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The article presents the discussion on refinements in management could further reduce mortality rates. Topics include computed tomography (CT) has been proposed as a modality that can ferret out deep-seated sites of infection to inform management; and representing the single most effective intervention to reduce mortality risk in S. aureus bacteremia since the invention of antibiotics.

The benefits of remdesivir in the treatment of hospitalized patients with COVID-19 remain debated with the National Institutes of Health and the World Health Organization providing contradictory recommendations for and against use. To evaluate the role of remdesivir for hospitalized inpatients as a function of oxygen requirements. Beginning with our prior systematic review, we searched MEDLINE using PubMed from 15 January 2021 through 5 May 2022. Randomised controlled trials; all languages. All hospitalized adults with COVID-19. Remdesivir, in comparison to either placebo, or standard of care. We used the ROB-2 criteria. The primary outcome was mortality, stratified by oxygen use (none, supplemental oxygen without mechanical ventilation, and mechanical ventilation). We conducted a frequentist random effects meta-analysis on the risk ratio scale and, to contextualize the probabilistic benefits, we also performed a Bayesian random effects meta-analysis on the risk difference scale. A ≥1% absolute risk reduction was considered clinically important. We identified eight randomized trials, totaling 10 751 participants. The risk ratio for mortality comparing remdesivir vs. control was 0.77 (95% CI, 0.5–1.19) in the patients who did not require supplemental oxygen; 0.89 (95% CI, 0.79–0.99) for nonventilated patients requiring oxygen; and 1.08 (95% CI, 0.88–1.31) in the setting of mechanical ventilation. Using neutral priors, the probabilities that remdesivir reduces mortality were 76.8%, 93.8%, and 14.7%, respectively. The probability that remdesivir reduced mortality by ≥ 1% was 77.4% for nonventilated patients requiring oxygen. Based on this meta-analysis, there is a high probability that remdesivir reduces mortality for nonventilated patients with COVID-19 requiring supplemental oxygen therapy. Treatment guidelines should be re-evaluated. [ABSTRACT FROM AUTHOR]

Background Several outpatient coronavirus disease 2019 (COVID-19) therapies have reduced hospitalization in randomized controlled trials. The choice of therapy may depend on drug efficacy, toxicity, pricing, availability, and available infrastructure. To facilitate comparative decision-making, we evaluated the efficacy of each treatment in clinical trials and estimated the cost per hospitalization prevented. Methods Wherever possible, we obtained relative risk for hospitalization from published randomized controlled trials. Otherwise, we extracted data from press releases, conference abstracts, government submissions, or preprints. If there was >1 study, the results were meta-analyzed. Using relative risk, we estimated the number needed to treat (NNT), assuming a baseline hospitalization risk of 5%, and compared the cost per hospitalization prevented with the estimate for an average Medicare COVID-19 hospitalization ($21 752). Drug pricing was estimated from GoodRx, from government purchases, or manufacturer estimates. Administrative and societal costs were not included. Results will be updated online as new studies emerge and/or final numbers become available. Results At a 5% risk of hospitalization, the estimated NNT was 80 for fluvoxamine, 91 for colchicine, 72 for inhaled corticosteroids, 24 for nirmatrelvir/ritonavir, 50 for molnupiravir, 28 for remdesivir, 25 for sotrovimab, 29 for casirivimab/imdevimab, and 29 for bamlanivimab/etesevimab. For drug cost per hospitalization prevented, colchicine, fluvoxamine, inhaled corticosteroids, and nirmatrelvir/ritonavir were below the Medicare estimated hospitalization cost. Conclusions Many countries are fortunate to have access to several effective outpatient therapies to prevent COVID-19 hospitalization. Given differences in efficacy, toxicity, cost, and administration complexity, this assessment serves as one means to frame treatment selection. [ABSTRACT FROM AUTHOR]

Background We sought to determine the comparative efficacy of fosfomycin vs ertapenem for outpatient treatment of complicated urinary tract infections (cUTIs). Methods We conducted a multicenter, retrospective cohort study involving patients with cUTI treated with outpatient oral fosfomycin vs intravenous ertapenem at 3 public hospitals in Los Angeles County between January 2018 and September 2020. The primary outcome was resolution of clinical symptoms 30 days after diagnosis. Results We identified 322 patients with cUTI treated with fosfomycin (n = 110) or ertapenem (n = 212) meeting study criteria. The study arms had similar demographics, although patients treated with ertapenem more frequently had pyelonephritis or bacteremia while fosfomycin-treated patients had more retained catheters, nephrolithiasis, or urinary obstruction. Most infections were due to extended-spectrum β-lactamase–producing E. coli and Klebsiella pneumoniae , 80%–90% of which were resistant to other oral options. Adjusted odds ratios for clinical success at 30 days, clinical success at last follow-up, and relapse were 1.21 (95% CI, 0.68–2.16), 0.84 (95% CI, 0.46–1.52), and 0.94 (95% CI, 0.52–1.70) for fosfomycin vs ertapenem, respectively. Patients treated with fosfomycin had significant reductions in length of hospital stay and length of antimicrobial therapy and fewer adverse events (1 vs 10). Fosfomycin outcomes were similar irrespective of duration of lead-in intravenous (IV) therapy or fosfomycin dosing interval (daily, every other day, every third day). Conclusions These results would support the conduct of a randomized controlled trial to verify efficacy. In the meantime, they suggest that fosfomycin may be a reasonable stepdown from IV antibiotics for cUTI. [ABSTRACT FROM AUTHOR]

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Background: Upper gastrointestinal bleeding is common among the critically ill. Recently, the Proton Pump Inhibitors (PPIs) vs. Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial suggested PPIs might increase mortality. We performed an updated meta-analysis to further inform discussion.Methods: We leveraged 2 recent systematic reviews to identify randomized controlled trials directly comparing PPIs and H-2 Receptor Antagonists (H2RAs) for stress ulcer prophylaxis in critically ill patients and reporting mortality. We extracted mortality data from each study and meta-analyzed them with the PEPTIC trial using a random effects model.Results: Of 28,559 total patients, 14,436 (50.5%) were allocated to PPI and 14,123 to H2RAs (49.5%). Compared to H2RAs, the pooled relative risk for mortality was 1.05 (95% confidence interval 1.00-1.10) with an estimated risk difference for mortality of 9 additional deaths per 1000 patients exposed to PPI (95% confidence interval 0-18); heterogeneity was low (I2 = 0%; P = 0.826).Conclusions: Stress ulcer prophylaxis with PPIs likely increases mortality compared to H2RAs. Whether stress ulcer prophylaxis is beneficial in critical care remains open to further study. [ABSTRACT FROM AUTHOR]

• A Bayesian re-analysis of remdesivir and corticosteroid randomized controlled trials was conducted. • Probabilities that remdesivir and corticosteroids reduced mortality by ≥1% were estimated. • Patients needing mechanical ventilation – 4% for remdesivir and 93% for corticosteroids. • Patients needing supplemental oxygen without mechanical ventilation – 81% for remdesivir and 93% for dexamethasone. • Patients who did not need oxygen support – neither remdesivir nor corticosteroids were likely to decrease mortality meaningfully. The global death toll from coronavirus disease 2019 (COVID-19) has exceeded 2 million, and treatments to decrease mortality are needed urgently. To examine the probabilities of a clinically meaningful reduction in mortality for remdesivir and systemic corticosteroids. This was a probabilistic re-analysis of clinical trial data for corticosteroids and remdesivir in the treatment of hospitalized patients with COVID-19 using a Bayesian random effects meta-analytic approach. Studies were identified from existing meta-analyses performed by the World Health Organization. Posterior probabilities of an absolute decrease in mortality compared with control patients, by subgroups based on oxygen requirements, were calculated for corticosteroids and remdesivir. Probabilities of ≥1%, ≥2% and ≥5% absolute decrease in mortality were quantified. For patients needing mechanical ventilation, the probability of ≥1% absolute decrease in mortality was 4% for remdesivir and 93% for corticosteroids. For patients needing supplemental oxygen without mechanical ventilation, the probability of ≥1% absolute decrease in mortality was 81% for remdesivir and 93% for dexamethasone. Finally, for patients who did not need oxygen support, the probability of ≥1% absolute decrease in mortality was 29% for remdesivir and 4% for dexamethasone. Using a Bayesian analytic approach, remdesivir had low probability of achieving a clinically meaningful reduction in mortality, except for patients needing supplemental oxygen without mechanical ventilation. Corticosteroids were more promising for patients needing oxygen support, especially mechanical ventilation. While awaiting more definitive studies, this probabilistic interpretation of the evidence will help to guide treatment decisions for clinicians, as well as guideline and policy makers. [ABSTRACT FROM AUTHOR]

When faced with a new and therefore frightening disease such as coronavirus disease 2019 (COVID-19), and given concerns over a potentially high case fatality rate, clinicians and patients will be strongly compelled to try unproven therapies. As the number of severely ill patients with coronavirus disease 2019 (COVID-19) continues to increase, we must learn as much as possible about this disease, as quickly as possible, to inform patient care. [Extracted from the article]

BACKGROUND Admission to hospital provides the opportunity to review patient medications; however, the extent to which the safety of drug regimens changes after hospitalization is unclear. OBJECTIVE To estimate the number of potentially inappropriate medications (PIMs) prescribed to patients at hospital discharge and their association with the risk of adverse events 30 days after discharge. DESIGN Prospective cohort study. SETTING Tertiary care hospitals within the McGill University Health Centre Network in Montreal, Quebec, Canada. PARTICIPANTS Patients from internal medicine, cardiac, and thoracic surgery, aged 65 years and older, admitted between October 2014 and November 2016. MEASURES Abstracted chart data were linked to provincial health databases. PIMs were identified using AGS (American Geriatrics Society) Beers Criteria®, STOPP, and Choosing Wisely statements. Multivariable logistic regression and Cox models were used to assess the association between PIMs and adverse events. RESULTS: Of 2,402 included patients, 1,381 (57%) were male; median age was 76 years (interquartile range [IQR] = 70‐82 years); and eight discharge medications were prescribed (IQR = 2‐8). A total of 1,576 (66%) patients were prescribed at least one PIM at discharge; 1,176 (49%) continued a PIM from prior to admission, and 755 (31%) were prescribed at least one new PIM. In the 30 days after discharge, 218 (9%) experienced an adverse drug event (ADE) and 862 (36%) visited the emergency department (ED), were rehospitalized, or died. After adjustment, each additional new PIM and continued community PIM were respectively associated with a 21% (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 1.01‐1.45) and a 10% (OR = 1.10; 95% CI = 1.01‐1.21) increased odds of ADEs. They were also respectively associated with a 13% (hazard ratio [HR] = 1.13; 95% CI = 1.03‐1.26) and a 5% (HR = 1.05; 95% CI = 1.00‐1.10) increased risk of ED visits, rehospitalization, and death. CONCLUSIONS: Two in three hospitalized patients were prescribed a PIM at discharge, and increasing numbers of PIMs were associated with an increased risk of ADEs and all‐cause adverse events. Improving hospital prescribing practices may reduce the frequency of PIMs and associated adverse events. J Am Geriatr Soc 68:1184–1192, 2020. See related editorial by Donna M. Fick in this issue. [ABSTRACT FROM AUTHOR]

The ACP presents recommendations for outpatient treatment of COVID-19 based on Sommer and colleagues' systematic review. The editorialists commend the authors of the recommendations and review for trying to summarize the rapidly evolving literature and discuss the challenges of updating reviews and associated recommendations as new evidence emerges and relevant outcomes evolve. [ABSTRACT FROM AUTHOR]

Background: Several professional societies have made value-based statements in support of restrictive transfusion strategies. The aim of this study was to determine whether completion of an accredited online training program in transfusion safety could improve transfusion knowledge among medical residents and increase transfusion appropriateness. Methods: We performed a controlled before–after evaluation of a mandatory accredited self-directed training program (Bloody Easy Lite for Physicians) that provides education about transfusion medicine on a 47-bed medical clinical teaching unit at a university-affiliated hospital centre in Montréal. The program consists of 2 modules and takes about 30 minutes to complete. We used the 45-bed medical teaching unit at another Montréal hospital as a contemporary control. We compared resident physicians' pre- and posttest scores and evaluated the impact on transfusion appropriateness by comparing the proportion occurring below a hemoglobin concentration of 80 g/L before (April 2013–June 2015) and after (July 2015–January 2016) the intervention. Results: Of the 55 residents on the intervention unit, 53 (96%) completed the training. The median pretest score was 50% (inter-quartile range [IQR] 40%–60%). The median posttest score was 90% (IQR 80%–90%) for module 1 and 80% (IQR 80%–90%) for module 2 (p < 0.001 for both pre–post comparisons). The proportion of transfusions below 80 g/L increased from 80.1% to 86.9% (p = 0.04) on the intervention unit and remained relatively unchanged on the control unit (75.6% v. 71.1%, p = 0.4). Although there was no statistically significant difference between the units in the proportion of transfusions below 80 g/L before the intervention (p = 0.07), a significant difference was observed after the intervention (p = 0.002). Interpretation: Mandatory training in transfusion safety via an online program resulted in improved transfusion knowledge among residents and an increase in the proportion of transfusions occurring at a hemoglobin concentration below 80 g/L. This low-cost educational initiative may improve transfusion appropriateness. [ABSTRACT FROM AUTHOR]

Objectives: To distribute the EMPOWER patient education brochure and use hospitalization as an opportunity to reduce inappropriate sedatives. Design: Participants were sequentially recruited until we achieved 30‐day follow‐up telephone and pharmacy records for 50 individuals. The proportion meeting the primary outcome was compared with that of a control cohort and with rates of cessation achieved in the community. Setting: Fifty‐two‐bed medical clinical teaching unit in Montréal, Canada. Participants: Inpatients aged 65 and older who were chronic, regular sedative users. Measurements: The primary outcome was short‐term sustained cessation 30‐days after discharge. As a secondary outcome, we compared self‐reported sleep disturbance before and after the intervention. Results: Sedatives were deprescribed in 32 of 50 (64%) participants who received the EMPOWER brochure, which was significantly higher than our historical rate of 21% (p<.001). Participants did not report significant worsening in their quality of sleep after sedative cessation. Conclusion: Hospitalized individuals are willing to deprescribe, and contact with the healthcare system provides the opportunity to initiate the process with educational brochures. This type of intervention requires few resources and is feasible and inexpensive. [ABSTRACT FROM AUTHOR]

Background: Evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, has been shown to reduce low-density lipoprotein levels by up to 60%. Despite the absence of a reduction in overall or cardiovascular mortality in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, some believe that, with longer treatment, such a benefit might eventually be realized. Our aim was to estimate the potential mortality benefit over a patient's lifetime and the cost per year of life saved (YOLS) for an average Canadian with established coronary artery disease. We also sought to estimate the price threshold at which evolocumab might be considered cost-effective for secondary prevention in Canada. Methods: We calibrated the Cardio-metabolic Model, a well-validated tool for predicting cardiovascular events and life expectancy, to the reduction in nonfatal events seen in the FOURIER trial. Assuming that long-term treatment will eventually result in mortality benefits, we estimated YOLSs and cost per YOLS with evolocumab treatment plus a statin compared to a statin alone. We then estimated the annual drug costs that would provide a 50% chance of being cost-effective at willingness-to-pay values of $50 000 and $100 000. Results: In secondary prevention in patients similar to those in the FOURIER study, evolocumab treatment would save an average of 0.34 (95% confidence interval [CI] 0.27-0.41) life-years at a cost of $101 899 (95% CI $97 325-$106 473), yielding a cost per YOLS of $299 482. We estimate that to have a 50% probability of achieving a cost per YOLS below $50 000 and $100 000 would require annual drug costs below $1200 and $2300, respectively. Interpretation: At current pricing, the use of evolocumab for secondary prevention is unlikely to be cost-effective in Canada. [ABSTRACT FROM AUTHOR]

The article describes the case of a 65-year-old man with a history of HIV infection presented to the emergency department with nausea, abdominal pain and confusion. Topics include the medical history of the patient, the change in his antiretroviral therapy, and the factors that physicians should consider when deprescribing medicines.

Importance: In 2016 recommendations for safer prescribing practices were circulated to all doctors in one of Canada’s largest provinces, by the college of physicians, following a coroner’s inquest into a vehicular death related to Z-drug use. We sought to determine how frequently Z-drug prescriptions in our institution were not adhering to these recommendations. Design: Retrospective cohort study. Setting: McGill University Health Centre, an 832-bed tertiary care institution in Montréal, Canada. Participants: All adult non-obstetrical patients admitted between April 1, 2015 and March 31, 2016. Exposure: The receipt of at least one dose of Z-drug as determined by pharmacy records. Main outcomes and measures: Adherence to four recommendations related to starting dose, maximal dose, concomitant drug administration, and duration of use were evaluated. Results: 1,409 unique patients received a Z-drug during 1,783 admissions representing use in 9.3% of non-obstetrical patients. Standing orders were seen in 42% (745/1783) of admissions. Non-conformity with the coroner’s recommendations was common. Overall, 672/1783 (38%) admissions involved a patient receiving more than the recommended daily maximum dose (643/999 older patients, 64%). Of 607 admissions which were longer than 10 days, 257 (39%) involved a prescription which exceeded 10 days. Conclusions and relevance: A coroner’s recommendation that doctors receive instructions about safe Z-drug prescribing is unprecedented, and was likely required given that use of Z-drugs occurs at doses and durations that often exceed best practice recommendations. Similar interventions may be required in other jurisdictions. [ABSTRACT FROM AUTHOR]

Background: Antibiotic use is an important quality improvement target. Nearly 50% of antibiotic use is unnecessary or inappropriate. To combat overuse, the Centers for Disease Control and Prevention (CDC) proposed “time-outs” to reevaluate antibiotics. Objective: To optimize antibiotic use through trainee-led time-outs. Design: Before–after study. Setting: Internal medicine (2 units, 46 beds) at a university hospital. Patients: Inpatients (n = 679). Intervention: From January 2012 until June 2013, while receiving monthly education on antimicrobial stewardship, resident physicians adjusted patients' antibiotic therapy through twice-weekly time-out audits using a structured electronic checklist. Measurements: Antibiotic costs were standardized and compared in the year before and after the audits. Use was measured as World Health Organization defined daily doses (DDDs) per 1000 patient-days. Total antibiotic use and the use of moxifloxacin, carbapenems, antipseudomonal penicillins, and vancomycin were compared by using interrupted time series. Rates of nosocomial Clostridium difficile infection were compared by using incidence rate ratios. Results: Total costs in the units decreased from $149 743CAD (January 2011 to January 2012) to $80 319 (January 2012 to January 2013), for a savings of $69 424 (46% reduction). Of the savings, $54 150 (78%) was related to carbapenems and $15 274 (22%) was due to other antibiotic classes. Adherence with the auditing process was 80%. In the time-series analyses, the only reliable and statistically significant change was a reduction in the rate of moxifloxicin use, by −1.9 DDDs per 1000 patient-days per month (95% CI, −3.8 to −0.02; P = 0.048). Rates of C. difficile infection decreased from 24.2 to 19.6 per 10 000 patient-days (incidence rate ratio, 0.8 [CI, 0.5 to 1.3]). Limitation: Other temporal factors may confound the findings. Conclusions: An antibiotic self-stewardship bundle to implement the CDC's suggested time-outs seems to have reduced overall costs and targeted antibiotic use. [ABSTRACT FROM AUTHOR]

Since then we have learned a great deal about coronavirus disease 2019 (COVID-19) and made important strides in patient care including pivoting away from pre-emptive intubation, which may have inflated early mortality [2]. Against this backdrop, in a recent issue of Clinical Microbiology and Infection, Rodríguez-Baño et al. [8] tackle the management of patients with an inflammatory presentation by providing observational data in support of tocilizumab for certain patients with COVID-19. Finally, the patients in the SAM-COVID-19 cohort differed from those in RECOVERY with a lower prevalence of heart and kidney disease and fewer mechanically ventilated patients (1%-3% versus 15%) who seem to benefit most from steroids. [Extracted from the article]

To the Editor: Sepsis is associated with a high risk of mortality; hence, there is a desire to ensure that adequate antibiotics are administered as soon as possible. Such an approach may have benefit if (a) the aminoglycoside adds a substantial amount of additional coverage to the paired second agent, (b) there is a compelling argument against the use of broader spectrum agents in emergency department patients with sepsis, and (c) the aminoglycoside does not harm the patient. [Extracted from the article]

Objective: Identifying features that differentiate patients with H1N1 influenza infection from those with other conditions may assist clinical decision making during waves of pandemic influenza activity. Methods: From April 27 to June 15, 2009, nasopharyngeal swabs were obtained from all adults presenting to two urban emergency departments (EDs) with illness including fever or respiratory symptoms. H1N1 infection was detected by reverse transcriptase--polymerase chain reaction. Chart review was performed to compare cases of H1N1 influenza (n = 117) to matched controls. Results: The median age of cases was 35 years versus 50 years for controls (p < .001). In those with pre-existing conditions, asthma was present in 31% of cases versus 14% of controls (OR 2.6, 95% CI 1.3-5.4). Cough (OR 7.8, 95% CI 3.2-19), fever (OR 3.0, 95% CI 1.7-5.4), headache (OR 2.0, 95% CI 1.2-3.2), and myalgias (OR 1.9, 95% CI 1.2-3.1) were significantly more common in H1N1 cases. The median white blood cell count was 5.7 x 107mL versus 10.9 x 109/mL (p < .001). The combination of fever and cough had an OR of 5.3. Fever, cough, low white blood cell (WBC) count, and tachycardia had the highest OR at 11. The absence of both fever and cough had a negative predictive value of 99%, but this occurred in only 8% of controls. Conclusion: In patients presenting to the ED, the combination of fever, cough, tachycardia, and WBC count < 10 x 109/mL was suggestive of H1N1 influenza infection. However, clinical features could not reliably distinguish influenza from other acute respiratory illnesses in adult ED patients. [ABSTRACT FROM AUTHOR]

Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone. To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis. Embase, MEDLINE, and CENTRAL from inception to June 21, 2023. Comparative randomized controlled trials (RCTs). PWH. Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo. Cochrane risk-of-bias tool for RCTs 2. Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed. A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36–0.83) and AP (RR = 0.53; 95% CI, 0.36–0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64–0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01–1.54) and AP (7.20; 95% CI, 5.37–9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups. TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

The article presents a case study of a 15-year-old girl who had necrotizing pseudomonas chondritis after the upper part of her left was pierced. It says that the antimicrobial treatment of the patient was changed from ciprofloxacin to piperacillin-tazobactam. It mentions that the bacterium Staphylococcus aureus was considered as the most frequent cause of skin infections due to piercing. It recommends various tips in preventing infection after piercing.

Background Omalizumab is an anti-immunoglobulin E monoclonal antibody used to treat moderate to severe chronic idiopathic urticaria, asthma, and nasal polyps. Recent research suggested that omalizumab may enhance the innate antiviral response and have anti-inflammatory properties. Objective We aimed to investigate the efficacy and safety of omalizumab in adults hospitalized for coronavirus disease 2019 (COVID-19) pneumonia. Methods This was a phase II randomized, double blind, placebo-controlled trial comparing omalizumab with placebo (in addition to standard of care) in hospitalized patients with COVID-19. The primary endpoint was the composite of mechanical ventilation and/or death at day 14. Secondary endpoints included all-cause mortality at day 28, time to clinical improvement, and duration of hospitalization. Results Of 41 patients recruited, 40 were randomized (20 received the study drug and 20 placebo). The median age of the patients was 74 years and 55.0% were male. Omalizumab was associated with a 92.6% posterior probability of a reduction in mechanical ventilation and death on day 14 with an adjusted odds ratio of 0.11 (95% credible interval 0.002-2.05). Omalizumab was also associated with a 75.9% posterior probability of reduced all-cause mortality on day 28 with an adjusted odds ratio of 0.49 (95% credible interval, 0.06-3.90). No statistically significant differences were found for the time to clinical improvement and duration of hospitalization. Numerically fewer adverse events were reported in the omalizumab group and there were no drug-related serious adverse events. Conclusions These results suggest that omalizumab could prove protective against death and mechanical ventilation in hospitalized patients with COVID-19. This study could also support the development of a phase III trial program investigating the antiviral and anti-inflammatory effect of omalizumab for severe respiratory viral illnesses requiring hospital admission. ClinicalTrials.gov ID: NCT04720612 [ABSTRACT FROM AUTHOR]

Background Standalone nucleic acid amplification tests (NAATs) are frequently used to diagnose Clostridioides difficile infections (CDI), although they may be unable to distinguish colonization from disease. A 2-stage algorithm pairing NAATs with toxin immunoassays (Toxin) may improve specificity. We evaluated clinical outcomes of patients who were NAAT+/Toxin+ versus NAAT+/Toxin− and treated versus untreated NAAT+/Toxin− cases through systematic review and meta-analysis. Methods We searched EMBASE and MEDLINE from inception to April 1, 2023 for articles comparing CDI outcomes among symptomatic patients tested by NAAT and Toxin tests. The risk differences (RD) of all-cause mortality and CDI recurrence were computed by random effects meta-analysis between patients who were NAAT+/Toxin+ and NAAT+/Toxin−, as well as between patients who were NAAT+/Toxin− and treated or untreated. Results Twenty-six observational studies comprising 12 737 patients were included. The 30-day all-cause mortality was not significantly different between those who were NAAT+/Toxin+ (8.4%) and NAAT+/Toxin− (6.7%) (RD = 0.41%, 95% confidence interval [CI] = −.67, 1.49). Recurrence at 60 days was significantly higher among patients who were NAAT+/Toxin+ (19.8%) versus NAAT+/Toxin− (11.0%) (RD = 7.65%, 95% CI = 4.60, 10.71). Among treated compared to untreated NAAT+/Toxin- cases, the all-cause 30-day mortalities were 5.0% and 12.7%, respectively (RD = −7.45%, 95% CI = −12.29, −2.60), but 60-day recurrence was not significantly different (11.6% vs 7.0%, respectively; RD = 5.25%, 95% CI −1.71, 12.22). Conclusions Treatment of patients who were NAAT+/Toxin− was associated with reduced all-cause mortality but not recurrence. Although subject to the inherent limitations of observational studies, these results suggest that some patients who are NAAT+/Toxin− may benefit from treatment. [ABSTRACT FROM AUTHOR]

Background: Medication overload or problematic polypharmacy is a major problem causing widespread harm, particularly to older adults. Taking multiple medications increases the risk of potentially inappropriate medications (PIMs), and residents in long-term care (LTC) are frequently prescribed 10 or more medications at once. One strategy to address this problem is for the physician and/or pharmacist to perform regular medication reviews; however, this process can be complicated and time-consuming. With a prescription review, medications may be decreased, changed, or stopped altogether. MedReviewRx is a software that runs an analysis using deprescribing rules to produce a report to guide medication reviews addressing medication overload for residents in LTC.Methods: This study will employ a mixed methods effectiveness-implementation hybrid type 2 study design. To measure effectiveness, a stepped wedge cluster randomized trial design is planned, which allows us to approximate a randomized clinical trial. Approximately 1000 residents living in LTC will be recruited from five facilities in New Brunswick. The study will begin with 3 months of baseline data on rates of deprescribing. Thereafter, every 3 months a new cluster will enter the intervention mode. The intervention consists of medication reviews augmented with the MedReviewRx software, which will be used by staff and clinicians in the facilities. The estimated study duration is 18 months and the main outcome will be the proportion of patients with one or more PIMs deprescribed (reduced/stopped or changed to a safer alternative) in the 90 days following a prescription review. The goal is to study the impact of MedReviewRx on medication overload among older adults living in LTC. In typical fashion of a stepped wedge cluster randomized trial, each cluster acts as an internal control (before and after) as well as a control for the other clusters (external control). Qualitative data collected will include resident/caregiver attitudes towards deprescribing and semi-structured interviews with staff working in the long-term care homes.Discussion: This study design addresses issues with seasonality and allows all clusters to participate in the intervention, which is an advantage when the intervention is related to quality improvement. This study will provide valuable information on PIM use, cost savings, and facilitators and challenges associated with medication reviews and deprescribing. This study represents an important step towards understanding and promoting tools to guide safe and rational reduction of PIM use among older adults.Trial Registration: NCT04762303 , Registered February 21, 2021. [ABSTRACT FROM AUTHOR]

Objectives: Severe acute respiratory syndrome-related coronavirus-2 binds and inhibits angiotensin-converting enzyme-2. The frequency of acute cardiac injury in patients with coronavirus disease 2019 is unknown. The objective was to compare the rates of cardiac injury by angiotensin-converting enzyme-2-binding viruses from viruses that do not bind to angiotensin-converting enzyme-2.Data Sources: We performed a systematic review of coronavirus disease 2019 literature on PubMed and EMBASE.Study Selection: We included studies with ten or more hospitalized adults with confirmed coronavirus disease 2019 or other viral pathogens that described the occurrence of acute cardiac injury. This was defined by the original publication authors or by: 1) myocardial ischemia, 2) new cardiac arrhythmia on echocardiogram, or 3) new or worsening heart failure on echocardiogram.Data Extraction: We compared the rates of cardiac injury among patients with respiratory infections with viruses that down-regulate angiotensin-converting enzyme-2, including H1N1, H5N1, H7N9, and severe acute respiratory syndrome-related coronavirus-1, to those with respiratory infections from other influenza viruses that do not bind angiotensin-converting enzyme-2, including Influenza H3N2 and influenza B.Data Synthesis: Of 57 studies including 34,072 patients, acute cardiac injury occurred in 50% (95% CI, 44-57%) of critically ill patients with coronavirus disease 2019. The overall risk of acute cardiac injury was 21% (95% CI, 18-26%) among hospitalized patients with coronavirus disease 2019. In comparison, 37% (95% CI, 26-49%) of critically ill patients with other respiratory viruses that bind angiotensin-converting enzyme-2 (p = 0.061) and 12% (95% CI, 7-22%) of critically ill patients with other respiratory viruses that do not bind angiotensin-converting enzyme-2 (p < 0.001) experienced a cardiac injury.Conclusions: Acute cardiac injury may be associated with whether the virus binds angiotensin-converting enzyme-2. Acute cardiac injury occurs in half of critically ill coronavirus disease 2019 patients, but only 12% of patients infected by viruses that do not bind to angiotensin-converting enzyme-2. [ABSTRACT FROM AUTHOR]

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized controlled trial that studied 9361 adults ≥50 years of age with systolic blood pressure >130 mm Hg and ≥1 cardiovascular risk factors. Patients were randomized to intensive (≤120 mm Hg) or standard (≤140 mm Hg) systolic targets. In August 2016, a limited dataset was released for secondary analysis. We hypothesized that excessive lowering of diastolic blood pressure could cause harm. Using the data from SPRINT, we sought to determine whether the development of diastolic hypotension during treatment was associated with adverse outcomes.Methods: We included 8046 patients from SPRINT with a baseline diastolic blood pressure ≥65 mm Hg at study enrollment (4041 intensive target; 4005 standard target). Using Cox proportional hazards models, we evaluated the association between the development of diastolic hypotension (defined as ≤55 mm Hg and modeled as a time-dependent covariate) and the combined outcome of cardiovascular morbidity (myocardial infarction, other acute coronary syndromes, stroke, heart failure) and all-cause death.Results: In multivariable analyses, patients who developed diastolic hypotension had an increased risk for our primary outcome (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.24-2.26). This was true in both the intensive (HR 1.53; 95% CI, 1.04-2.26) and standard (HR 2.23; 95% CI, 1.40-3.54; P for interaction = .09) treatment arms.Conclusions: We found an association between diastolic hypotension and the combined endpoint of cardiovascular events and all-cause mortality among SPRINT participants with normal to high diastolic blood pressure at entry. Attention to diastolic blood pressure may be important for optimizing outcomes when targeting systolic blood pressure reduction. [ABSTRACT FROM AUTHOR]

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a multifactorial Bayesian adaptive platform trial that aims to improve the way that S. aureus bloodstream infection, a globally common and severe infectious disease, is treated. In a world first, the SNAP trial will simultaneously investigate the effects of multiple intervention modalities within multiple groups of participants with different forms of S. aureus bloodstream infection. Here, we formalise the trial structure, modelling approach, and decision rules that will be used for the SNAP trial. By summarising the statistical principles governing the design, our hope is that the SNAP trial will serve as an adaptable template that can be used to improve comparative effectiveness research efficiency in other disease areas. Trial registrationNCT05137119. Registered on 30 November 2021. [ABSTRACT FROM AUTHOR]

Early identification of extended-spectrum ß-lactamase (ESBL) and carbapenemase-producing Enterobacterales (CP-CRE) is critical for timely therapy. Rapid phenotypic tests identifying these resistance mechanisms from pure bacterial colonies have been developed. To determine the operating characteristics of available rapid phenotypic tests when applied directly to positive blood cultures. Bivariate random effects models were used unless convergence was not achieved where we used separate univariate models for sensitivity and specificity. MEDLINE, CENTRAL, Embase, BIOSIS, and Scopus from inception to 16 March 2021. Studies using any rapid phenotypic assay for detection of ESBL or CP-CRE directly from blood cultures positive for Enterobacterales, including those utilizing spiked blood cultures. Case reports/series, posters, abstracts, review articles, those with ≤5 resistant isolates, and studies lacking data or without full text were excluded. Consecutive patient samples (main analysis) or spiked blood cultures (sensitivity analysis). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assays (MALDI-TOF) and commercially available chromogenic or immunogenic assays. Conventional laboratory methods and/or polymerase chain reaction (PCR). Quality Assessment of Diagnostic Accuracy Studies Version 2 (QUADAS-2). For detection of the ESBL phenotype the respective pooled sensitivities and specificities for consecutive clinical samples were as follows: 94% (95% CI 93–99%) and 97% (95% CI 95–100%) for MALDI-TOF/mass spectrometry (n = 1); and 98% (95% CI 92–100%) and 100% (95% CI 96–100%) for chromogenic assays (n = 7). For the CP-CRE phenotype the respective pooled sensitivity and specificities for consecutive clinical samples were as follows: 100% (95% CI 99–100%) and 100% (95% CI 100–100%) for MALDI-TOF (n = 2); 96% (95% CI 77–99%) and 100% (95% CI 81–100%) for chromogenic assays (n = 4); and 98% (95% CI 96–100%) and 100% (95% CI 100–100%) for immunogenic testing (n = 2). Rapid phenotypic assays that can be directly applied to positive blood cultures to detect ESBL and carbapenemase production from Enterobacterales exist and, although clinical studies are limited, they appear to have high sensitivity and specificity. Their potential to facilitate patient care through timely identification of bacterial resistance should be further explored. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Deciphering Cholesterol Treatment Guidelines: A Clinician's Perspective," by O. P. Ganda that was published in a 2015 issue.

A letter to the editor is presented in response to the article "Diagnosis and treatment of Clostridium difficile in adults: a systematic review" by N. Bagdasarian and colleagues, published in the previous issues of the journal.

Background: Omicron is the current predominant variant of concern of SARS-CoV-2. We hypothesized that vaccination alters outcomes of patients hospitalized with COVID-19 during the Omicron wave and that these patients have different characteristics and outcomes than in previous waves. Methods: This is a substudy of the Host Response Mediators in Coronavirus (COVID-19) Infection (ARBs CORONA I) trial, which included adults admitted to hospital with acute COVID-19 up to July 2022 from 9 hospitals in British Columbia, Ontario and Quebec. We excluded emergency department visits without hospital admission, readmissions and admissions for another reason. Using adjusted regression analysis, we compared mortality and organ dysfunction between vaccinated (≥ 2 doses) and unvaccinated patients during the Omicron wave, as well as between all patients in the Omicron and first 3 waves of the COVID-19 pandemic. Results: During the Omicron wave, 28-day mortality was significantly lower in vaccinated (n = 19/237) than unvaccinated hospitalized patients (n = 12/127) (adjusted odds ratio [OR] 0.36, 95% confidence interval [CI] 0.15--0.89); vaccinated patients had lower risk of admission to the intensive care unit, invasive ventilation and acute respiratory distress syndrome and shorter hospital length of stay. Patients hospitalized during the Omicron wave had more comorbidities than in previous waves, and lower 28-day mortality than in waves 1 and 2 (adjusted OR 0.38, 95% CI 0.24--0.59; and 0.42, 95% CI 0.26--0.65) but not wave 3 (adjusted OR 0.81, 95% CI 0.43--1.51) and had less organ dysfunction than in the first 2 waves. Interpretation: Patients who were at least double vaccinated had lower mortality than unvaccinated patients hospitalized during the Omicron wave. Patients hospitalized during the Omicron wave had more chronic disease and lower mortality than in the first 2 waves, but not wave 3. Changes in vaccination, treatments and predominant SARS-CoV-2 variant may have decreased mortality in patients hospitalized during the Omicron wave. [ABSTRACT FROM AUTHOR]

Background The management of infective endocarditis (IE) is complex owing to a high burden of morbidity and mortality. Recent guidelines recommend dedicated multidisciplinary teams (MDTs) for the management of IE. The aim of this systematic review and meta-analysis was to evaluate and summarize the effect of MDT management on patient outcomes. Methods A systematic review was performed and, where feasible, results were meta-analyzed; otherwise, results were summarized narratively. Data extraction and quality assessment were performed in duplicate. Restricted maximum likelihood random effects models were used to calculate unadjusted risk ratios and 95% CIs. Results Screening of 2343 studies based on title and abstract yielded 60 full-text reviews; 18 studies were summarized narratively, of which 15 were included in a meta-analysis of short-term mortality. Meta-analysis resulted in a risk ratio of 0.61 (95% CI,.47–.78; I 2 = 62%) for mortality in favor of a dedicated MDT as compared with usual care. Length of stay was variable, with 55% (10/18) of studies reporting an increased length of stay. Most studies (16/18, 88.9%) reported a decreased time to surgery and an increased rate of surgery (13/18, 73%). No studies reported on patient-reported outcomes. Conclusions This is the first systematic review and meta-analysis to assess the impact of MDT management on IE. The sum of evidence demonstrated a significant association between MDTs and improved short-term mortality. Further research is needed to evaluate benefits of virtual MDT care, cost-effectiveness, and the impact on patient-reported outcomes and long-term mortality. [ABSTRACT FROM AUTHOR]

Background Prior randomized clinical trials have reported benefit of fluvoxamine ≥200 mg/d vs placebo for patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods This randomized, double-blind, placebo-controlled, fully remote multisite clinical trial evaluated whether fluvoxamine prevents clinical deterioration in higher-risk outpatients with acute coronavirus disease 2019 (COVID-19). Between December 2020 and May 2021, nonhospitalized US and Canadian participants with confirmed symptomatic infection received fluvoxamine (50 mg on day 1, 100 mg twice daily thereafter) or placebo for 15 days. The primary modified intent-to-treat (mITT) population included participants who started the intervention within 7 days of symptom onset with a baseline oxygen saturation ≥92%. The primary outcome was clinical deterioration within 15 days of randomization, defined as having both (1) shortness of breath (severity ≥4 on a 0–10 scale or requiring hospitalization) and (2) oxygen saturation <92% on room air or need for supplemental oxygen. Results A total of 547 participants were randomized and met mITT criteria (n = 272 fluvoxamine, n = 275 placebo). The Data Safety Monitoring Board recommended stopping early for futility related to lower-than-predicted event rates and declining accrual concurrent with vaccine availability in the United States and Canada. Clinical deterioration occurred in 13 (4.8%) participants in the fluvoxamine group and 15 (5.5%) participants in the placebo group (absolute difference at day 15, 0.68%; 95% CI, −3.0% to 4.4%; log-rank P =.91). Conclusions This trial did not find fluvoxamine efficacious in preventing clinical deterioration in unvaccinated outpatients with symptomatic COVID-19. It was stopped early and underpowered due to low primary outcome rates. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT04668950. [ABSTRACT FROM AUTHOR]

Therefore, for the 73% of participants who received vancomycin, the length of therapy may have been inappropriately short, which may have contributed to the 47.3% treatment failure and recurrence rate observed. Overall, the development of microbiome therapeutics for I C difficile i is exciting; however, when deciding how to position SER-109 in the clinical care of patients, it is essential to know the true proportion of recurrence and understand the clinical outcomes of participants had they received IDSA guideline-directed therapy for I C difficile i . Comment & Response B To the Editor b The ECOSPOR III trial compared an investigational microbiome therapy (SER-109) with placebo for the treatment of recurrent I Clostridioides difficile i infection, with results on recurrence through 24 weeks published recently in I JAMA i .[[1]] Although it is encouraging to see a new agent for treatment of recurrent I C difficile i infection, we have some questions about this study. [Extracted from the article]

Background: Hepatitis 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. Methods: We 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. Results: 30,335 hepatitis B tests were performed at an estimated total cost of $584,683. 53.9% of patients were screened with a single test. 29% of patients who received secondary testing had no evidence of exposure on primary testing. Using the protocol of initial testing of total core antibody and surface antibody with reflexive testing, we would save an estimated $181,632 (95% CI $154,201.90 –$208,910.50) per year while providing more complete information. Interpretation: Screening 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. [ABSTRACT FROM AUTHOR]

Introduction and objective: Diagnostic testing for Clostridioides difficile infection (CDI) by nucleic acid amplification test (NAAT) cannot distinguish between colonization and infection. A positive NAAT may therefore represent a false positive for infection, since diarrhea due to various aetiologies may occur in hospitalized patients. Our objective was to help answer the question: “does this medical inpatient with diarrhea have CDI?” Design: We conducted a retrospective cohort study (n = 248) on the Clinical Teaching Units of the Royal Victoria Hospital (Montréal, Canada). Patients were included if they had a NAAT between January 2014 and September 2015 and their admission diagnosis was not CDI. CDI cases and non-CDI cases were compared, and independent predictors of CDI were determined by logistic regression. Results: Several factors were independently associated with CDI, including: hemodialysis (OR: 13.5, 95% CI: 2.85–63.8), atrial fibrillation (OR: 3.70, 95% CI: 1.52–9.01), whether the patient received empiric treatment (OR: 3.01, 95% CI: 1.04–8.68), systemic antibiotic therapy prior to testing (OR: 4.23, 95% CI: 1.71–10.5), previous positive NAAT (OR: 3.70, 95% CI: 1.41–9.72), and a leukocyte count of 11x109/L or higher (OR: 3.43, 95% CI: 1.42–8.26). The area under the curve was 0.80. Conclusion: For patients presenting with hospital-onset diarrhea, various parameters can help differentiate between CDI and other causes. A clinical prediction calculator derived from our cohort () might assist clinicians in estimating the risk of CDI for inpatients; those with low pre-test probability may not require immediate testing, treatment, nor prolonged isolation. [ABSTRACT FROM AUTHOR]

Objectives There is clinical uncertainty over the optimal treatment for penicillin-susceptible Staphylococcus aureus (PSSA) infections. Furthermore, there is concern that phenotypic penicillin susceptibility testing methods are not reliably able to detect some blaZ -positive S. aureus. Methods Nine S. aureus isolates, including six genetically diverse strains harbouring blaZ , were sent in triplicate to 34 participating laboratories from Australia (n  = 14), New Zealand (n  = 6), Canada (n  = 12), Singapore (n  = 1) and Israel (n  = 1). We used blaZ PCR as the gold standard to assess susceptibility testing performance of CLSI (P10 disc) and EUCAST (P1 disc) methods. Very major errors (VMEs), major error (MEs) and categorical agreement were calculated. Results Twenty-two laboratories reported 593 results according to CLSI methodology (P10 disc). Nineteen laboratories reported 513 results according to the EUCAST (P1 disc) method. For CLSI laboratories, the categorical agreement and calculated VME and ME rates were 85% (508/593), 21% (84/396) and 1.5% (3/198), respectively. For EUCAST laboratories, the categorical agreement and calculated VME and ME rates were 93% (475/513), 11% (84/396) and 1% (3/198), respectively. Seven laboratories reported results for both methods, with VME rates of 24% for CLSI and 12% for EUCAST. Conclusions The EUCAST method with a P1 disc resulted in a lower VME rate compared with the CLSI methods with a P10 disc. These results should be considered in the context that among collections of PSSA isolates, as determined by automated MIC testing, less than 10% harbour blaZ. Furthermore, the clinical relevance of phenotypically susceptible, but blaZ -positive S. aureus , remains unclear. [ABSTRACT FROM AUTHOR]