handed out. In a substudy conducted during the same time period, acceptance towards immunization was recorded. This Acceptance Study Group consists of all HIV-infected patients visiting the Cologne clinic. They were offered vaccination. In case of refusal, motivation was recorded. Results In the Tolerability Study Group, a total of 475 patient diaries returned in the three study centres could be evaluated, 119 of those (25%) reported no side effects. Distribution of symptoms was as follows: Pain 285/475 patients (60%), swelling 96 (20%), redness 54 (11%), fever 48/475 (10%), muscle/joint ache 173 (36%), headache 127 (27%), and fatigue 210 (44%). Association of side effects with clinical data was calculated for patients in Cologne and Bonn. Incidence of side effects was significantly associated with CDC stages A, B compared to C, and with a detectable viral load (> 50 copies/mL). No correlation was noted for CD4 cell count, age, gender or ethnicity. In the Acceptance Study Group, 538 HIV-infected patients were offered vaccination, 402 (75%) accepted, while 136 (25%) rejected. Main reasons for rejection were: Negative media coverage (35%), indecisiveness with preference to wait until a later date (23%), influenza not seen as personal threat (19%) and scepticism towards immunization in general (10%). Conclusion A total of 622 HIV-infected patients were vaccinated against nH1N1-influenza in the three study centres. No severe adverse events were reported. The tolerability was in most parts comparable to general population. Acceptance rate towards influenza vaccination was high (75%). Those refusing the immunization mentioned negative media coverage as the major influence on their decision.

Background: A previous study from Germany showed high antibiotic use in university hospitals, particularly in intensive care units (ICU) and hematology-oncology services, but there has been no information about recent antibiotic use in non-university hospitals. In the present study, we collected data from 40 non-university regional general hospitals located in the southwestern part of the country, and analyzed use density in the medical and surgical services of these hospitals.Materials and Methods: Hospital pharmacy records for the calendar years 2001 and 2002 were evaluated. The number of defined daily doses (DDD, definition according to the WHO/ATC 2001 index) and prescribed daily doses (PDD) per 100 patient days (DDD/100 or PDD/100, respectively) were calculated to compare antibiotic use densities in medical and surgical services. Data for surgery included various subspecialties and gynecology.Results: Antibiotic use in the participating hospitals increased minimally between 2001 and 2002 both in medicine as well as in surgery. Use density in internal medicine (ICU areas excluded) in the year 2002 ranged between 13.5 and 93.7 DDD/100 with a weighted mean of 49.9 DDD/100 (corresponding to 28.6 PDD/100, respectively). Values for surgery were lower with a weighted mean of 43.4 DDD/100 (corresponding to 26.1 PDD/100, range, 10 to 65.4 DDD/100), respectively. Hospital size was not a strong predictor of use density, while large differences were observed between intensive care areas and normal wards. Mean use densities in intensive care areas in 2002 were 105.6 DDD/100 (or 49.7 PDD/100) in medical intensive care units, 116.9 DDD/100 (or 61.2 PDD/100) in surgical intensive care units, and 112.7 DDD/100 (or 66.7 PDD/100) in mixed, interdisciplinary intensive care units. Betalactams made up > 50% of all PDDs, while fluoroquinolones were the second most frequently prescribed drugs (15% of all PDDs). Fluoroquinolones were usually given orally. Overall glycopeptide and aminoglycoside use was < 1 PDD/100.Conclusion: This recent data from a large regional nonuniversity acute care hospital sample confirms that hospital antibiotic use density largely depends on patient care areas and less on hospital size. Surprisingly low use was observed for glycopeptides and aminoglycosides. The data may be useful as a benchmark for further pharmacoepidemiologic evaluation and focused drug use control interventions. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) has become a major cause of mortality in patients after allogeneic stem cell transplantation. To assess the potential of prospective polymerase chain reaction (PCR) screening for early diagnosis of IA, 84 recipients of an allogeneic stem cell transplant were analyzed with the investigators blinded to clinical and microbiologic data. Of 1193 blood samples analyzed, 169 (14.2%) were positive by PCR. In patients with newly diagnosed IA (n = 7), PCR positivity preceded the first clinical signs by a median of 2 days (range, 1-23 days) and preceded clinical diagnosis of IA by a median of 9 days (range, 2-34 days). Pretransplantation IA (relative risk [RR], 2.37), acute graft-versus-host disease (RR, 2.75), and corticosteroid treatment (RR, 6.5) were associated with PCR positivity. The PCR assay revealed a sensitivity of 100% (95% confidence interval [CI], 48%-100%) and a specificity of 65% (95% CI, 53%-75%). None of the PCR-negative patients developed IA during the study period. Thus, prospective PCR screening allows for identification of Copyright © 2000 The University of Chicago [ABSTRACT FROM AUTHOR]

Background: Previous studies have shown that interleukin-8 serum levels in febrile neutropenic patients are significantly higher in patients with gram-negative bacteremia than in patients with other causes of fever and may indicate unfavorable outcomes. We assessed the value of interleukin-8 serum levels at fever onset to predict clinical complications in order to confirm these earlier findings.Patients and Methods: In a prospective observational study of adult patients receiving cancer chemotherapy, serum samples obtained at the onset of 147 febrile neutropenic episodes were measured by an immunoluminescence assay.Results: Complicated courses of fever including severe sepsis or septic shock, respiratory insufficiency or death were observed in 13 episodes (9%); in six episodes complications had developed within 1 week after fever onset and five of them were associated with bloodstream infections. At an interleukin-8 cutoff level of 1,000 pg/ml, these early complications were predicted with a sensitivity of 83%, a specificity of 97%, a positive predictive value of 50%, and a negative predictive value of 99%, respectively.Conclusion: Interleukin-8 levels at fever onset may be used for the prediction of early medical complications associated with bacteremia and can help identify patients who might benefit from intensive care admission. [ABSTRACT FROM AUTHOR]

Fluoroquinolone resistance in Escherichia coli is principally caused by two kinds of mutations: those affecting the target proteins of the drugs, i.e. DNA gyrase and topoisomerase IV, and those affecting regulatory genes such as marA, soxS or robA. Recently, overexpression of the latter genes was linked to increased organic solvent tolerance in E. coli. Among 138 clinical fluoroquinolone-resistant and -susceptible clinical isolates of E. coli we found a high association between fluoroquinolone resistance and organic solvent tolerance. This finding suggests that E. coli may undergo an adaptive response to extrinsic substances other than quinolones while mutating to fluoroquinolone resistance. [ABSTRACT FROM PUBLISHER]

Multi-resistant bacteria such as Escherichia coli and Klebsiella pneumoniae are a growing threat worldwide. The spread of Carbapenemase-producing strains is particularly worrying. New antibiotics and combination therapies offer treatment options, but the development of resistant pathogens remains a major challenge., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: For Clostridioides difficile infections (CDIs) in Germany no longitudinal multi-centre studies with standardized protocols for diagnosing CDI are available. Recent evaluations of general surveillance databases in Germany indicate a downward trend in CDI rates. We aimed to describe the actual burden and trends of CDI in German university hospitals from 2016 to 2020., Methods: Our study was a prospective multi-centre study covering six German university hospitals. We report the data in total, stratified by year, by medical specialty as well as by CDI severity. Multi-variable regression analyses were performed to assess risk factors for severe CDI., Results: We registered 3780 CDI cases among 1,436,352 patients. The median length of stay (LOS) of CDI cases was 20 days (interquartile range 11-37) compared with a general LOS of 4.2 days. In-hospital all-cause mortality in CDI patients was 11.7% (N = 444/3780), while mortality attributed to CDI was 0.4% (N = 16/3761). CDI recurrence rate was comparatively low at 7.2%. The incidence density of severe healthcare-associated healthcare onset (HAHO)-CDI showed a significant decrease from 2.25/10,000 patient days (pd) in 2016 to 1.49/10,000 pd in 2020 (trend calculation P=0.032)., Conclusions: Compared with a European point-prevalence study in 2013/2014, where overall CDI incidence density was 11.2 cases/10,000 pd in Germany (EUCLID), we see in our study halved overall CDI rates of 5.6 cases/10,000 pd in 2020. Our study shows current data on the distribution of CDI cases in German university hospitals and thus provides international comparative data on the key indicators of CDI., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: We present the 'COVID-19 evidence ecosystem' (CEOsys) as a German network to inform pandemic management and to support clinical and public health decision-making. We discuss challenges faced when organizing the ecosystem and derive lessons learned for similar networks acting during pandemics or health-related crises., Study Design and Setting: Bringing together 18 university hospitals and additional institutions, CEOsys key activities included research prioritization, conducting living systematic reviews (LSRs), supporting evidence-based (living) guidelines, knowledge translation (KT), detecting research gaps, and deriving recommendations, backed by technical infrastructure and capacity building., Results: CEOsys rapidly produced 31 high-quality evidence syntheses and supported three living guidelines on COVID-19-related topics, while also developing methodological procedures. Challenges included CEOsys' late initiation in relation to the pandemic outbreak, the delayed prioritization of research questions, the continuously evolving COVID-19-related evidence, and establishing a technical infrastructure. Methodological-clinical tandems, the cooperation with national guideline groups and international collaborations were key for efficiency., Conclusion: CEOsys provided a proof-of-concept for a functioning evidence ecosystem at the national level. Lessons learned include that similar networks should, among others, involve methodological and clinical key stakeholders early on, aim for (inter)national collaborations, and systematically evaluate their value. We particularly call for a sustainable network., Competing Interests: Declaration of competing interest F.B. reports a relationship with Pfizer that includes: speaking and lecture fees; reports a relationship with Hans-Bockler-Foundation that includes: funding grants; reports a relationship with German Research Foundation that includes: funding grants; reports a relationship with German Federal Ministry of Health that includes: funding grants; reports a relationship with Federal German Ministry of Education and Research that includes: funding grants; reports a relationship with Charité Foundation that includes: funding grants; reports a relationship with Joint Federal Committee that includes: funding grants; reports a relationship with General Electric that includes: speaking and lecture fees; reports a relationship with Medtronic that includes: board membership. I.K. reports the following grants or contracts from any entity in the past 36 months (type of grant: third party fund; recipient: institutional): German Cancer Aid Foundation, German Ministry of Health (BMG), German Federal Joint Committee independent Funding Programme for Clinical Practice Guidelines developed under the auspices of AWMF member societies (2020-2023), German Ministry for Education and Research (BMBF; 2020-2022); reports consulting fees (recipient: personal) were provided by: European Federation of Periodontology (honoraria, travel costs; 2020-2023), British Society for Periodontology (honoraria, travel costs; 2020-2023), European Society of Endotontology (ESE; honoraria; 2021 – 2023), European Society for Contact Dermatitis (ESCD; honoraria; 2021-2021); reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events (recipient: personal) by EBM Frankfurt, Working Group at the Institute for Family Medicine, Goethe-University Frankfurt (honoraria, travel costs; 2020-2022), German Society for Pediatric Infectiology (honoraria; 2021-2022), European Business School (EBS) Wiesbaden (honoraria; 2021-2022), European Association of Dental Implantologists (BDIZ; honoraria, travel costs; 2022-2022); reports payment for expert testimony was provided by German Accreditation Body (DAkkS; honoraria, travel costs); reports participation on a Data Safety Monitoring Board or Advisory Board (Agency for Quality in Medicine (ÄZQ) (a nonprofit organization)—advisory board; type of grant: honoraria, 2020-2023); reports leadership or a fiduciary role in other board, society, committee, or advocacy group (unpaid, nonfinancial): AWMF-Representative in the Board of Trustees- IQTIG (German Institute for Quality and Transparency in Health Care) a nonprofit, governmental institution), Honorary Member—German Society for Breast Health, Member—German Network for Evidence based Medicine (DNEbM), German Society of Surgery (DGCH), Member—Steering Committee for the Guideline Program in Oncology of the German Cancer Society, German Cancer Aid and AWMF, Member—Advisory Board for the Program National Disease Management Guidelines under the auspices of AWMF, German Cancer Society and AWMF, Deputy Chair- Standing Commission on Guidelines of the German Medical Association, the National Association of Statutory Health Insurance Physicians, and the AWMF, Primary Contact on behalf of the AWMF in the Guidelines International Network, Trustee, Guidelines International Network, AWMF Curriculum for guideline developers and guideline advisors; Reviewer, GIN-Mcmaster INGUIDE Program. Other financial or nonfinancial interests: Research interests (Guidelines, Health Services Research, Digitalization); and explicitly declares that she has no ties to pharmaceutical or medical product industry. M.S. reports financial support and administrative support were provided by Charité Universitätsmedizin Berlin Infectious Diseases; reports a relationship with Charité University Hospital Berlin that includes: employment. F.v.D. reports a relationship with Charité University Hospital Berlin that includes: funding grants; reports a relationship with University Medicine Greifswald that includes: funding grants. There are no competing interests for any other author., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Arboviral diseases remain a significant health concern worldwide, with over half the world's population at risk for dengue alone. Without a vaccine or targeted treatment, the most effective strategy of prevention is vector management with community involvement. mHealth interventions, like WhatsApp, offer promising results for engaging communities and promoting healthier behaviors. This study explores the feasibility of integrating WhatsApp in vector control activities to improve arbovirus prevention in Colombia. A mixed-methods approach was employed to assess the WhatsApp-based intervention. WhatsApp messages were sent to 45 community women for 5 weeks to increase their knowledge and practices about dengue, Zika, and chikungunya. Pre-and-post surveys and focus group discussions were conducted in community settings to measure the feasibility and acceptability of this intervention. Chat reviews were done to assess the usability of users. A total of 1566 messages were exchanged in 45 WhatsApp chats. High acceptance and good usability (82% of users used the app for replying) were reported in this study. WhatsApp messages were perceived as short, clear, and enjoyable. Users liked the frequency, and design of messages. Pre- and post-surveys demonstrated improvements in the knowledge and practices of arboviral diseases. The intention to apply this knowledge in practice was reflected in a significant improvement, particularly in cleaning the laundry tank once a week (pre 62.1% to post 89.6%, p  < 0.008). This study suggests that using WhatsApp as an additional tool could be a feasible, acceptable, and affordable strategy for improving the adoption of better practices in the prevention of arboviral diseases.

Background: Antimicrobial stewardship (AMS) programs are effective tools for improving antibiotic prescription quality. Their implementation requires the regular surveillance of antibiotic consumption at the patient and institutional level. Our study captured and analyzed antibiotic consumption density (ACD) for hospitalized pediatric patients., Method: We collected antibacterial drug consumption data for 2020 from hospital pharmacies at 113 pediatric departments of acute care hospitals in Germany. ACD was calculated as defined daily dose (DDD, WHO/ATC Index 2019) per 100 patient days (pd). In addition, we analyzed the trends in antibiotic use during 2013-2020., Results: In 2020, median ACD across all participating hospitals was 26.7 DDD/100 pd, (range: 10.1-79.2 DDD/100 pd). It was higher at university vs. non-university hospitals (38.6 vs. 25.2 DDD/100 pd, p < 0.0001). The highest use densities were seen on oncology wards and intensive care units at university hospitals (67.3 vs. 38.4 DDD/100 pd). During 2013-2020, overall ACD declined (- 10%) and cephalosporin prescriptions also decreased (- 36%). In 2020, cephalosporins nevertheless remained the most commonly dispensed class of antibiotics. Interhospital variability in cephalosporin/penicillin ratio was substantial. Antibiotics belonging to WHO AWaRe "Watch" and "Reserve" categories, including broad-spectrum penicillins (+ 31%), linezolid (+ 121%), and glycopeptides (+ 43%), increased over time., Conclusion: Significant heterogeneity in ACD and prescription of different antibiotic classes as well as high prescription rates for cephalosporins and an increased use of reserve antibiotics indicate improvable antibiotic prescribing quality. AMS programs should urgently prioritize these issues to reduce antimicrobial resistance., (© 2023. The Author(s).)

Background: Staphylococcus aureus bloodstream infection is treated with at least 14 days of intravenous antimicrobials. We assessed the efficacy and safety of an early switch to oral therapy in patients at low risk for complications related to S aureus bloodstream infection., Methods: In this international, open-label, randomised, controlled, non-inferiority trial done in 31 tertiary care hospitals in Germany, France, the Netherlands, and Spain, adult patients with low-risk S aureus bloodstream infection were randomly assigned after 5-7 days of intravenous antimicrobial therapy to oral antimicrobial therapy or to continue intravenous standard therapy. Randomisation was done via a central web-based system, using permuted blocks of varying length, and stratified by study centre. The main exclusion criteria were signs and symptoms of complicated S aureus bloodstream infection, non-removable foreign devices, and severe comorbidity. The composite primary endpoint was the occurrence of any complication related to S aureus bloodstream infection (relapsing S aureus bloodstream infection, deep-seated infection, and mortality attributable to infection) within 90 days, assessed in the intention-to-treat population by clinical assessors who were masked to treatment assignment. Adverse events were assessed in all participants who received at least one dose of study medication (safety population). Due to slow recruitment, the scientific advisory committee decided on Jan 15, 2018, to stop the trial after 215 participants were randomly assigned (planned sample size was 430 participants) and to convert the planned interim analysis into the final analysis. The decision was taken without knowledge of outcome data, at a time when 126 participants were enrolled. The new sample size accommodated a non-inferiority margin of 10%; to claim non-inferiority, the upper bound of the 95% CI for the treatment difference (stratified by centre) had to be below 10 percentage points. The trial is closed to recruitment and is registered with ClinicalTrials.gov (NCT01792804), the German Clinical trials register (DRKS00004741), and EudraCT (2013-000577-77)., Findings: Of 5063 patients with S aureus bloodstream infection assessed for eligibility, 213 were randomly assigned to switch to oral therapy (n=108) or to continue intravenous therapy (n=105). Mean age was 63·5 (SD 17·2) years and 148 (69%) participants were male and 65 (31%) were female. In the oral switch group, 14 (13%) participants met the primary endpoint versus 13 (12%) in the intravenous group, with a treatment difference of 0·7 percentage points (95% CI -7·8 to 9·1; p=0·013). In the oral switch group, 36 (34%) of 107 participants in the safety population had at least one serious adverse event compared with 27 (26%) of 103 participants in the intravenous group (p=0·29)., Interpretation: Oral switch antimicrobial therapy was non-inferior to intravenous standard therapy in participants with low-risk S aureus bloodstream infection. However, it is necessary to carefully assess patients for signs and symptoms of complicated S aureus bloodstream infection at the time of presentation and thereafter before considering early oral switch therapy., Funding: Deutsche Forschungsgemeinschaft., Translations: For the German, Spanish, French and Dutch translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AJK received funding for this study from the Deutsche Forschungsgemeinschaft and is Chairperson of the German Sepsis Society. HSe received grants or research support from the Bundesministerium für Bildung und Forschung (BMBF) Germany and the German Center for Infection Research, and has been a consultant for Debiopharm, Gilead, MSD, and Shionogi. AS has received grants from Gilead Sciences (IN-ES-540–6089) and Pfizer, consulting fees and lecture honoraria from Pfizer, MSD, Angelini, Shionogi, Gilead, and Menarini, and travel support from Pfizer. JR-B has received grants or research support from the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/00001) and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC, CB21/13/00012), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, which are co-financed by the European Development Regional Fund. SH received honoraria and travel support from Shionogi, Pfizer, Infectopharm, and AdvanzPharma. NJ reports receiving honoraria for lectures from AbbVie, Bayer, Infectopharm, and Medacta, travel support from Gilead, Pfizer, and Correvio, participation in paid advisory board meetings for MSD, and membership in the steering committee of the German Society of Internal Medicine. SRi received honoraria for lectures from Falk Foundation, Pfizer, bioMérieux, Akademie für Infektionsmedizin, Med Update, streamedup!, and Deutscher Apotheker-Verlag. TW reports receiving honoraria for presentations from AstraZeneca, Advanz, MSD, Pfizer, and Shionogi, grants or research support from BMBF Germany, and travel support from Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: To analyse recent epidemiological trends of bloodstream infections (BSI) caused by Enterococcus spp. In adult patients admitted to tertiary care centres in Germany., Methods: Epidemiological data from the multicentre R-NET study was analysed. Patients presenting with E. faecium or E. faecalis in blood cultures in six German tertiary care university hospitals between October 2016 and June 2020 were prospectively evaluated. In vancomycin-resistant enterococci (VRE), the presence of vanA/vanB was confirmed via molecular methods., Results: In the 4-year study period, 3001 patients with BSI due to Enterococcus spp. were identified. E. faecium was detected in 1830 patients (61%) and E. faecalis in 1229 patients (41%). Most BSI occurred in (sub-) specialties of internal medicine. The pooled incidence density of enterococcal BSI increased significantly (4.0-4.5 cases per 10,000 patient days), which was primarily driven by VRE BSI (0.5 to 1.0 cases per 10,000 patient days). In 2020, the proportion of VRE BSI was > 12% in all study sites (range, 12.8-32.2%). Molecular detection of resistance in 363 VRE isolates showed a predominance of the vanB gene (77.1%)., Conclusion: This large multicentre study highlights an increase of BSI due to E. faecium, which was primarily driven by VRE. The high rates of hospital- and ICU-acquired VRE BSI point towards an important role of prior antibiotic exposure and invasive procedures as risk factors. Due to limited treatment options and high mortality rates of VRE BSI, the increasing incidence of VRE BSI is of major concern., (© 2024. The Author(s).)

Background: Limited evidence on utilisation of health care by recently arrived asylum seekers and refugees in high-income countries is available. This study aims to describe the implementation of an integrated care facility (ICF) in an initial reception centre and measure the utilisation of care and the influence of operational parameters., Methods: In a retrospective cohort study design, using medical records, we followed inhabitants of a reception centre in Germany between 11.10.2015 and 30.05.2018. We assessed frequency of visits and revisits to a newly established integrated care facility (ICF), and the effects of the ICF on visits to the local emergency department (LED) in the regional tertiary hospital using survival analysis and time series regression. We also explore the influence of operational parameters on the different implementation phases; phase 1: provisional clinic with 1-2 hours of physician presence daily, phase 2: implementation of ICF with 2-4 hours of care by a team of doctors and nurses daily, phase 3: routine running of ICF with daily operational hours of 10am-2pm with care provided by an interdisciplinary team of doctors and nurses., Results: 14,419 total medical visits were recorded from 1,883 persons seeking health care in the ICF. The absolute number of visits per day remained similar over the study period (19·9/day), yet the relative number of visits changed from 2·2 to 15 per 100 inhabitants from phase 2 to 3, respectively. Most visits were due to respiratory infections (612/3080, 20%), and trauma and musculoskeletal conditions (441/3080, 14%). The rate of revisits to ICF was 2·9 per person per month (95%CI 2·9-3), more for those older, female, from North Africa and those with a translator present. The ratio of visits to the LED changed from 0·3/100 inhabitants per day to 0·14/100 inhabitants after implementation of the ICF and back to 0·3/100 inhabitants during the routine running., Conclusions: Though seasonal variation and referral practices must be considered, a high rate of revisits to the ICF were recorded. While visits to the LED decreased after the implementation of the ICF, visits returned to the pre-ICF levels during the routine running of the ICF. The results show that AS&R require reliable access to health care, yet the needs of specific groups of migrants may be different, especially those with language barriers, minority groups or those from certain regions. As such, care should be migrant sensitive and adapt to the changing needs of the population. Though more research is required to better understand the differing needs of migrants, this study may help to inform guidelines surrounding migrant sensitive standards of care in Germany., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bockey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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

Multidrug resistance poses global challenges, particularly with regard to Gram-negative bacterial infections. In view of the lack of new antibiotics, drug enhancers, such as efflux pump inhibitors (EPIs), have increasingly come into focus. A number of chemically diverse agents have been reported to inhibit AcrB, the main multidrug transporter in Escherichia coli , and homologs in other Gram-negative bacteria. However, due to the often varying methodologies used for their characterization, results remain difficult to compare. In this study, using a defined selection of antibiotics known to be efflux substrates, we reevaluated 38 published compounds for their in vitro EPI activity. When examined in an E. coli strain with stable wild-type AcrB overexpression, we found 17 compounds showing at least fourfold enhancing potency with more than 2 out of 10 test drugs (belonging to eight antibiotic classes). Pyranopyridines (MBX series) were confirmed as the most potent inhibitors among agents reported so far. A new and surprising finding was that their activity, unlike that of the pyridylpiperazine EPI BDM88855, was highly susceptible to the AcrB double-mutation G141D&#95;N282Y, which had previously been shown to diminish drug enhancing of 1-(1-naphthylmethyl)piperazine in a predominantly substrate-specific manner. Conversely, transmembrane region mutation V411A, while eliminating the drug potentiating of the BDM compound, did not decrease the activity of the MBX EPIs. Besides comparative reassessment of the potency of reported EPIs, the study demonstrated the usefulness of mutagenesis approaches providing tools for an initial discrimination of EPIs regarding their mode of function.IMPORTANCEInfections with difficult-to-treat multidrug-resistant bacteria pose an urgent global threat in view of the stagnating development of new antimicrobial substances. Efflux pumps in Gram-negative pathogens are known to substantially contribute to multidrug resistance making them promising targets for chemotherapeutic interventions to restore the efficacy of conventional antibiotics. In the present study, the in vitro activity of previously reported efflux pump inhibitors was reassessed using standardized conditions. Relevant drug sensitizing activity could be proven for almost half of the tested compounds. Further characterization of potent inhibitors was achieved by investigating the impact of specific efflux pump mutations. A double-mutation previously known to decrease the activity of the arylpiperazine 1-(1-naphthylmethyl)piperazine also impaired that of the highly efficient pyranopyridine efflux pump inhibitors. Our findings provide direct comparability of reported efflux pump inhibitors and contribute to the elucidation of their mode of action., Competing Interests: The authors declare no conflict of interest.

Objectives: Evidence on the work-related societal impact of long-term health-related consequences following SARS-CoV-2 is emerging. We characterize the modified work ability index (mWAI) of employees 6 to 12 months after an acute infection compared to pre-infection., Methods: Analyses were based on a population-based, multi-center cross-sectional study including employees aged 18-65 years with positive SARS-CoV-2 polymerase chain reaction (tested between October 2020-April 2021 in defined geographic regions in Germany). Prevalences and results of adjusted logistic regression analyses were given., Results: In 9752 employees (mean age 45.6 years, 58% females, response 24%), n = 1217 (13.1%) participants were regarded as having low mWAI compared to pre-infection. Outpatient medical treatment, inpatient treatment, and admission to intensive care during infection were associated with mWAI <15 th percentile (P15, each odds ratio [OR] >3.0). Post-COVID symptom clusters most strongly linked to mWAI

During August-December 2022, toxigenic Corynebacterium diphtheriae was isolated from 25 refugees with skin infections and 2 refugees with asymptomatic throat colonization at a refugee reception center in Germany. None had systemic toxin-mediated illness. Of erosive/ulcerative skin infections, 96% were polymicrobial. Erosive/ulcerative wounds in refugees should undergo testing to rule out cutaneous diphtheria.

Objectives: To analyse the influence of antibiotic consumption on healthcare-associated healthcare onset (HAHO) Clostridioides difficile infection (CDI) in a German university hospital setting., Methods: Monthly ward-level antibiotic consumption measured in DDD/100 patient days (pd) and CDI surveillance data from five university hospitals in the period 2017 through 2019 were analysed. Uni- and multivariable analyses were performed with generalized estimating equation models., Results: A total of 225 wards with 7347 surveillance months and 4 036 602 pd participated. With 1184 HAHO-CDI cases, there was a median incidence density of 0.17/1000 pd (IQR 0.03-0.43) across all specialties, with substantial differences among specialties. Haematology-oncology wards showed the highest median incidence density (0.67/1000 pd, IQR 0.44-1.01), followed by medical ICUs (0.45/1000 pd, IQR 0.27-0.73) and medical general wards (0.32/1000 pd, IQR 0.18-0.53). Multivariable analysis revealed carbapenem (mostly meropenem) consumption to be the only antibiotic class associated with increased HAHO-CDI incidence density. Each carbapenem DDD/100 pd administered increased the HAHO-CDI incidence density by 1.3% [incidence rate ratio (IRR) 1.013; 95% CI 1.006-1.019]. Specialty-specific analyses showed this influence only to be valid for haematological-oncological wards. Overall, factors like ward specialty (e.g. haematology-oncology ward IRR 2.961, 95% CI 2.203-3.980) or other CDI cases on ward had a stronger influence on HAHO-CDI incidence density (e.g. community-associated CDI or unknown association case in same month IRR 1.476, 95% CI 1.242-1.755) than antibiotic consumption., Conclusions: In the German university hospital setting, monthly ward-level carbapenem consumption seems to increase the HAHO-CDI incidence density predominantly on haematological-oncological wards. Furthermore, other patient-specific factors seem to be equally important to control HAHO-CDI., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Annual screening for asymptomatic infections with Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) is recommended by international guidelines in people living with HIV but uptake in routine care remains poor. This study analyzed the effects of the implementation of a CT/NG screening program in a primary HIV treatment center., Methods: In this single-center cohort study, we included men having sex with men (MSM) living with HIV during the study period from January 2016 to December 2019. From January 2018 on, annual sexual health counseling including CT/NG screening was proactively offered to all MSM presenting at the center. CT/NG screening rates, test positivity rates and case detection rates in the years 2018 and 2019 were compared to those in the years 2016 and 2017., Results: A total of 234 patients were enrolled in the study contributing to 798.7 patient years (py) during the four-year study period. Screening rates increased from 3.1% and 3.9% in 2016 and 2017 to 51.1% in 2018 and decrease to 35.4% in 2019. Over the study period, 19.7% (46/234) had at least one positive CT/NG result. After the intervention, case detection per 100 py increased for CT (2016: 2.6, 2017: 3.7, 2018: 7.7, 2019: 7.1) and NG (2016: 3.2, 2017: 3.1, 2018: 5.3, 2019: 7.6). The number needed to test was 8.9 for CT and 10.4 for NG., Conclusion: Regular CT/NG screening is feasible in a primary care setting, leads to an increase in case detection and may contribute to decrease transmission and complications of CT/NG., Trial Registration: The trial is registered in ClinicalTrials.gov (NCT02149004)., (© 2022. The Author(s).)

Objectives: Assessment of vancomycin-resistant Enterococcus faecium (VREfm) prevalence upon hospital admission and analysis of risk factors for colonization., Methods: From 2014 to 2018, patients were recruited within 72 hours of admission to seven participating German university hospitals, screened for VREfm and questioned for potential risk factors (prior multidrug-resistant organism detection, current/prior antibiotic consumption, prior hospital, rehabilitation or long-term care facility stay, international travel, animal contact and proton pump inhibitor [PPI]/antacid therapy). Genotype analysis was done using cgMLST typing. Multivariable analysis was performed., Results: In 5 years, 265 of 17,349 included patients were colonized with VREfm (a prevalence of 1.5%). Risk factors for VREfm colonization were age (adjusted OR [aOR], 1.02; 95% CI, 1.01-1.03), previous (aOR, 2.71; 95% CI, 1.87-3.92) or current (aOR, 2.91; 95% CI, 2.60-3.24) antibiotic treatment, prior multidrug-resistant organism detection (aOR, 2.83; 95% CI, 2.21-3.63), prior stay in a long-term care facility (aOR, 2.19; 95% CI, 1.62-2.97), prior stay in a hospital (aOR, 2.91; 95% CI, 2.05-4.13) and prior consumption of PPI/antacids (aOR, 1.29; 95% CI, 1.18-1.41). Overall, the VREfm admission prevalence increased by 33% each year and 2% each year of life. 250 of 265 isolates were genotyped and 141 (53.2%) of the VREfm were the emerging ST117. Multivariable analysis showed that ST117 and non-ST117 VREfm colonized patients differed with respect to admission year and prior multidrug-resistant organism detection., Discussion: Age, healthcare contacts and antibiotic and PPI/antacid consumption increase the individual risk of VREfm colonization. The VREfm admission prevalence increase in Germany is mainly driven by the emergence of ST117., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To analyse the adherence and impact of quality-of-care indicators (QCIs) in the management of Staphylococcus aureus bloodstream infection in a prospective and multicentre cohort., Methods: Analysis of the prospective, multicentre international S. Aureus Collaboration cohort of S. Aureus bloodstream infection cases observed between January 2013 and April 2015. Multivariable analysis was performed to evaluate the impact of adherence to QCIs on 90-day mortality., Results: A total of 1784 cases were included. Overall, 90-day mortality was 29.9% and mean follow-up period was 118 days. Adherence was 67% (n = 1180/1762) for follow-up blood cultures, 31% (n = 416/1342) for early focus control, 77.6% (n = 546/704) for performance of echocardiography, 75.5% (n = 1348/1784) for adequacy of targeted antimicrobial therapy, 88.6% (n = 851/960) for adequacy of treatment duration in non-complicated bloodstream infections and 61.2% (n = 366/598) in complicated bloodstream infections. Full bundle adherence was 18.4% (n = 328/1784). After controlling for immortal time bias and potential confounders, focus control (adjusted hazard ratio = 0.76; 95% CI, 0.59-0.99; p 0.038) and adequate targeted antimicrobial therapy (adjusted hazard ratio = 0.75; 95% CI, 0.61-0.91; p 0.004) were associated with low 90-day mortality., Discussion: Adherence to QCIs in S. Aureus bloodstream infection did not reach expected rates. Apart from the benefits of application as a bundle, focus control and adequate targeted therapy were independently associated with low mortality., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

BackgroundThe exact epidemiology of tick-borne encephalitis virus (TBEV) infections is unknown because many TBEV infections have an influenza-like or asymptomatic course. Surveillance data are based on patients with any (predominantly neurological) symptoms that prompted diagnostic testing. Infection- and vaccine-induced antibodies against TBEV can be distinguished using an NS1 IgG ELISA.AimIn a seroprevalence study we aimed to investigate TBEV antibody prevalence, incidences, manifestation indices and potential protection rates in a highly endemic district in south-western Germany.MethodsWe analysed 2,220 samples from healthy blood donors collected between May and September 2021. The reported number of TBEV infections was provided on a sub-district level by the local public health authorities. Blood samples were first screened using a TBEV IgG ELISA. In a second step, all positive samples were further analysed with a recently established NS1 IgG ELISA. The presence of specific antibodies against TBEV (excluding cross-reacting antibodies against other flaviviruses) was confirmed by testing screening-positive samples with a microneutralisation assay.ResultsOf 2,220 included samples, 1,257 (57%) tested positive by TBEV IgG ELISA and 125 tested positive for infection-induced TBEV NS1 antibodies, resulting in a TBEV NS1 IgG seroprevalence at 5.6% in our population. The yearly incidence based on the NS1 ELISA findings resulted in 283 cases per 100,000 inhabitants.ConclusionUsing the TBEV NS1 IgG assay, we confirmed a manifestation index of ca 2% and a high incidence of predominantly silent TBEV infections (> 250/100,000/year), which exceeds the incidence of notified cases (4.7/100,000/year) considerably.

Species within the Enterobacter cloacae complex (ECC) include globally important nosocomial pathogens. A three-year study of ECC in Germany identified Enterobacter xiangfangensis as the most common species (65.5%) detected, a result replicated by examining a global pool of 3246 isolates. Antibiotic resistance profiling revealed widespread resistance and heteroresistance to the antibiotic colistin and detected the mobile colistin resistance (mcr)-9 gene in 19.2% of all isolates. We show that resistance and heteroresistance properties depend on the chromosomal arnBCADTEF gene cassette whose products catalyze transfer of L-Ara4N to lipid A. Using comparative genomics, mutational analysis, and quantitative lipid A profiling we demonstrate that intrinsic lipid A modification levels are genospecies-dependent and governed by allelic variations in phoPQ and mgrB, that encode a two-component sensor-activator system and specific inhibitor peptide. By generating phoPQ chimeras and combining them with mgrB alleles, we show that interactions at the pH-sensing interface of the sensory histidine kinase phoQ dictate arnBCADTEF expression levels. To minimize therapeutic failures, we developed an assay that accurately detects colistin resistance levels for any ECC isolate., (© 2023. The Author(s).)

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 (n = 134) within four risk groups ((1) cancer (n = 56); (2) immunosuppression (n = 16); (3) laboratory-based risk factors (n = 36); and (4) advanced age (n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer (P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response., (© 2022. The Author(s).)