Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Antimicrobial Stewardship and Intensive Care Unit Mortality: A Systematic Review.

BACKGROUND: Antimicrobial stewardship programs (ASPs) using audit and feedback in the intensive care unit (ICU) setting can reduce harms related to inappropriate antibiotic use. However, inappropriate discontinuation or narrowing of antibiotic treatment could increase infection-related mortality in this population. Individual ASP studies are underpowered to detect differences in mortality. METHODS: We conducted a systematic review and meta-analysis of audit and feedback in the ICU setting, using mortality as our outcome. RESULTS: Of 2447 citations, 11 studies met our inclusion criteria. Although a variety of study designs were used to assess reductions in antibiotic use, mortality was analyzed using an uncontrolled before-after study design in all studies. Five studies directed audit and feedback to all or most ICU patients receiving antibiotics and measured overall ICU mortality. In the meta-analysis of these studies, the pooled relative risk of ICU mortality was 1.03 (95% confidence interval, .93-1.14). A second meta-analysis of 3 smaller studies that evaluated mortality only in patients directly assessed by the ASP found a pooled relative risk of ICU mortality of 1.06 (95% confidence interval, .80 to 1.4). Three studies were not appropriate for meta-analysis, but their results were consistent with our overall findings. CONCLUSIONS: Our systematic review did not identify a change in mortality associated with antimicrobial stewardship using audit and feedback in the ICU setting. These results increase our confidence that audit and feedback can be safely implemented in this setting. Future studies should report standardized estimates of mortality and use more robust study designs to assess mortality, when feasible.

Memory Matters: A Mixed-Methods Feasibility Study of a Mobile Aid to Stimulate Reminiscence in Individuals With Memory Loss.

Reminiscence interventions are potentially effective in improving well-being of persons with memory loss (PWMLs) and may also enhance relationships with family and professional caregivers. Using a parallel convergent mixed-methods design, the feasibility of "Memory Matters" (MM), a mobile device application developed to promote reminiscence, was evaluated. Eighteen PWMLs and eight family members were enrolled from a long-term care facility and asked to use MM for 4 weeks. Participants were observed using MM at enrollment and 2 weeks and completed 1-month interviews. Six staff participants also completed a system review checklist and/or focus group at 1 month. Three qualitative domains were identified: (a) context of use, (b) barriers to use, and (c) MM influences on outcomes. Participants reported real-time social engagement, ease of use, and other benefits. However, PWMLs were unlikely to overcome barriers without assistance. Empirical data indicated that family and staff perceived MM favorably. Participants agreed that MM could provide stimulating, reminiscence-based activity. [Journal of Gerontological Nursing, 42(7), 15-24.].

Duration of antibiotic therapy for critically ill patients with bloodstream infections: A retrospective cohort study.

BACKGROUND: The optimal duration of antibiotic treatment for bloodstream infections is unknown and understudied. METHODS: A retrospective cohort study of critically ill patients with bloodstream infections diagnosed in a tertiary care hospital between March 1, 2010 and March 31, 2011 was undertaken. The impact of patient, pathogen and infectious syndrome characteristics on selection of shorter (≤10 days) or longer (>10 days) treatment duration, and on the number of antibiotic-free days, was examined. The time profile of clinical response was evaluated over the first 14 days of treatment. Relapse, secondary infection and mortality rates were compared between those receiving shorter or longer treatment. RESULTS: Among 100 critically ill patients with bloodstream infection, the median duration of antibiotic treatment was 11 days, but was highly variable (interquartile range 4.5 to 17 days). Predictors of longer treatment (fewer antibiotic-free days) included foci with established requirements for prolonged treatment, underlying respiratory tract focus, and infection with Staphylococcus aureus or Pseudomonas species. Predictors of shorter treatment (more antibiotic-free days) included vascular catheter source and bacteremia with coagulase-negative staphylococci. Temperature improvements plateaued after the first week; white blood cell counts, multiple organ dysfunction scores and vasopressor dependence continued to decline into the second week. Among 72 patients who survived to 10 days, clinical outcomes were similar between those receiving shorter and longer treatment. CONCLUSION: Antibiotic treatment durations for patients with bloodstream infection are highly variable and often prolonged. A randomized trial is needed to determine the duration of treatment that will maximize cure while minimizing adverse consequences of antibiotics.

HISTORIQUE: On ne connaît pas la durée optimale de l'antibiothérapie des bactériémies, qui est trop peu étudiée. MÉTHODOLOGIE: Les chercheurs ont entrepris une étude de cohorte rétrospective de patients gravement malades atteints d'une bactériémie qui ont été diagnostiqués dans un hôpital de soins tertiaires entre le 1er mars 2010 et le 31 mars 2011. Ils ont examiné les conséquences des caractéristiques du patient, du pathogène et du syndrome infectieux sur le choix d'un traitement plus court (dix jours ou moins) ou plus long (plus de dix jours) et sur le nombre de jours sans prise d'antibiotiques. Ils ont évalué le profil temporel de la réponse clinique au cours des 14 premiers jours du traitement et ont comparé le taux de récidives, d'infections secondaires et de mortalité entre ceux qui recevaient un traitement plus court et plus long. RÉSULTATS: Chez 100 patients gravement malades ayant une bactériémie, l'antibiothérapie avait une durée médiane de 11 jours, mais était très variable (plage interquartile de 4,5 à 17 jours). Les prédicteurs d'un traitement plus long (moins de journées sans antibiotiques) comprenaient des foyers comportant des exigences établies de traitement prolongé, un accent sur une infection sous-jacente des voies respiratoires et une infection par des espèces de Staphylococcus aureus ou de Pseudomonas. Les prédicteurs d'un traitement plus court (plus de journées sans antibiotiques) incluaient une origine dans un cathéter vasculaire et une bactériémie à staphylocoques négative à la coagulase. L'atténuation de la température a plafonné au bout de la première semaine, tandis que la numération des globules blancs, les indices de dysfonction multiorganique et la dépendance aux vasopresseurs a continué de décliner pendant la deuxième semaine. Chez les 72 patients qui ont survécu jusqu'à dix jours, les issues cliniques étaient similaires chez ceux qui recevaient un traitement plus court ou plus long. CONCLUSION: La durée de l'antibiothérapie des patients atteints d'une bactériémie est très variable et souvent prolongée. Il faudra procéder à un essai aléatoire pour déterminer la durée du traitement qui favorisera la guérison au maximum tout en limitant le plus possible les conséquences négatives des antibiotiques.

Duration of antibiotic therapy for bacteremia: a systematic review and meta-analysis.

INTRODUCTION: The optimal duration of antibiotic therapy for bloodstream infections is unknown. Shorter durations of therapy have been demonstrated to be as effective as longer durations for many common infections; similar findings in bacteremia could enable hospitals to reduce antibiotic utilization, adverse events, resistance and costs. METHODS: A search of the MEDLINE, EMBASE and COCHRANE databases was conducted for the years 1947-2010. Controlled trials were identified that randomized patients to shorter versus longer durations of treatment for bacteremia, or the infectious foci most commonly causing bacteremia in critically ill patients (catheter-related bloodstream infections (CRBSI), intra-abdominal infections, pneumonia, pyelonephritis and skin and soft-tissue infections (SSTI)). RESULTS: Twenty-four eligible trials were identified, including one trial focusing exclusively on bacteremia, zero in catheter related bloodstream infection, three in intra-abdominal infection, six in pyelonephritis, thirteen in pneumonia and one in skin and soft tissue infection. Thirteen studies reported on 227 patients with bacteremia allocated to 'shorter' or 'longer' durations of treatment. Outcome data were available for 155 bacteremic patients: neonatal bacteremia (n = 66); intra-abdominal infection (40); pyelonephritis (9); and pneumonia (40). Among bacteremic patients receiving shorter (5-7 days) versus longer (7-21 days) antibiotic therapy, no significant difference was detected with respect to rates of clinical cure (45/52 versus 47/49, risk ratio 0.88, 95% confidence interval [CI] 0.77-1.01), microbiologic cure (28/28 versus 30/32, risk ratio 1.05, 95% CI 0.91-1.21), and survival (15/17 versus 26/29, risk ratio 0.97, 95% CI 0.76-1.23). CONCLUSIONS: No significant differences in clinical cure, microbiologic cure and survival were detected among bacteremic patients receiving shorter versus longer duration antibiotic therapy. An adequately powered randomized trial of bacteremic patients is needed to confirm these findings.

Creating objects with 3D printers to stimulate reminiscence in memory loss: A mixed-method feasibility study.

OBJECTIVE: The objective of the current project was to determine the feasibility of using 3D printed technology to facilitate reminiscence-related activities for persons with memory loss (PWMLs). METHODS: A parallel convergent mixed methods design was used. Fifteen PWMLs, 13 family members, and six staff from two residential long-term care facilities participated. Participants were observed and interviewed initially, during a 2-week reminiscence session, and again during a 1-month reminiscence session. Staff participants also completed a 1-month focus group, and staff and family members were administered a 3D printing review checklist at 1-month. RESULTS: The integrated qualitative and quantitative data strongly suggested that PWMLs enjoyed using the 3D objects, were engaged while doing so and appeared to value the objects due to their personalized nature. The use of 3D printed objects also appeared to encourage family involvement as well as family and staff interactions with PWMLs. Barriers to use included memory impairment and behavioral issues. CONCLUSIONS: The use of 3D printed objects could provide an easy-to-use, well-received, person-centered approach that augments current reminiscence strategies for PWMLs.

How many patients? How many limbs? Analysis of patients or limbs in the orthopaedic literature: a systematic review.

BACKGROUND: Clinical studies assessing orthopaedic interventions often include data from two limbs or multiple joints within single individuals. Without appropriate design or statistical approaches to address within-individual correlations, this practice may contribute to false precision and possible bias in estimates of treatment effect. We conducted a systematic review of the orthopaedic literature to determine the frequency of inappropriate inclusion of nonindependent limb or joint observations in clinical studies. METHODS: We identified seven orthopaedic journals with high Science Citation Index impact factors and retrieved all clinical studies for 2003 for any intervention on any limb or joint. RESULTS: We identified 288 clinical studies, 143 of which involved two limbs or multiple joint observations from single individuals. These studies included nineteen randomized clinical trials (13%) fifty-eight two-group cohort studies (41%), and sixty-six one-group cohort studies (46%). Seventy-six (53%) of the 143 studies involved statistical comparisons between patient groups with use of tests of association, and an additional sixty studies (42%) presented estimates of proportions without statistical comparisons. Only sixteen of the seventy-six studies involving statistical comparisons involved the use of any technique or methodological approach to account for multiple, nonindependent observations. A median of approximately 13% of the patients in these studies contributed more than one observation. The median proportion of nonindependent observations to total observations (the unit of analysis) was approximately 23%. CONCLUSIONS: Our findings suggest that a high proportion (42%) of clinical studies in high-impact-factor orthopaedic journals involve the inappropriate use of multiple observations from single individuals, potentially biasing results. Orthopaedic researchers should attend to this issue when reporting results.

Retrospective cohort study of inappropriate piperacillin-tazobactam use for lower respiratory tract and skin and soft tissue infections: Opportunities for antimicrobial stewardship.

BACKGROUND: Patients with skin and skin structure infections (SSTIs) and lower respiratory tract infections (LRTIs) are frequently prescribed piperacillin-tazobactam (TZP) on hospital admission. Inappropriate broad-spectrum coverage may be associated with patient harm, excess expenditure, and escalating rates of antimicrobial resistance. METHODS: Patients who received empirical TZP for a diagnosis of LRTI or SSTI from January 1-June 30, 2012, were identified retrospectively. Clinical and antimicrobial data were systematically collected from electronic hospital information systems. Using published guidelines, microbiologic results, and individual clinical responses, the appropriateness of TZP use was assessed. Drug utilization after potential standard audit of therapy on day 3 was also evaluated. RESULTS: We reviewed 60 patients with SSTI and 169 patients with LRTI. Inappropriate empirical TZP therapy was found in 41.7% in those with SSTI, and a further 15% had inappropriate continuation of therapy. In LRTI patients, 38.3% received inappropriate empirical TZP, and 10.3% of the treatment courses were continued inappropriately. Community-acquired pneumonia was the most frequent diagnosis where TZP was used inappropriately (96%). A day 3 audit of therapy may have saved 256 days of TZP. CONCLUSION: In our institution, inappropriate empirical TZP is common for community-onset infections of mild to moderate severity. A prospective audit and feedback program may be a strategy to reduce inappropriate use of TZP as empirical therapy.

Recurrent disseminated intravascular coagulation caused by intermittent dosing of rifampin.

Daily rifampin therapy is associated with minimal adverse effects, but administration on an intermittent or interrupted basis has been associated with severe immunoallergic reactions such as hemolytic anemia, acute renal failure, and disseminated intravascular coagulation. We describe a patient with Mycobacterium leprae infection who experienced recurrent episodes of disseminated intravascular coagulation after intermittent exposures to rifampin, and review eight previously reported cases of rifampin-associated disseminated intravascular coagulation. In six (75%) cases, previous exposure to rifampin was reported and seven (87.5%) patients were receiving the medication on an intermittent or interrupted basis. Clinical features of rifampin-associated disseminated intravascular coagulation included fever, hypotension, abdominal pain, and vomiting within hours of ingestion. Average time to reaction was 3-6 doses if rifampin was being administered on a monthly schedule. Three (37.5%) of eight reported cases were fatal. A complete history of previous exposure to rifampin is recommended before intermittent therapy with this medication.