Emulating a Target Trial of Shorter Compared to Longer Course of Antibiotic Therapy for Gram-Negative Bacteremia.

BACKGROUND: Despite the availability of antimicrobial therapies, gram-negative bacteremia remains a significant cause of morbidity and mortality on a global level. Recent randomized controlled trials support shorter antibiotic treatment duration for individuals with uncomplicated gram-negative bacteremia. The target trial framework using the cloning approach utilizes real-world data but eliminates the issue of immortal time bias seen in observational studies by emulating the analysis of randomized trials with full adherence. METHOD: A hypothetical target trial allocating individuals with gram-negative bacteremia to either short antibiotic treatment duration (5-7 days) or longer antibiotic treatment duration (8-14 days) was specified and emulated using the cloning, censoring, and weighting approach. The primary outcome was 90-day all-cause mortality. Secondary outcome was a composite endpoint of clinical and microbiological relapse. The emulated trial included individuals from four hospitals in Copenhagen from 2018 through 2021. RESULTS: In sum, 1040 individuals were included. The median age of the cohort was 76 years, the majority were male (54%), had community-acquired gram-negative bacteremia (86%), urinary tract infection as the source of the infection (78%), and Escherichia coli as the pathogen of the infection (73%). The adjusted 90-day risk difference in all-cause mortality was 1.3% (95% confidence interval [CI]: -.7, 3.3), and the risk ratio was 1.12 (95% CI: .89, 1.37). The adjusted 90-day risk difference in relapse was 0.7% (95% CI: -2.3, 3.8), and the risk ratio was 1.07 (95% CI: .71, 1.45). CONCLUSIONS: We found comparative outcomes for shorter treatment duration compared to longer treatment duration in patients with gram-negative bacteremia.

The effect of immunosuppressants on the prognosis of SARS-CoV-2 infection.

BACKGROUND: Immunosuppression may worsen severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We conducted a nationwide cohort study of the effect of exposure to immunosuppressants on the prognosis of SARS-CoV-2 infection in Denmark. METHODS: We identified all SARS-CoV-2 test-positive patients from February 2020 to October 2020 and linked healthcare data from nationwide registers, including prescriptions for the exposure (immunosuppressant drugs). We estimated relative risks of hospital admission, intensive care unit (ICU) admission and death (each studied independently up to 30 days from testing) with a log-linear binomial regression adjusted for confounders using a propensity score-based matching weights model. RESULTS: A composite immunosuppressant exposure was associated with a significantly increased risk of death (adjusted relative risk 1.56 (95% CI 1.10-2.22)). The increased risk of death was mainly driven by exposure to systemic glucocorticoids (adjusted relative risk 2.38 (95% CI 1.72-3.30)), which were also associated with an increased risk of hospital admission (adjusted relative risk 1.34 (95% CI 1.10-1.62)), but not of ICU admission (adjusted relative risk 1.76 (95% CI 0.93-3.35)); these risks were greater for high cumulative doses of glucocorticoids than for moderate doses. Exposure to selective immunosuppressants, tumour necrosis factor inhibitors or interleukin inhibitors was not associated with an increased risk of hospitalisation, ICU admission or death, nor was exposure to calcineurin inhibitors, other immunosuppressants, hydroxychloroquine or chloroquine. CONCLUSIONS: Exposure to glucocorticoids was associated with increased risks of hospital admission and death. Further investigation is needed to determine the optimal management of coronavirus disease 2019 (COVID-19) in patients with pre-morbid glucocorticoid usage, specifically whether these patients require altered doses of glucocorticoids.

Early Switch From Intravenous to Oral Antibiotics for Patients With Uncomplicated Gram-Negative Bacteremia.

Importance: Gram-negative bacteremia is a global health concern, and optimizing the transition from intravenous (IV) to oral antibiotics is a critical step in improving patient treatment and resource utilization. Objective: To assess the association of switching to oral antibiotics within 4 days after initial blood culture with 90-day all-cause mortality compared with prolonged IV antibiotic treatment for patients with uncomplicated gram-negative bacteremia. Design, Setting, and Participants: This cohort study conducted using the target trial emulation framework included observational data from adults with uncomplicated gram-negative bacteremia in 4 hospitals in Copenhagen, Denmark, from January 1, 2018, through December 31, 2021. The duration of follow-up was 90 days. Eligibility criteria included a blood culture positive for growth of gram-negative bacteria, clinical stability within 4 days of initial blood culture, an available susceptibility report on day 4, and initiation of appropriate empirical IV antibiotic treatment within 24 hours of blood culture. Exposure: Switching to oral antibiotics within 4 days after initial blood culture compared with continuing IV antibiotic treatment for at least 5 days after initial blood culture. Main Outcomes and Measures: The main outcome was 90-day all-cause mortality. Inverse probability of treatment weighting was applied to adjust for confounding. Intention-to-treat and per-protocol analyses were performed using pooled logistic regression to estimate absolute risk, risk difference (RD), and risk ratio (RR); 95% CIs were computed using bootstrapping. Results: A total of 914 individuals were included in the target trial emulation analysis (512 [56.0%] male; median age, 74.5 years [IQR, 63.3-83.2 years]); 433 (47.4%) transitioned early to oral antibiotic treatment, and 481 (52.6%) received prolonged IV treatment. Ninety-nine individuals (10.8%) died during follow-up. The proportion of individuals who died was higher in the group receiving prolonged IV treatment (69 [14.3%] vs 30 [6.9%]). In the intention-to-treat analysis, 90-day all-cause mortality risk was 9.1% (95% CI, 6.7%-11.6%) for the early-switch group and 11.7% (95% CI, 9.6%-13.8%) for the group receiving prolonged IV treatment; the RD was -2.5% (95% CI, -5.7% to 0.7%) and RR was 0.78 (95% CI, 0.60-1.10). In the per-protocol analysis, the RD was -0.1% (95% CI, -3.4% to 3.1%) and RR was 0.99 (95% CI, 0.70-1.40). Conclusions and Relevance: In this cohort study of uncomplicated gram-negative bacteremia, early transition to oral antibiotics within 4 days of initial blood culture was associated with 90-day all-cause mortality risk comparable to that of continuing IV antibiotic treatment and may be an effective alternative to prolonged IV treatment.

Higher levels of IL-1ra, IL-6, IL-8, MCP-1, MIP-3α, MIP-3ß, and fractalkine are associated with 90-day mortality in 132 non-immunomodulated hospitalized patients with COVID-19.

INTRODUCTION: Immune dysregulation with an excessive release of cytokines has been identified as a key driver in the development of severe COVID-19. The aim of this study was to evaluate the initial cytokine profile associated with 90-day mortality and respiratory failure in a cohort of patients hospitalized with COVID 19 that did not receive immunomodulatory therapy. METHODS: Levels of 45 cytokines were measured in blood samples obtained at admission from patients with confirmed COVID-19. Logistic regression analysis was utilized to determine the association between cytokine levels and outcomes. The primary outcome was death within 90 days from admission and the secondary outcome was need for mechanical ventilation. RESULTS: A total of 132 patients were included during the spring of 2020. We found that one anti-inflammatory cytokine, one pro-inflammatory cytokine, and five chemokines were associated with the odds of 90-day mortality, specifically: interleukin-1 receptor antagonist, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, macrophage inflammatory protein-3ß, and fractalkine. All but fractalkine were also associated with the odds of respiratory failure during admission. Monocyte chemoattractant protein-1 showed the strongest estimate of association with both outcomes. CONCLUSION: We showed that one anti-inflammatory cytokine, one pro-inflammatory cytokine, and five chemokines were associated with 90-day mortality in patients hospitalized with COVID-19 that did not receive immunomodulatory therapy.

Circulating Adiponectin Levels Are Inversely Associated with Mortality and Respiratory Failure in Patients Hospitalized with COVID-19.

Background: Chronic low-grade inflammation associated with a dysregulated adipose tissue might contribute to amplifying the inflammatory response in severe COVID-19. The aim of this study was to examine the association between levels of circulating leptin and adiponectin and the severity and mortality of COVID-19. Methods: Serum levels of leptin and adiponectin were determined at admission in 123 individuals with confirmed COVID-19 and their association with 90-day mortality and respiratory failure was analyzed by logistic regression analysis and expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Results: The median values of circulating leptin and adiponectin were 7.2 ng/mL (IQR 3.8-13.4) and 9.0 µg/mL (IQR 5.7-14.6), respectively. After adjustment for age, sex, body mass index, hypertension, diabetes, chronic obstructive pulmonary disease, and oxygen saturation at admission, a doubling of circulating adiponectin was associated with a 38% reduction in odds of 90-day mortality (OR 0.62, CI 0.43-0.89) and a 40% reduction in odds of respiratory failure (OR 0.60, CI 0.42-0.86). The association tended to be strongest in individuals below the median age of 72 years. Circulating leptin was not associated with outcomes. Conclusions: Circulating adiponectin at admission was inversely associated with mortality and respiratory failure in SARS-CoV-2 infection. Further studies are needed to elucidate how exactly adipokines, especially adiponectin, are linked to the progression and prognosis of COVID-19.

Prediction of Respiratory Failure and Mortality in COVID-19 Patients Using Long Pentraxin PTX3.

The course of COVID-19 is unpredictable, ranging from asymptomatic to respiratory failure and death. Prognostic biomarkers are urgently needed. We hypothesized that long pentraxin PTX3 could be a valuable plasma biomarker due to its essential role in inflammatory processes. In a prospective hospitalized COVID-19 derivation cohort (n = 126) during the spring of 2020, we measured PTX3 within 4 days of admission. The predictive value of mechanical ventilation (MV) and 30-day mortality compared with clinical parameters and other markers of inflammation were assessed by logistic regression analysis and expressed as odds ratio (OR) with 95% confidence interval (CI). Analyses were repeated in a prospective validation cohort (n = 112) of hospitalized patients with COVID-19 treated with remdesivir and dexamethasone. Thirty-day mortality in the derivation cohort was 26.2%. In patients who died, the median PTX3 concentration upon admission was 19.5 ng/mL (IQR: 12.5-33.3) versus 6.6 ng/mL (IQR 2.9-12.3) (p < 0.0001) for survivors. After adjustment for covariates, the odds of 30-day mortality increased two-fold for each doubling of PTX3 (OR 2.03 [95% CI: 1.23-3.34], p = 0.006), which was also observed in the validation cohort (OR 1.70 [95% CI: 1.09-2.67], p = 0.02). Similarly, PTX3 levels were associated with MV. After adjustment for covariates, OR of MV was 2.34 (95% CI: 1.33-4.12, p = 0.003) in the derivation cohort and 1.64 (95% CI: 1.03-2.62, p = 0.04) in the validation cohort. PTX3 appears to be a useful clinical biomarker to predict 30-day respiratory failure and mortality risk in COVID-19 patients treated with and without remdesivir and dexamethasone.