Occurrence and trends of Clostridioides difficile infections in hospitalized patients: a prospective multi-centre cohort study in six German university hospitals, 2016-2020.

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.

Vertebral osteomyelitis in patients with Staphylococcus aureus bloodstream infection: Evaluation of risk factors for treatment failure.

OBJECTIVES: Staphylococcus aureus is the most common cause of pyogenic vertebral osteomyelitis (VO). Studies indicate that S. aureus VO results in poor outcome. We aimed to investigate risk factors for treatment failure in patients with Staphylococcus aureus bloodstream infection (SAB) and VO. METHODS: We conducted a post hoc-analysis of data from a German bi-center prospective SAB cohort (2006-2014). Patients were followed-up for one year. Primary outcome was treatment failure defined as relapse and/or death within one year. RESULTS: A total of 1069 patients with SAB were analyzed, with 92 VO patients. In addition to antibiotic treatment, surgery was performed in 60/92 patients. Treatment failed in 44/92 patients (death, n = 42; relapse, n = 2). Multivariable analysis revealed higher age (HR 1.04 [per year], 95%CI 1.01-1.07), Charlson comorbidity index (HR 1.20, 95%CI 1.06-1.36), presence of neurologic deficits (HR 2.53, 95%CI 1.15-5.53) and local abscess formation (HR 3.35, 95%CI 1.39-8.04) as independent risk factors for treatment failure. In contrast, surgery seemed to be associated with a favourable outcome (HR 0.45 (95%CI 0.20-0.997)). CONCLUSION: SAB patients with VO exhibit a high treatment failure rate. Red flags are older age, comorbidities, neurologic deficits and local abscess formation. Whether these patients benefit from intensified treatment (e.g. radical surgery, prolongation of antibiotics) should be investigated further.

[Antibiotic stewardship (ABS). Part 1: Basics]. / Antibiotic Stewardship (ABS). Teil 1: Grundlagen.

Against the background of increasing antimicrobial resistance, antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. For Germany and Austria, a comprehensive S3 guideline is available, which was last updated in 2018. The control of antibiotic or anti-infective use in hospitals should be guided by specialized ABS teams. At the hospital level, ABS also includes a structured ongoing analysis of local antibiotic use and resistance data. Recommendations for locally adapted therapy regimens should be derived and implemented from this data analysis. ABS consists of regular ward rounds ("ABS visits"), during which members of the ABS team review the indication, dosage, route of administration and duration of antimicrobial therapy at the bedside. Here, the key challenge is to save antibiotics without compromising the individual patient. Digitalization and artificial intelligence offer new options for ABS, while the adaption of inpatient concepts to outpatient care is also important.

[Antibiotic stewardship (ABS). Part 2: Application]. / Antibiotic Stewardship (ABS). Teil 2: Anwendung.

Antibiotic stewardship (ABS) is an important measure to counteract the spread of resistant pathogens and multidrug resistance. The most important ABS tools include the implementation of local guidelines, the development of a house-related list of anti-infective agents, regular ABS visits and practice-oriented internal training events. Effective strategies for therapy optimization include indication testing and therapy evaluation, dose optimization as well as determining an appropriate duration of therapy. Oralization of anti-infectives (sequence therapy) should be supported by consistent clinical criteria in in-house guidelines. The incidence of Clostridioides difficile infections (CDI) can be more than halved by restricting the so-called "4C antibiotics". Point-of-care tests help to minimize the use of antibiotics in the outpatient setting. Vaccination reduces the need for antibiotic therapy.

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

Burden of bacterial bloodstream infection-a brief update on epidemiology and significance of multidrug-resistant pathogens.

BACKGROUND: Bloodstream infections comprise a wide variety of pathogens and clinical syndromes with considerable overlap with similar syndromes of non-bacteraemic infections and diverse risk factors, therapeutic implications and outcomes. Yet, this heterogeneous 'entity' has the advantage to be pathogen-defined compared with the broad and even more heterogeneous entity 'sepsis', and so has become helpful for clinicians and epidemiologists for research and surveillance purposes. The increasing availability of population-based and large multicentre well-defined cohort studies should allow us to assess with much confidence and in detail its burden, the significance of antimicrobial resistance, and areas of uncertainty regarding further epidemiological evolution and optimized treatment regimens. AIM: To review key aspects of bloodstream infection epidemiology and burden, and summarize recent news and questions concerning critical developments. SOURCES: Peer-reviewed articles based on the search terms 'bloodstream infection' and 'bacteremia' combined with the terms 'epidemiology' and 'burden'. The emphasis was on new information from studies in adult patients and on the added burden due to pathogen resistance to first- and second-line antimicrobial agents. CONTENT: Topics covered include recent developments in the epidemiology of bloodstream infection due to key pathogens and published information about the relevance of resistance for patient outcomes. IMPLICATIONS: Despite the availability of population-based studies and an increasing number of large well-defined multicentre cohort studies, more surveillance and systematic data on bloodstream infection epidemiology at regional level and in resource-limited settings may be needed to better design new methods for prevention and define the need for and further develop optimized therapeutic strategies.

Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper.

SCOPE: Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective. METHODS: A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method. Question addressed and recommendations: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence-guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors ('who') and actions ('what needs to be done') of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals. CONCLUSIONS: Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.

Towards precision medicine in sepsis: a position paper from the European Society of Clinical Microbiology and Infectious Diseases.

BACKGROUND: Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored. AIMS: To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research. SOURCES: A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed. CONTENT: The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1). IMPLICATIONS: A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways.

[Infectious diseases - a specialty of internal medicine]. / Infektiologie ­ ein Schwerpunkt der Inneren Medizin.

Infectious diseases have recently gained wide public interest. Emerging infections and rising rates of antibiotic resistance are determining this trend. Both challenges will need to be addressed in international and local collaborations between different specialties in medicine and basic science. Infectious diseases as a clinical specialty in this scenario is directly responsible for the care of patients with infectious diseases. Its involvement in the care of patients with complicated infections has proved to be highly effective. Antibiotic stewardship programmes are effective measures in slowing the development of antibiotic resistance and have been widely implemented. But antibiotic stewardship specialists should not be confused with or taken as an alternative to infectious disease experts. Infectious diseases requires appropriate and specific training. It mainly uses the instrumentarium of internal medicine. With the current challenges in modern medicine, infectious diseases in Germany should thus be upgraded from a subspecialty to a clinical specialty, ideally within Internal Medicine.

Secular trends of bloodstream infections during neutropenia in 15 181 haematopoietic stem cell transplants: 13-year results from a European multicentre surveillance study (ONKO-KISS).

OBJECTIVES: Antibacterial resistance is emerging in patients undergoing haematopoietic stem cell transplantation (HSCT), and most data on the epidemiology of bloodstream infections (BSI)-causing pathogens come from retrospective single-centre studies. This study sought to investigate trends in the epidemiology of BSI in HSCT patients from a prospective multicentre cohort. METHODS: We investigated changes in the incidence of causative organisms of BSI during neutropenia among adult HSCT patients for 2002-2014. The data were collected from a prospective cohort for infection surveillance in 20 haematologic cancer centres in Germany, Austria and Switzerland (ONKO-KISS). RESULTS: A total of 2388 of 15 181 HSCT patients with neutropenia (1471 allogeneic (61.6%) and 917 autologous (38.4%) HSCT) developed BSI (incidence 15.8% per year). The incidence of Gram-negative BSI increased over time both in patients after allogeneic HSCT (allo-HSCT) and autologous HSCT (auto-HSCT). BSI caused by Escherichia coli in allo-HSCT patients increased from 1.1% in 2002 to 3.8% in 2014 (3/279 vs. 31/810 patients, p <0.001), and the incidence of BSI caused by enterococci increased from 1.8% to 3.3% (5 vs. 27 patients, p <0.001). In contrast, the incidence of BSI due to coagulase-negative staphylococci decreased in allo-HSCT patients from 8.2% to 5.1%, (23 vs. 40 patients, p <0.001) and in auto-HSCT patients from 7.7% to 2.0% (13/167 vs. 30/540 patients; p = 0.028 for period 2002-2011). No significant trends were observed for the incidence of BSI due to methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci or extended-spectrum ß-lactamase-producing Enterobacteriaceae. The BSI case fatality remained unchanged over the study period (total of 477 fatalities, 3.1%). CONCLUSIONS: The incidence of Gram-negative BSI significantly increased over time in this vulnerable patient population, providing evidence for reevaluating empiric therapy for neutropenic fever in HSCT patients.

First report of invasive liver abscess syndrome with endophthalmitis caused by a K2 serotype ST2398 hypervirulent Klebsiella pneumoniae in Germany, 2016.

We report a case of severe infection with liver abscess and endophthalmitis caused by a hypervirulent Klebsiella pneumoniae strain in an immunocompetent German male patient without travel history to Asia. Phenotypic and molecular characterization showed high similarity to the reference genome NTUH-K2044 isolated in Asia. The isolate was assigned as ST2398 (clonal complex 66). The findings underline global spread of hypervirulent Klebsiella pneumoniae strains to Europe.

In vitro susceptibility to 19 agents other than ß-lactams among third-generation cephalosporin-resistant Enterobacteriaceae recovered on hospital admission.

Objectives: As part of the multicentre Antibiotic Therapy Optimisation Study, MIC values of 19 non-ß-lactam agents were determined for third-generation cephalosporin-resistant Escherichia coli , Klebsiella species and Enterobacter species (3GCREB) isolates collected in German hospitals. Methods: A total of 328 E. coli , 35 Klebsiella spp. (1 Klebsiella oxytoca and 34 Klebsiella pneumoniae ) and 16 Enterobacter spp. (1 Enterobacter aerogenes and 15 Enterobacter cloacae ) isolates were submitted to broth microdilution antimicrobial susceptibility testing with the MICRONAUT system. MICs of fluoroquinolones (levofloxacin and moxifloxacin), aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, neomycin and paromomycin), tetracyclines (tetracycline, minocycline and tigecycline), macrolides (erythromycin, clarithromycin and azithromycin) and miscellaneous agents [trimethoprim/sulfamethoxazole, chloramphenicol, nitrofurantoin, colistin and fosfomycin intravenous (iv)] were determined and reviewed against 2016 EUCAST breakpoints. Results: The MIC of levofloxacin was >2 mg/L for 128 of 328 E. coli and 8 of 35 Klebsiella spp., but only 1 of 16 Enterobacter spp. Rates of resistance to trimethoprim/sulfamethoxazole were high (>70%), except for Enterobacter spp. Rates of resistance to colistin and fosfomycin iv were still low. About 20% of the tested isolates were resistant to chloramphenicol. Only 1 (of 328) E. coli isolate had an MIC of amikacin >16 mg/L and only 33 of 328 E. coli and 1 of 35 Klebsiella spp. had an MIC of tobramycin >4 mg/L, whereas average gentamicin MICs were in general more elevated. A tigecycline MIC >2 mg/L was only found for 1 of 16 Enterobacter spp., but in none of the E. coli or Klebsiella spp. isolates. Conclusions: Our study gives insight into previously unreported non-ß-lactam MIC distributions of 3GCREB isolates.

Combination antimicrobial therapy in patients with Staphylococcus aureus bacteraemia-a post hoc analysis in 964 prospectively evaluated patients.

OBJECTIVES: The evidence for using combination antimicrobial therapy (CoRx) in Staphylococcus aureus bacteraemia (SAB) is limited. We aimed to investigate whether CoRx is associated with higher survival or lower SAB-related late complications. METHODS: We performed a post hoc analysis of a prospective SAB cohort study. CoRx was defined as a cell wall-active antistaphylococcal agent plus either rifampicin, a fluoroquinolone, fosfomycin or an aminoglycoside. To adjust for survivor bias multivariable Cox models that included CoRx as a time-dependent covariable were calculated. RESULTS: Of 964 evaluable patients, 512 (53%) received CoRx, most of them (301/512, 59%) rifampicin-containing CoRx. All-cause mortality after 30 and 90 days was similar for the two groups, although the patients in the CoRx group had more often endocarditis, deep-seated or disseminated infections and severe sepsis/septic shock. For the entire cohort, only age, comorbidity and severe sepsis/septic shock were associated with a higher mortality and infectious disease consultation, but not CoRx with a lower mortality. However, in the subgroup of patients with implanted foreign bodies or devices CoRx was independently associated with a lower mortality at 30 days (hazard ratio 0.6, 95% confidence interval 0.3-1.1) and at 90 days (hazard ratio 0.6, 95% confidence interval 0.4-0.9). SAB-related late complications in this subgroup occurred in 15 (10.6%) of 142 patients in the monotherapy group vs. nine (4.5%) of 202 patients in the CoRx group (p 0.03). CONCLUSIONS: In a setting of optimized management of adult patients with SAB secured by infectious disease consultations, this observational study could not prove CoRx to be independently associated with improved survival or reduced late complications in the entire cohort. However, administration of CoRx may be associated with lower mortality and fewer SAB-related late complications in the subgroup of patients with implanted foreign bodies or devices. Prospective randomized trials should be performed to prove this benefit.

Colonization with third-generation cephalosporin-resistant Enterobacteriaceae on hospital admission: prevalence and risk factors.

OBJECTIVES: The objectives of this study were to prospectively assess the rectal carriage rate of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) in non-ICU patients on hospital admission and to investigate resistance mechanisms and risk factors for carriage. METHODS: Adult patients were screened for 3GCREB carriage at six German tertiary care hospitals in 2014 using rectal swabs or stool samples. 3GCREB isolates were characterized by phenotypic and molecular methods. Each patient answered a questionnaire about potential risk factors for colonization with MDR organisms (MDROs). Univariable and multivariable risk factor analyses were performed to identify factors associated with 3GCREB carriage. RESULTS: Of 4376 patients, 416 (9.5%) were 3GCREB carriers. Escherichia coli was the predominant species (79.1%). ESBLs of the CTX-M-1 group (67.3%) and the CTX-M-9 group (16.8%) were the most frequent ß-lactamases. Five patients (0.11%) were colonized with carbapenemase-producing Enterobacteriaceae. The following risk factors were significantly associated with 3GCREB colonization in the multivariable analysis (P < 0.05): centre; previous MDRO colonization (OR = 2.12); antibiotic use within the previous 6 months (OR = 2.09); travel outside Europe (OR = 2.24); stay in a long-term care facility (OR = 1.33); and treatment of gastroesophageal reflux disease (GERD) (OR = 1.22). CONCLUSIONS: To our knowledge, this is the largest admission prevalence study of 3GCREB in Europe. The observed prevalence of 9.5% 3GCREB carriage was higher than previously reported and differed significantly among centres. In addition to previously identified risk factors, the treatment of GERD proved to be an independent risk factor for 3GCREB colonization.

PEPDar: A randomized prospective noninferiority study of ritonavir-boosted darunavir for HIV post-exposure prophylaxis.

OBJECTIVES: PEPDar compared the tolerability and safety of ritonavir-boosted darunavir (DRV/r)-based post-exposure prophylaxis (PEP) with the tolerability and safety of standard of care (SOC). The primary endpoint was the early discontinuation rate among the per-protocol population. METHODS: PEPDar was an open-label, randomized, multicentre, prospective, noninferiority safety study. Subjects were stratified by type of event (occupational vs. nonoccupational, i.e. sexual) and were randomized to receive DRV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) or SOC PEP. Twenty-two private or university HIV clinics in Germany participated. Subjects were ≥ 18 years old and had documented or potential HIV exposure and indication for HIV PEP. They initiated PEP not later than 72 h after the event and were HIV negative. RESULTS: A total of 324 subjects were screened, the per-protocol population was 305, and 273 subjects completed the study. One hundred and fifty-five subjects received DRV/r-based PEP and 150 subjects received ritonavir-boosted lopinavir (LPV/r)-based PEP for 28-30 days; 298 subjects also received tenofovir/emtricitabine. The early discontinuation rate in the DRV/r arm was 6.5% compared with 10.0% in the SOC arm (P = 0.243). Adverse drug reactions (ADRs) were reported in 68% of DRV/r subjects and 75% of SOC subjects (P = 0.169). Fewer DRV/r subjects (16.1%) had at least one grade 2 or 3 ADR compared with SOC subjects (29.3%) (P = 0.006). All grades of diarrhoea, nausea, and sleep disorders were significantly less frequent with DRV/r, while headache was significantly more frequent. No HIV seroconversion was reported during follow-up. CONCLUSIONS: Noninferiority of DRV/r to SOC was demonstrated. DRV/r should be included as a standard component of recommended regimens in PEP guidelines.