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.

Antimicrobial use and aetiology of bloodstream infections in critically ill patients during early stages of SARS-CoV-2 pandemic.

Background: During early stages of COVID-19 pandemic, antimicrobials were commonly prescribed. Aim: To describe clinical, microbiological and antimicrobial use changes in bloodstream infections (BSI) of ICU patients during the first wave of COVID-19 pandemic compared to pre-COVID-19 era. Methods: Observational cohort study of patients admitted to ICU of Bellvitge University Hospital was conducted during the COVID-19 pandemic (March-June 2020) and before COVID-19 pandemic (March-June 2019). Differences in clinical characteristics, antimicrobial consumption and incidence and aetiology of BSI were measured. Findings: COVID-19 patients had significantly less comorbidities with obesity the only risk factor that increased in frequency. COVID-19 patients more frequently required invasive supportive care measures, had longer median ICU stay and higher mortality rates. The incidence of BSIs was higher in COVID-19 period (RR 3.2 [95%CI 2.2-4.7]), occurred in patients who showed prolonged median ICU stay (21days) and was associated with high mortality rate (47%). The highest increases in the aetiological agents were observed for AmpC-producing bacteria (RR 11.1 [95%CI 2.6-47.9]) and non-fermenting rods (RR 7.0 [95%CI 1.5-31.4]). The emergence of bacteraemia caused by Gram-negative rods resistant to amoxicillin-clavulanate, which was used as empirical therapy during early stages of the pandemic, led to an escalation towards broader-spectrum antimicrobials such as meropenem and colistin which was also associated with the emergence of resistant isolates. Conclusions: The epidemiological shift towards resistant phenotypes in critically ill COVID-19 patients was associated with the selective use of antimicrobials. Our study provides evidence of the impact of empirical therapy on the selection of bacteria and their consequences on BSI over the subsequent months.

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.

Immunomodulatory therapy, risk factors and outcomes of hospital-acquired bloodstream infection in patients with severe COVID-19 pneumonia: a Spanish case-control matched multicentre study (BACTCOVID).

OBJECTIVES: The effect of the use of immunomodulatory drugs on the risk of developing hospital-acquired bloodstream infection (BSI) in patients with COVID-19 has not been specifically assessed. We aim to identify risk factors for, and outcomes of, BSI among hospitalized patients with severe COVID-19 pneumonia. METHODS: We performed a severity matched case-control study (1:1 ratio) nested in a large multicentre prospective cohort of hospitalized adults with COVID-19. Cases with BSI were identified from the cohort database. Controls were matched for age, sex and acute respiratory distress syndrome. A Cox proportional hazard ratio model was performed. RESULTS: Of 2005 patients, 100 (4.98%) presented 142 episodes of BSI, mainly caused by coagulase-negative staphylococci, Enterococcus faecalis and Pseudomonas aeruginosa. Polymicrobial infection accounted for 23 episodes. The median time from admission to the first episode of BSI was 15 days (IQR 9-20), and the most frequent source was catheter-related infection. The characteristics of patients with and without BSI were similar, including the use of tocilizumab, corticosteroids, and combinations. In the multivariate analysis, the use of these immunomodulatory drugs was not associated with an increased risk of BSI. A Cox proportional hazard ratio (HR) model showed that after adjusting for the time factor, BSI was associated with a higher in-hospital mortality risk (HR 2.59; 1.65-4.07; p < 0.001). DISCUSSION: Hospital-acquired BSI in patients with severe COVID-19 pneumonia was uncommon and the use of immunomodulatory drugs was not associated with its development. When adjusting for the time factor, BSI was associated with a higher mortality risk.

Impact of comprehensive molecular testing to reduce antibiotic use in community-acquired pneumonia (RADICAP): a randomised, controlled, phase IV clinical trial protocol.

INTRODUCTION: Community-acquired pneumonia (CAP) continues to be a major health problem worldwide and is one of the main reasons for prescribing antibiotics. However, the causative agent is often not identified, resulting in antibiotic overtreatment, which is a key driver of antimicrobial resistance and adverse events. We aim to test the hypothesis that comprehensive molecular testing, compared with routine microbiological testing, would be effective in reducing antibiotic use in patients with CAP. METHODS AND ANALYSIS: We will perform a randomised, controlled, open-label clinical trial with two parallel groups (1:1) at two tertiary hospitals between 2020 and 2022. Non-severely immunosuppressed adults hospitalised for CAP will be considered eligible. Patients will be randomly assigned to receive either the experimental diagnosis (comprehensive molecular testing plus routine microbiological testing) or standard diagnosis (only microbiological routine testing). The primary endpoint will be antibiotic consumption measured as days of antibiotic therapy per 1000 patient-days. Secondary endpoints will be de-escalation to narrower antibiotic treatment, time to switch from intravenous to oral antibiotics, days to reaching an aetiological diagnosis, antibiotic-related side effects, length of stay, days to clinical stability, intensive care unit admission, days of mechanical ventilation, hospital readmission up to 30 days after randomisation and death from any cause by 48 hours and 30 days after randomisation. We will need to include 440 subjects to be able to reject the null hypothesis that both groups have equal days of antibiotic therapy per 1000 patient-days with a probability >0.8. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Bellvitge Hospital (AC028/19) and from the Spanish Medicines and Medical Devices Agency, and it is valid for all participating centres under existing Spanish legislation. Results will be presented at international meetings and will be made available to patients, their caregivers and funders. TRIAL REGISTRATION NUMBER: ClinicalTrials: NCT04158492. EudraCT: 2018-004880-29.

Beneficial effect of corticosteroids in preventing mortality in patients receiving tocilizumab to treat severe COVID-19 illness.

OBJECTIVES: To assess the characteristics and risk factors for mortality in patients with severe coronavirus disease-2019 (COVID-19) treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS). METHODS: From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality. RESULTS: A total of 1,092 patients with COVID-19 were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186 patients, 155 (83.3 %) patients were receiving noninvasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (±4.3) and 4.3 days (±3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p < 0.001), chronic heart failure (HR = 4.4, p = 0.003), and chronic liver disease (HR = 4.69, p = 0.004). The use of CS, in combination with TCZ, was identified as a protective factor against mortality (HR = 0.26, p < 0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up. CONCLUSIONS: In patients with severe COVID-19 receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed a beneficial effect in preventing in-hospital mortality.