Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections

It is unclear whether CVC removal is necessary to successfully manage enterococcal CA-BSI. MEthoDs: A 12-month retrospective cohort study of adults with enterococcal CA-BSI was conducted at a tertiary care hospital; clinical, microbiological and outcome data were collected. rEsuLts: A total of 111 patients had an enterococcal CA-BSI. [37.9]; P=0.03), but similar rates of recurrent bacteremia (nine [11.0%] versus two (7.0%); P=0.7) and a similar post-BSI length of hospital stay (median days [range]) (11.1 [1.7 to 63.1 days] versus 9.3 [1.9 to 31.8 days]; P=0.3). Catheter retention was an independent predictor of mortality (OR 3.34 [95% CI 1.21 to 9.26]). ConCLusIons: To the authors' knowledge, the present article describes the largest enterococcal CA-BSI series to date. Mortality was increased among patients who had their catheter retained. Additional prospective studies are necessary to determine the optimal management of enterococcal CA-BSI. [37, Catheter removal versus retention in the management of catheter-associated enterococcal bloodstream infections The aim of the present study was to examine the epidemiology, treatment and subsequent outcomes of patients with enterococcal CA-BSI, comparing patients with retained versus removed catheters. Our hypothesis was that catheter management does not affect patient outcomes. MEthoDs setting Barnes-Jewish Hospital (BJH), a 1250-bed teaching hospital, is the largest hospital in Missouri (USA), and has a referral base that includes the St Louis Metropolitan area, eastern Missouri and western Illinois. It houses all medical specialties, including a stem cell transplantation unit. BJH is affiliated with the Washington University School of Medicine (St Louis, Missiouri, USA). study design A retrospective cohort study of patients with enterococcal CA-BSIs during their hospital stay was performed. CA-BSI was defined as enterococcal bacteremia in a patient with a central venous catheter (CVC) in place for at least 48 h and no alternative source of infection. The hospital's medical informatics database was queried for blood cultures positive for any Enterococcus species; this dataset was merged with a manually collected dataset of CVC usage in the hospital, which is part of the hospital infection control database. Inclusion and exclusion criteria Adult patients admitted to BJH between January 1, 2006 and December 31, 2006, who presented with, or developed, an enterococcal bloodstream infection and had a CVC present at the time of detection of this infection were included. All types and locations of CVCs were included. Blood cultures were obtained during routine care either peripherally and/or from the CVC. Patients who presented to the hospital with a CVC already in place were included. Patient history and physical examination as well as admitting diagnosis and microbiology results were reviewed to determine whether the catheter was the primary focus of the bacteremia. Patients with a primary focus of bacteremia other than the catheter, patients with a CVC in place for <48 h, and patients who died on the day of the positive blood culture were excluded. Polymicrobial infections were included except concurrent Staphylococcus aureus bacteremia or candidemia within ±3 days of the enterococcal bacteremia (n=20) because both entities are established indications for catheter removal. Data collection Demographic characteristics, medical history, clinical presentation, diagnostic and therapeutic procedures, antibiotic treatment and key markers of outcome (recurrence of bloodstream infection, length of hospital stay after the bloodstream infection, crude mortality) were abstracted from the medical records. Admission Charlson comorbidity and McCabe severity of illness scores were determined. Duration of catheter retention time after the bacteremia was recorded. Information on antibiotic lock therapy was collected; however, this treatment modality was not used in patients from this cohort. Postdischarge mortality at both 30 days and three months after bacteremia was obtained from the Social Security Death Index (www. ssdi-search.com). Definitions Renal insufficiency was defined by a serum creatinine level >132.6 μmol/L. Sepsis and sepsis-induced hypotension were defined using established criteria (13). Appropriate therapy was defined as pathogen-directed treatment with antibiotics matching susceptibilities. A catheter was considered to be retained if it was present for the duration of the hospitalization after the first positive blood culture. Recurrence of bacteremia (used here synonymously with intermittent bacteremia) was defined as a second positive blood culture after ≥1 negative blood culture and an interval of ≥1 day during their hospitalization. Community-onset enterococcal bloodstream infection was defined as having the first positive blood culture drawn within 48 h of hospital admission. Data analysis and statistical methods Data entry was performed using Access and Excel (Microsoft Corporation, USA). Data analysis was performed using SPSS 17 (IBM Corporation, USA). Univariate comparisons among categorical variables and outcome measures were performed using the χ 2 test or Fisher's exact test. A two-sided P <0.05 was considered to be statistically significant. Also calculated was the absolute difference in proportion (∆ p ) of rates of outcome measures including the 95% CI of this difference to describe the precision of this point estimate. Analysis of the difference in proportions and 95% CI enabled the interpretation of statistical significance (if the 95% CI did not cross zero) as well as clinical significance (if the upper limit of the 95% CI exceeded a predefined difference). An absolute difference in recurrence of bacteremia and mortality rates of 15% was considered to represent a clinically significant difference; this estimate was chosen based on previous literature regarding catheter management and clinical experience (14,15). Comparisons among continuous independent variables were performed using the Student's t test or Mann-Whitney U test as appropriate. Variables found to have P<0.1 in univariate testing were considered for entry into a forward, stepwise multivariate logistic regression model. The study was approved by the Washington University Human Research Protection Office (#07-0690). rEsuLts Demographics, comorbidities and clinical presentation There were 111 patients with enterococcal CA-BSI who met inclusion criteria. The mean (± SD) age was 58.2±15.3 years; 56 (50.5%) patients were male; and 77 (69.4%) were white. There were 36 (32%) patients admitted to the oncology/bone marrow transplant service. The most frequent comorbidities were malignancies (n=62 [55.9%]), diabetes (n=35 [31.5%]) and renal insufficiency (n=31 [27.9%]). Twenty-five (22.5%) patients had metastatic solid tumours, 28 (25.2%) had leukemia, six (5.4%) had lymphomas and three (2.7%) had nonmetastatic solid tumours. There were 20 (18%) patients who were neutropenic at the time of bloodstream infection. Of all bloodstream infections, 90 (81%) were hospital-acquired. None of the patients were diagnosed with infective endocarditis during the admission. Microbiology Of the enterococcal bloodstream infections, 45 (40.5%) were caused by E faecalis and 61 (55.0%) by E faecium. Of the bacteremias caused by E faecalis, 10 (22.2%) were due to vancomycin-resistant isolates while 57 (93.4%) of the bacteremias caused by E faecium were vancomycin resistant. An additional five (4.5%) infections were caused by other Enterococcus species. A total of 37 patients (33.3%) had polymicrobial infections in which the most common polymicrobial organism was coagulase-negative Staphylococcus (n=26 [23.4%]). There were 24 (34.9%) polymicrobial E faecalis bacteremias and 10 (27.0%) polymicrobial E faecium bacteremias. Additionally, there was no difference in polymicrobial bacteremias among patients who had their catheter removed versus retained (28 [34.1%] versus nine [31.0%]; P=0.8). Vancomycin-susceptible E faecalis caused 30 (36.6%) of 82 infections in which catheters were removed during the hospitalization and five (17.2%) of 29 infections in which they were retained (P=0.09). Vancomycin-resistant E faecium (VRE) caused 42 (51.2%) of infections in which catheters were removed and 15 (51.7%) in which they were retained (P=0.9). Overall, there was no difference in the number of vancomycin-resistant isolates regardless of whether a catheter was removed Catheter management The CVC was retained during the hospitalization in 29 (26.1%) patients. In univariate analysis, patients with removed CVCs were similar to patients whose CVC was retained DIsCussIon Removal of an intravascular catheter is, with few exceptions, considered to be an essential part of managing CA-BSI. However, robust data to support this approach are only available for a limited number of pathogens responsible for these infections. Despite the lack of sufficient data to provide an evidence-based recommendation with regard to CA-BSI caused by Enterococcus species, national guidelines recommend removing the involved catheters (9). To our knowledge, the present study represents the largest investigation into catheter management and outcomes of enterococcal bloodstream infections. The main finding of the present study was increased mortality in patients whose catheters were retained during the hospitalization. Our findings suggest that catheter removal should be considered to improve patient survival. Also, the difference in the two outcome proportions exceeded the predetermined clinically meaningful difference of 15%, which gives us a quantitative estimate of the impact of catheter removal. The patient groups were very similar with respect to demographic characteristics and comorbidities, including adjunctive antibiotic treatment with the aminoglycoside gentamicin. These findings are congruent with the single study encountered in the scientific literature that scrutinized outcomes of enterococcal CA-BSI and specifically investigated catheter management, albeit in a smaller number of patients (11). There, the authors retrospectively examined 61 enterococcal CA-BSI, with 82% of the episodes due to E faecalis and polymicrobial infections found in 18% of the study population. Of note, they did not exclude patients with concurrent Staphylococcus aureus or yeast bloodstream infections, although these infections likely guided catheter management significantly more than the detection of enterococci. Sandoe et al (11) evaluated whether successful treatment of a bloodstream infection was possible without removal of the catheter, which was achieved in five of 13 cases (38%). If the catheter was removed, the chance for cure was higher (40 of 48 [83%]). They found a combination of a cell wall-active agent with an aminoglycoside to be significantly more effective than monotherapy when the catheter was retained. The authors concluded that, although the removal of the catheter was performed in the majority of cases, it did not appear to be a necessary part of the management as long as antimicrobial treatment was optimized. In our study, even though we did not set cure as an end point, 67 (81.7%) of 82 patients with catheters removed survived the hospital admission and 61 (74.4%) survived at 30 days postbacteremia. These rates were much lower for patients with retained catheters. In summary, these data suggest that although enterococcal CA-BSI are not an absolute indication for catheter removal, removal should be favoured over catheter retention. Reasons for catheter retention may have been that the treating physicians of patients who were severely ill at the time of enterococcal bloodstream infection were reluctant to remove the catheter because it was essential for nonantibiotic medications; that the patients had limited options for alternative intravenous access; or that their comorbidities increased the risk of catheter removal and replacement. Catheter management may have been driven by reasons other than the infection alone, and removing the catheter could have been a lower priority or higher risk in the patients' overall medical management. Because we collected crude mortality data, it is also conceivable that patients died from causes not related to the CA-BSI. Of note, we did not observe a difference in recurrence of infection depending on catheter management; it is possible that the size of the cohort prevented us from noting a statistically significant difference. Our patients are notable for a high percentage of comorbid conditions, including metastatic solid tumours (23%) and leukemia (25%); accordingly, the crude in-hospital mortality rate was high in our study population. An independent factor associated with death was the detection of VRE in the stool, which may be a marker for frequent health care exposure. Despite this finding, CA-BSIs with vancomycinresistant E faecium did not result in increased mortality compared with non-VRE infections. This is different from an earlier prospective study and a more recent meta-analysis, in which vancomycin resistance was found to be associated with increased mortality Limitations of the present study include its retrospective design, the fact that the diagnosis of recurrent infection depended on the treating physician ordering blood cultures and that postdischarge outcomes, including completion of planned antibiotic therapy, follow-up blood cultures, and catheter removal postdischarge, were not studied. In addition, catheter management is potentially influenced by other reasons for retention (difficulty of finding alternative access, bleeding diathesis) and we did not report outcomes for different catheter types. Finally, changes in the usage of daptomycin and linezolid have occurred since the time of the study. Although this was the largest study of enterococcal CA-BSI to date, it is still a relatively small sample to detect rare outcomes. ConCLusIons Based on our study findings, catheter removal is preferable to retention in patients with enterococcal CA-BSI. A large prospective or multicentre study should be performed to identify patients at highest risk for mortality and to add strength to our results. DECLArAtIons: None of the following authors has a conflict of interest to declare: J Marschall, ML Piccirillo, J Doherty

Lethal Influenza Virus Infection in Macaques Is Associated with Early Dysregulation of Inflammatory Related Genes

The enormous toll on human life during the 1918–1919 Spanish influenza pandemic is a constant reminder of the potential lethality of influenza viruses. With the declaration by the World Health Organization of a new H1N1 influenza virus pandemic, and with continued human cases of highly pathogenic H5N1 avian influenza virus infection, a better understanding of the host response to highly pathogenic influenza viruses is essential. To this end, we compared pathology and global gene expression profiles in bronchial tissue from macaques infected with either the reconstructed 1918 pandemic virus or the highly pathogenic avian H5N1 virus A/Vietnam/1203/04. Severe pathology was observed in respiratory tissues from 1918 virus-infected animals as early as 12 hours after infection, and pathology steadily increased at later time points. Although tissues from animals infected with A/Vietnam/1203/04 also showed clear signs of pathology early on, less pathology was observed at later time points, and there was evidence of tissue repair. Global transcriptional profiles revealed that specific groups of genes associated with inflammation and cell death were up-regulated in bronchial tissues from animals infected with the 1918 virus but down-regulated in animals infected with A/Vietnam/1203/04. Importantly, the 1918 virus up-regulated key components of the inflammasome, NLRP3 and IL-1β, whereas these genes were down-regulated by A/Vietnam/1203/04 early after infection. TUNEL assays revealed that both viruses elicited an apoptotic response in lungs and bronchi, although the response occurred earlier during 1918 virus infection. Our findings suggest that the severity of disease in 1918 virus-infected macaques is a consequence of the early up-regulation of cell death and inflammatory related genes, in which additive or synergistic effects likely dictate the severity of tissue damage

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

Nonrandom selection and the attributable cost of surgical-site infections.

OBJECTIVE: To study the extent to which selection bias poses problems for estimating the attributable cost of deep chest surgical-site infection (SSI) following coronary artery bypass graft (CABG) surgery. DESIGN: Reanalysis of a prospective case-control study. SETTING: A large, Midwestern community medical center. PATIENTS: Cases were all patients who had an SSI (N = 41) following CABG and CABG and valve surgery between April 1996 and March 1998. Controls were every tenth uninfected patient (N = 160). METHODS: Estimates of the attributable cost of deep chest SSI were computed using unmatched comparison, matched comparison, linear regression, and Heckman\u27s two-stage approach. RESULTS: The attributable cost of deep chest SSI was estimated to be $20,012 by unmatched comparison,$19,579 by matched comparison, $20,103 by linear regression, and$14,211 by Heckman\u27s two-stage method. Controlling for selection bias substantially reduced the cost estimate, but the coefficient capturing selection bias was not statistically significant. CONCLUSIONS: Deep chest SSI significantly increases the cost of care for patients who undergo CABG surgery. Unmatched comparison, matched comparison, and linear regression estimated the attributable cost to be approximately $20,000. Although controlling for selection bias with Heckman\u27s two-stage method resulted in a substantially smaller estimate, the coefficient for selection bias was not statistically significant, suggesting that the estimates derived from the other models should be acceptable. However, the magnitude of the difference between the models shows that the effect of selection bias can be substantial. Some exploration for selection bias is recommended when estimating the attributable cost of SSIs

Characteristics and Circumstances of Falls in a Hospital Setting: A Prospective Analysis

OBJECTIVE: To describe the epidemiology of hospital inpatient falls, including characteristics of patients who fall, circumstances of falls, and fall-related injuries. DESIGN: Prospective descriptive study of inpatient falls. Data on patient characteristics, fall circumstances, and injury were collected through interviews with patients and/or nurses and review of adverse event reports and medical records. Fall rates and nurse staffing levels were compared by service. SETTING: A 1,300-bed urban academic hospital over 13 weeks. PATIENTS: All inpatient falls reported for medicine, cardiology, neurology, orthopedics, surgery, oncology, and women and infants services during the study period were included. Falls in the psychiatry service and falls during physical therapy sessions were excluded. MEASUREMENTS AND MAIN RESULTS: A total of 183 patients fell during the study period. The average age of patients who fell was 63.4 years (range 17 to 96). Many falls were unassisted (79%) and occurred in the patient's room (85%), during the evening/overnight (59%), and during ambulation (19%). Half of the falls (50%) were elimination related, which was more common in patients over 65 years old (83% vs 48%; P < .001). Elimination-related falls increased the risk of fall-related injury (adjusted odds ratio, 2.4; 95% confidence interval 1.1 to 5.3). The medicine and neurology services had the highest fall rates (both were 6.12 falls per 1,000 patient-days), and the highest patient to nurse ratios (6.5 and 5.3, respectively). CONCLUSIONS: Falls in the hospital affect young as well as older patients, are often unassisted, and involve elimination-related activities. Further studies are necessary to prevent hospital falls and reduce fall injury rates

A Case-control Study of Patient, Medication, and Care-related Risk Factors for Inpatient Falls

OBJECTIVE: To comprehensively analyze potential risk factors for falling in the hospital and describe the circumstances surrounding falls. DESIGN: Case-control study. Data on potential risk factors and circumstances of the falls were collected via interviews with patients and/or nurses and review of adverse event reports, medical records, and nurse staffing records. SETTING: Large urban academic hospital. PATIENTS: Ninety-eight inpatients who fell and 318 controls matched on approximate length of stay until the index fall. MEASUREMENTS AND MAIN RESULTS: In a multivariate model of patient-related, medication, and care-related variables, factors that were significantly associated with an increased risk of falling included: gait/balance deficit or lower extremity problem (adjusted odds ratio [aOR], 9.0; 95% confidence interval [CI], 2.0 to 41.0), confusion (aOR, 3.6; 95% CI, 1.6 to 8.4), use of sedatives/hypnotics (aOR, 4.3; 95% CI, 1.6 to 11.5), use of diabetes medications (aOR, 3.2; 95% CI, 1.3 to 7.9), increasing patient-to-nurse ratio (aOR, 1.6; 95% CI, 1.2 to 2.0), and activity level of “up with assistance” compared with “bathroom privileges” (aOR, 8.7; 95% CI, 2.3 to 32.7). Urinary or stool frequency or incontinence was of borderline significance (aOR, 2.3; 95% CI, 0.99 to 5.6). Having one or more side rails raised was associated with a decreased risk of falling (aOR, 0.006; 95% CI, 0.001 to 0.024). CONCLUSIONS: Patient health status, especially abnormal gait or lower extremity problems, medications, as well as care-related factors, increase the risk of falling. Fall prevention programs should target patients with these risk factors and consider using frequently scheduled mobilization and toileting, and minimizing use of medications related to falling

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics