Focusing on antimicrobial resistant infections –are we missing the forest for the trees and the patients for pathogens?

Antimicrobial resistance (AMR) is a challenge because it is associated with worse patient outcomes. To solve the problem will take development of interventions and policies which improve patient outcomes by prolonging survival, improving patient symptoms, function and quality of life. Logically, we should look to focusing resources in areas that would have the greatest impact on public health. AMR takes the approach of focusing on individual pathogens and “pathogen-focused” development. However, evaluating overall infections and their impact on patient outcomes reveals that 17 of 18 infection deaths are associated with susceptible pathogens. Here we discuss recentering on patients and patient outcomes instead of pathogens, and propose six suggestions on how a patient focus impacts areas and incentives for clinical research

Investigating Potential Interactions Between Neurohypophyseal Peptides, their Drug Analogs, and Coagulation Factor VIII

The neurohypophysis is known to secrete vasopressin during times of severe haemorrhage, and oxytocin during labour and delivery, events in which blood loss also occurs. Evidence suggests that there may be an interaction between these peptides and the coagulation cascade, and currently, desmopressin, a drug analog of vasopressin, is a first line therapy for mild Hemophilia A, a common coagulopathy. In this work, interactions between vasopressin and oxytocin with a crucial member of the coagulation cascade, the cofactor Factor VIII, were investigated using fluorescence spectroscopy, interference immunoassays, commercially produced Factor VIII activity kits, and equilibrium dialysis. The results suggest not only that the peptides interact with the coagulation factor, but do so in a way that enhances its activity and prolongs its active form half-life, as seen through the enhancement of the activity of the FXase complex by assay. This theory was then expanded to study the analogs of vasopressin and oxytocin, desmopressin and carbetocin, drugs currently used clinically in the treatment of hemorrhagic conditions. Similar results were obtained. On the whole, these results indicate a potential newly discovered role for the neurohypophyseal hormones, as well as their drug counterparts being used in clinical practice today and may suggest an expanded clinical use in the control of severe haemorrhage

Hepatitis B testing practices at a tertiary care centre and their associated costs: A retrospective analysis.

BackgroundHepatitis B is a viral infection requiring specific serologic testing to diagnose the stage of the disease. There are many tests which can be ordered in a variety of combinations. This study aimed to assess routine Hepatitis B screening practices in a tertiary care centre and determine the diagnostic and economic benefits of protocolized ordering.MethodsWe evaluated all measurements of Hepatitis B total core antibodies, core IgM antibodies, surface antibodies and surface antigens performed at our institution between January 1, 2015 and December 31, 2015. We also recorded secondary testing (envelope antigens and antibodies, and viral DNA). Costs were estimated using provincial insurance reimbursement values. Using the subset of patients who received complete testing, we developed a reflexive screening protocol to minimize costs while simultaneously improving diagnostic utility.Results30,335 hepatitis B tests were performed at an estimated total cost of $584,683. 53.9$181,632 (95% CI $154,201.90 -$208,910.50) per year while providing more complete information.InterpretationScreening practices for Hepatitis B are frequently inadequate to diagnose and stage the infection and often included unnecessary testing. Protocolization of Hepatitis B testing could limit this practice while resulting in significantly lower costs

Which Trial Do We Need? Optimal Antibiotic Duration for Patients with Sepsis

Given the potential benefits of shortened antibiotic courses, prior studies comparing shorter versus longer antibiotic courses have typically adopted a non-inferiority design [3,11]. However, in a study of critically ill patients in whom suboptimal treatment could result in death, a non-inferiority trial would pose a serious ethical dilemma - how to select an acceptable increased risk of mortality to use as a non-inferiority margin? For these reasons, we have designed a trial that requires shorter antibiotic therapy demonstrate superior clinical outcomes over longer antibiotic therapy, allowing partial/full credit to be awarded based on patient and clinicians\u27 perceptions of outcome importance and severity. Should clinical outcomes be comparable among the study arms, the DOOR/RADAR framework acknowledges potential unmeasured benefits of shorter courses (e.g., reduced costs, unmeasured toxicity, and antibiotic pressures selecting for individual and global microbial resistance) and accordingly assigns superiority to shorter antibiotic courses. The duration of antibiotic therapy reflected in this adjustment would be the actual (rather than assigned) duration, allowing for a pragmatic analysis of the interventions as applied in practice while mitigating differences between intention-to-treat and per-protocol analyses resulting from poor protocol adherence

Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial

Abstract Background Staphylococcus aureus bacteremia is associated with significant morbidity and mortality. To treat this infection, the current standard of care includes intravenous anti-staphylococcal beta-lactam antibiotics and obtaining adequate source control. Combination therapy with an aminoglycoside or rifampin, despite early promise, can no longer be routinely recommended due to an absence of proven benefit and risk of harm. Daptomycin is a rapidly acting bactericidal antibiotic that is approved for the treatment of Staphylococcus aureus bacteremia as monotherapy but has not been shown to be superior to the current standard of care. As demonstrated in vitro, the addition of daptomycin to beta-lactam therapy may result in enhanced anti-staphylococcal activity. Our objective is to assess the efficacy and safety of prescribing the combination of daptomycin with cefazolin or cloxacillin for the treatment of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia in adults. We hypothesize that adjunctive therapy with daptomycin will reduce the duration of bacteremia in this population. Methods The DASH-RCT trial is a randomized, double blind, placebo-controlled trial designed per the Standard Protocol Items: Recommendation for Interventional Trials (SPIRIT) and Consolidated Standards of Reporting Trials (CONSORT) guidelines. We recruit adults with confirmed MSSA bacteremia, at the McGill University Health Center. Patients are eligible if they are 18 years or older, can receive cefazolin or cloxacillin monotherapy, and are enrolled within 72 h of the first blood culture being drawn. Exclusion criteria include anaphylaxis to study drugs, having polymicrobial bacteremia, anticipated hospital admission for < 5 days, and healthcare team refusal. While receiving standard of care, study patients are randomized to a 5-day course of adjunctive daptomycin or placebo. The trial began in December 2016 and is expected to end in December 2018, after recruiting an estimated 102 patients. Discussion The DASH-RCT will compare the use of daptomycin as an adjunct to an anti-staphylococcal beta-lactam versus placebo in the treatment of MSSA bacteremia. We believe that a short course of dual therapy will result in earlier eradication of bacteremia and that subsequent research could evaluate effects on metastatic infection, relapse, and/or mortality. Ongoing issues in the trial include a delay between presentation of infection, enrollment in the trial, and the potential for unrecognized deep foci of infection at diagnosis. Trial registration ClinicalTrials.gov, NCT02972983. Registered on 25 November 2016. Trial protocol: http://individual.utoronto.ca/leet/dash/dashprotocol.pd

Additional file 1: of Daptomycin versus placebo as an adjunct to beta-lactam therapy in the treatment of Staphylococcus aureus bacteremia: study protocol for a randomized controlled trial

SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*. (DOC 120 kb

Reliability of Admission Procalcitonin Testing for Capturing Bacteremia Across the Sepsis Spectrum: Real-World Utilization and Performance Characteristics, 65 U.S. Hospitals, 2008-2017

OBJECTIVES: Serum procalcitonin is often ordered at admission for patients with suspected sepsis and bloodstream infections (BSIs), although its performance characteristics in this setting remain contested. This study aimed to evaluate use patterns and performance characteristics of procalcitonin-on-admission in patients with suspected BSI, with or without sepsis. DESIGN: Retrospective cohort study. SETTING: Cerner HealthFacts Database (2008-2017). PATIENTS: Adult inpatients (≥ 18 yr) who had blood cultures and procalcitonin drawn within 24 hours of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Testing frequency of procalcitonin was determined. Sensitivity of procalcitonin-on-admission for detecting BSI due to different pathogens was calculated. Area under the receiver operating characteristic curve (AUC) was calculated to assess discrimination by procalcitonin-on-admission for BSI in patients with and without fever/hypothermia, ICU admission and sepsis defined by Centers for Disease Control and Prevention Adult Sepsis Event criteria. AUCs were compared using Wald test and p values were adjusted for multiple comparisons. At 65 procalcitonin-reporting hospitals, 74,958 of 739,130 patients (10.1%) who had admission blood cultures also had admission procalcitonin testing. Most patients (83%) who had admission day procalcitonin testing did not have a repeat procalcitonin test. Median procalcitonin varied considerably by pathogen, BSI source, and acute illness severity. At a greater than or equal to 0.5 ng/mL cutoff, sensitivity for BSI detection was 68.2% overall, ranging between 58.0% for enterococcal BSI without sepsis and 96.4% for pneumococcal sepsis. Procalcitonin-on-admission displayed moderate discrimination at best for overall BSI (AUC, 0.73; 95% CI, 0.72-0.73) and showed no additional utility in key subgroups. Empiric antibiotic use proportions were not different between blood culture sampled patients with a positive procalcitonin (39.7%) and negative procalcitonin (38.4%) at admission. CONCLUSIONS: At 65 study hospitals, procalcitonin-on-admission demonstrated poor sensitivity in ruling out BSI, moderate-to-poor discriminator for both bacteremic sepsis and occult BSI and did not appear to meaningfully alter empiric antibiotic usage. Diagnostic stewardship of procalcitonin-on-admission and risk assessment of admission procalcitonin-guided clinical decisions is warranted

Blood Culture Results Before and After Antimicrobial Administration in Patients With Severe Manifestations of Sepsis A Diagnostic Study

Background: Administering antimicrobial agents before obtaining blood cultures could potentially decrease time to treatment and improve outcomes, but it is unclear how this strategy affects diagnostic sensitivity. Objective: To determine the sensitivity of blood cultures obtained shortly after initiation of antimicrobial therapy in patients with severe manifestations of sepsis. Design: Patient-level, single-group, diagnostic study. (Clinical Trials.gov: NCT01867905) Setting: 7 emergency departments in North America. Participants: Adults with severe manifestations of sepsis, including systolic blood pressure less than 90 mm Hg or a serum lactate level of 4 mmol/L or more. Intervention: Blood cultures were obtained before and within 120 minutes after initiation of antimicrobial treatment. Measurements: Sensitivity of blood cultures obtained after initiation of antimicrobial therapy. Results: Of 3164 participants screened, 325 were included in the study (mean age, 65.6 years; 62.8% men) and had repeated blood cultures drawn after initiation of antimicrobial therapy (median time, 70 minutes [interquartile range, 50 to 110 minutes]). Preantimicrobial blood cultures were positive for 1 or more microbial pathogens in 102 of 325 (31.4%) patients. Post-antimicrobial blood cultures were positive for 1 or more microbial pathogens in 63 of 325 (19.4%) patients. The absolute difference in the proportion of positive blood cultures between pre- and postantimicrobial testing was 12.0% (95% CI, 5.4% to 18.6%; P < 0.001). Sensitivity of postantimicrobial culture was 52.9% (CI, 42.8% to 62.9%). When the results of other microbiological cultures were included, microbial pathogens were found in 69 of 102 (67.6% [CI, 57.7% to 76.6%]) patients. Limitation: Only a proportion of screened patients were recruited. Conclusion: Among patients with severe manifestations of sepsis, initiation of empirical antimicrobial therapy significantly reduces the sensitivity of blood cultures drawn shortly after treatment initiation