Changing Trends in the Global Consumption of Treatments Used in Hospitalized Patients for COVID-19: A Time Series Multicentre Study.

AIM: To analyze trends in the prescription of COVID-19 treatments for hospitalized patients during the pandemic. METHODS: Multicenter, ecological, time-series study of aggregate data for all adult patients with COVID-19 treated in five acute-care hospitals in Barcelona, Spain, between March 2020 and May 2021. Trends in the monthly prevalence of drugs used against COVID-19 were analyzed by the Mantel-Haenszel test. RESULTS: The participating hospitals admitted 22,277 patients with COVID-19 during the study period, reporting an overall mortality of 10.8%. In the first months of the pandemic, lopinavir/ritonavir and hydroxychloroquine were the most frequently used antivirals, but these fell into disuse and were replaced by remdesivir in July 2020. By contrast, the trend in tocilizumab use varied, first peaking in April and May 2020, declining until January 2021, and showing a discrete upward trend thereafter. Regarding corticosteroid use, we observed a notable upward trend in the use of dexamethasone 6 mg per day from July 2020. Finally, there was a high prevalence of antibiotics use, especially azithromycin, in the first three months, but this decreased thereafter. CONCLUSIONS: Treatment for patients hospitalized with COVID-19 evolved with the changing scientific evidence during the pandemic. Initially, multiple drugs were empirically used that subsequently could not demonstrate clinical benefit. In future pandemics, stakeholders should strive to promote the early implementation of adaptive randomized clinical trials.

Evaluation of the host immune response assay SeptiCyte RAPID for potential triage of COVID-19 patients.

Tools for the evaluation of COVID-19 severity would help clinicians with triage decisions, especially the decision whether to admit to ICU. The aim of this study was to evaluate SeptiCyte RAPID, a host immune response assay (Immunexpress, Seattle USA) as a triaging tool for COVID-19 patients requiring hospitalization and potentially ICU care. SeptiCyte RAPID employs a host gene expression signature consisting of the ratio of expression levels of two immune related mRNAs, PLA2G7 and PLAC8, measured from whole blood samples. Blood samples from 146 adult SARS-CoV-2 (+) patients were collected within 48 h of hospital admission in PAXgene blood RNA tubes at Hospital del Mar, Barcelona, Spain, between July 28th and December 1st, 2020. Data on demographics, vital signs, clinical chemistry parameters, radiology, interventions, and SeptiCyte RAPID were collected and analyzed with bioinformatics methods. The performance of SeptiCyte RAPID for COVID-19 severity assessment and ICU admission was evaluated, relative to the comparator of retrospective clinical assessment by the Hospital del Mar clinical care team. In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity: critical vs. mild (AUC = 0.93, p < 0.0001), critical vs. moderate (AUC = 0.77, p = 0.002), severe vs. mild (AUC = 0.85, p = 0.0003), severe vs. moderate (AUC = 0.63, p = 0.05). This discrimination was significantly better (by AUC or p-value) than could be achieved by CRP, lactate, creatine, IL-6, or D-dimer. Some of the critical or severe cases had "early" blood draws (before ICU admission; n = 33). For these cases, when compared to moderate and mild cases not in ICU (n = 37), SeptiCyte RAPID had AUC = 0.78 (p = 0.00012). In conclusion, SeptiCyte RAPID was able to stratify COVID-19 cases according to clinical severity as defined by the WHO COVID-19 Clinical Management Living Guidance of January 25th, 2021. Measurements taken early (before a patient is considered for ICU admission) suggest that high SeptiScores could aid in predicting the need for later ICU admission.

Individuals With Higher CD4/CD8 Ratio Exhibit Increased Risk of Acute Respiratory Distress Syndrome and In-Hospital Mortality During Acute SARS-CoV-2 Infection.

Background: CD4/CD8 ratio has been used as a quantitative prognostic risk factor in patients with viral infections. This study aims to assess the association between in-hospital mortality and at admission CD4/CD8 ratio among individuals with acute SARS-CoV-2 infection. Methods: This is a longitudinal cohort study with data of all consecutive patients admitted to the COVID-19 unit at Hospital del Mar, Barcelona, Spain for ≥48 h between March to May 2020. The CD4+ CD8+ T-cell subset differentiation was assessed by flow cytometry at admission as well as a complete blood test. Patients were classified according to CD4/CD8 ratio tertiles. The primary outcome was in-hospital mortality and the secondary outcome was acute respiratory distress (ARDS). Results: A total of 338 patients were included in the cohort. A high CD4/CD8 ratio (third tertile) was associated with a higher in-hospital mortality [adjusted Cox model hazard ratio (HR) 4.68 (95%CI 1.56-14.04, p = 0.006), reference: second tertile HR 1]. Similarly, a high CD4/CD8 ratio (third tertile) was associated with a higher incidence of ARDS [adjusted logistic regression model OR 1.97 (95%CI 1.11-3.55, p = 0.022) reference: second tertile HR 1]. There was a trend of higher in-hospital mortality and incidence of ARDS in patients within the first tertile of CD4/CD8 ratio compared with the second one, but the difference was not significant. No associations were found with total lymphocyte count or inflammatory parameters, including D-dimer. Conclusion: CD4/CD8 ratio is a prognostic factor for the severity of COVID-19, reflecting the negative impact on prognosis of those individuals whose immune response has abnormal CD8+ T-cell expansion during the early response to the infection.

Comparison of hospitalized COVID-19 and influenza patients requiring supplemental oxygen in a cohort study: clinical impact and resource consumption.

BACKGROUND: To compare clinical characteristics, outcomes, and resource consumption of patients with COVID-19 and seasonal influenza requiring supplemental oxygen. METHODS: Retrospective cohort study conducted at a tertiary-care hospital. Patients admitted due to seasonal influenza between 2017 and 2019, or with COVID-19 between March and May 2020 requiring supplemental oxygen were compared. Primary outcome: 30-day mortality. Secondary outcomes: 90-day mortality and hospitalization costs. Attempted sample size to detect an 11% difference in mortality was 187 patients per group. RESULTS: COVID-19 cases were younger (median years, 67 (IQR 54-78) vs 76 (IQR 64-83); p < 0.001) and more frequently overweight whereas influenza cases had more hypertension, immunosuppression, and chronic heart, respiratory and renal disease. Compared to influenza, COVID-19 cases had more pneumonia (98% vs 60%, <0.001), higher MEWS and CURB-65 scores and were more likely to show worse progression on the WHO ordinal scale (33% vs 4%; p < 0.001). The 30-day mortality rate was higher for COVID-19 than for influenza: 15% vs 5% (p = 0.001). The median age of non-surviving cases was 81 (IQR 74-88) and 77.5 (IQR 65-84) (p = 0.385), respectively. COVID-19 was independently associated with 30-day (HR 4.6, 95%CI, 2-10.4) and 90-day (HR 5.2, 95%CI, 2.4-11.4) mortality. Sensitivity and subgroup analyses, including a subgroup considering only patients with pneumonia, did not show different trends. Regarding resource consumption, COVID-19 patients had longer hospital stays and higher critical care, pharmacy, and complementary test costs. CONCLUSIONS: Although influenza patients were older and had more comorbidities, COVID-19 cases requiring supplemental oxygen on admission had worse clinical and economic outcomes.

Severe Hypoalbuminemia at Admission Is Strongly Associated with Worse Prognosis in Older Adults with SARS-CoV-2 Infection.

Serum albumin levels have been associated with prognosis in several conditions among older adults. The aim of this study is to assess the prognostic value in mortality of serum albumin in older adults with SARS-CoV-2 infection. METHODS: Cohort observational study with consecutive older-adults (≥65 years old), with confirmed SARS-CoV-2 infection admitted to a university hospital between March-May 2020. A logistic regression model was fitted to assess the impact of albumin levels on in-hospital mortality adjusted by potential confounders. RESULTS: Among a total of 840 patients admitted to the hospital, 405 (48%) were older adults with a total of 92 deaths (23%) among them. Those who died were older, had more comorbidities, higher inflammation status and lower levels of serum albumin at admission [3.10 g/dL (0.51) vs. 3.45 g/dL (0.45); p < 0.01. Serum albumin levels at admission were negatively correlated with inflammatory markers such as C-Reactive protein (Pearson Coeff -0.4634; p < 0.001) or IL-6 (Pearson's Coeff -0.244; p = 0.006) at admission but also to other clinical outcomes such time to clinical stability (Pearson's Coeff -0.259; p < 0.001). Severe hypoalbuminemia associated with increased risk of mortality was defined as ≤3 g/dL at admission according to the AUC/ROC analysis (0.72 95% CI 0.63-0.81) In a multivariate logistic regression model adjusting by age, inflammation, comorbidities and severity at admission severe hypoalbuminemia was a strong predictor of in-hospital mortality (OR 2.18 95% CI 1.03-4.62; p = 0.039). CONCLUSION: Severe hypoalbuminemia with ≤3 g/dL is an independent risk factor for mortality among older adults with SARS-CoV-2 infection. There is a consistent correlation between albumin levels and inflammatory biomarkers. Further studies are needed to determine whether the supplementation of albumin as coadjuvant treatment will have a positive impact on the prognosis of this infection.

Impact of Generic Entry on Hospital Antimicrobial Use: A Retrospective Quasi-Experimental Interrupted Time Series Analysis.

BACKGROUND: The impact of antimicrobials generic entry (GE) is controversial. Their introduction could provide an economic benefit yet may also increase their consumption, leading to a higher risk of resistance. Our aim was to analyze the impact of GE on trends of antimicrobial consumption in an acute-care hospital. METHODS: A retrospective quasi-experimental interrupted time series analysis was conducted at a 400-bed tertiary hospital in Barcelona, Spain. All antimicrobials for systemic use for which a generic product entered the hospital from January 2000 to December 2019 were included. Antimicrobial consumption was expressed as DDD/100 bed days. RESULTS: After GE, the consumption of cefotaxime (0.09, p < 0.001), meropenem (0.54, p < 0.001), and piperacillin-tazobactam (0.13, p < 0.001) increased, whereas the use of clindamycin (-0.03, p < 0.001) and itraconazole (-0.02, p = 0.01) was reduced. An alarming rise in cefepime (0.004), daptomycin (1.02), and cloxacillin (0.05) prescriptions was observed, despite not achieving statistical significance. On the contrary, the use of amoxicillin (-0.07), ampicillin (-0.02), cefixime (-0.06), fluconazole (-0.13), imipenem-cilastatin (-0.50) and levofloxacin (-0.35) decreased. These effects were noticed beyond the first year post GE. CONCLUSIONS: GE led to an increase in the consumption of broad-spectrum molecules. The potential economic benefit of generic antibiotics could be diluted by an increase in resistance. Antimicrobial stewardship should continue to monitor these molecules despite GE.

Prevalence and Prognostic Value of Myocardial Injury in the Initial Presentation of SARS-CoV-2 Infection among Older Adults.

Myocardial involvement during SARS-CoV-2 infection has been reported in many prior publications. We aim to study the prevalence and the clinical implications of acute myocardial injury (MIN) during SARS-CoV-2 infection, particularly in older patients. The method includes a longitudinal observational study with all consecutive adult patients admitted to a COVID-19 unit between March-April 2020. Those aged ≥65 were considered as older adult group. MIN was defined as at least 1 high-sensitive troponin (hs-TnT) concentration above the 99th percentile upper reference limit with different sex-cutoff. Results. Among the 634 patients admitted during the period of observation, 365 (58%) had evidence of MIN, and, of them, 224 (61%) were older adults. Among older adults, MIN was associated with longer time to recovery compared to those without MIN (13 days (IQR 6-21) versus 9 days (IQR 5-17); p < 0.001, respectively. In-hospital mortality was significantly higher in older adults with MIN at admission versus those without it (71 (31%) versus 11 (12%); p < 0.001). In a logistic regression model adjusting by age, sex, severity, and Charlson Comorbidity Index, the OR for in-hospital mortality was 2.1 (95% CI: 1.02-4.42; p = 0.043) among those older adults with MIN at admission. Older adults with acute myocardial injury had greater time to clinical recovery, as well as higher odds of in-hospital mortality.

Multicentre, randomised, open-label, phase IV-III study to evaluate the efficacy of cloxacillin plus fosfomycin versus cloxacillin alone in adult patients with methicillin-susceptible Staphylococcus aureus bacteraemia: study protocol for the SAFO trial.

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a frequent condition, with high mortality rates. There is a growing interest in identifying new therapeutic regimens able to reduce therapeutic failure and mortality observed with the standard of care of beta-lactam monotherapy. In vitro and small-scale studies have found synergy between cloxacillin and fosfomycin against S. aureus. Our aim is to test the hypothesis that cloxacillin plus fosfomycin achieves higher treatment success than cloxacillin alone in patients with MSSA bacteraemia. METHODS: We will perform a superiority, randomised, open-label, phase IV-III, two-armed parallel group (1:1) clinical trial at 20 Spanish tertiary hospitals. Adults (≥18 years) with isolation of MSSA from at least one blood culture ≤72 hours before inclusion with evidence of infection, will be randomly allocated to receive either cloxacillin 2 g/4-hour intravenous plus fosfomycin 3 g/6-hour intravenous or cloxacillin 2 g/4-hour intravenous alone for 7 days. After the first week, sequential treatment and total duration of antibiotic therapy will be determined according to clinical criteria by the attending physician.Primary endpoints: (1) Treatment success at day 7, a composite endpoint comprising all the following criteria: patient alive, stable or with improved quick-Sequential Organ Failure Assessment score, afebrile and with negative blood cultures for MSSA at day 7. (2) Treatment success at test of cure (TOC) visit: patient alive and no isolation of MSSA in blood culture or at another sterile site from day 8 until TOC (12 weeks after randomisation).We assume a rate of treatment success of 74% in the cloxacillin group. Accepting alpha risk of 0.05 and beta risk of 0.2 in a two-sided test, 183 subjects will be required in each of the control and experimental groups to obtain statistically significant difference of 12% (considered clinically significant). ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge University Hospital (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), and is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders. TRIAL REGISTRATION NUMBER: The protocol has been approved by AEMPS with the Trial Registration Number EudraCT 2018-001207-37. ClinicalTrials.gov Identifier: NCT03959345; Pre-results.

Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection.

BACKGROUND: Zinc is an essential micronutrient that impacts host-pathogen interplay at infection. Zinc balances immune responses, and also has a proven direct antiviral action against some viruses. Importantly, zinc deficiency (ZD) is a common condition in elderly and individuals with chronic diseases, two groups with an increased risk for severe severe coronavirus disease 2019 (COVID-19) outcomes. We hypothesize that serum zinc content (SZC) influences COVID-19 disease progression, and thus might represent a useful biomarker. METHODS: We ran an observational cohort study with 249 COVID-19 patients admitted in Hospital del Mar. We have studied COVID-19 severity and progression attending to SZC at admission. In parallel, we have studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) replication in the Vero E6 cell line modifying zinc concentrations. FINDINGS: Our study demonstrates a correlation between serum zinc levels and COVID-19 outcome. Serum zinc levels lower than 50 µg/dL at admission correlated with worse clinical presentation, longer time to reach stability, and higher mortality. Our in vitro results indicate that low zinc levels favor viral expansion in SARS-CoV-2 infected cells. INTERPRETATION: Low SZC is a risk factor that determines COVID-19 outcome. We encourage performing randomized clinical trials to study zinc supplementation as potential prophylaxis and treatment with people at risk of zinc deficiency.

Evolution of Antimicrobial Consumption During the First Wave of COVID-19 Pandemic.

Background: The first wave of COVID-19 pandemic may have significantly impacted antimicrobial consumption in hospitals. The objective of this study was to assess the evolution of antimicrobial consumption during this period. Methods: A retrospective quasi-experimental before-after study was conducted in a Spanish tertiary care hospital. The study compared two periods: pre-pandemic, from January 2018 to February 2020, and during the COVID-19 pandemic from March to June 2020. Antimicrobial consumption was analyzed monthly as defined daily doses (DDD)/100 bed-days and overall hospital and ICU consumption were evaluated. Results: An increase in the hospital consumption was noticed. Although only ceftaroline achieved statistical significance (p = 0.014), a rise was observed in most of the studied antimicrobials. A clear temporal pattern was detected. While an increase in ceftriaxone and azithromycin was observed during March, an increment in the consumption of daptomycin, carbapenems, linezolid, ceftaroline, novel cephalosporin/ß-lactamase inhibitors or triazoles during April-May was noticed. In the ICU, these findings were more evident, namely ceftriaxone (p = 0.029), carbapenems (p = 0.002), daptomycin (p = 0.002), azithromycin (p = 0.030), and linezolid (p = 0.011) but followed a similar temporal pattern. Conclusion: An increase in the antimicrobial consumption during the first wave of COVID-19 pandemic was noticed, especially in the ICU. Availability of updated protocols and antimicrobial stewardship programs are essential to optimize these outcomes.