Short course antibiotic treatment of Gram-negative bacteraemia (GNB5): a study protocol for a randomised controlled trial.

INTRODUCTION: Prolonged use of antibiotics is closely related to antibiotic-associated infections, antimicrobial resistance and adverse drug events. The optimal duration of antibiotic treatment for Gram-negative bacteremia (GNB) with a urinary tract source of infection is poorly defined. METHODS AND ANALYSIS: Investigator-initiated multicentre, non-blinded, non-inferiority randomised controlled trial with two parallel treatment arms. One arm will receive shortened antibiotic treatment of 5 days and the other arm will receive antibiotic treatment of 7 days or longer. Randomisation will occur in equal proportion (1:1) no later than day 5 of effective antibiotic treatment as determined by antibiogram. Immunosuppressed patients and those with GNB due to non-fermenting bacilli (Acinetobacter spp, Pseudomonas spp), Brucella spp, Fusobacterium spp or polymicrobial growth are ineligible.The primary endpoint is 90-day survival without clinical or microbiological failure to treatment. Secondary endpoints include all-cause mortality, total duration of antibiotic treatment, hospital readmission and Clostridioides difficile infection. Interim safety analysis will be performed after the recruitment of every 100 patients. Given an event rate of 12%, a non-inferiority margin of 10%, and 90% power, the required sample size to determine non-inferiority is 380 patients. Analyses will be performed on both intention-to-treat and per-protocol populations. ETHICS AND DISSEMINATION: The study is approved by the Danish Regional Committee on Health Research (H-19085920) and the Danish Medicines Agency (2019-003282-17). The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.Gov:NCT04291768.

Use of Inhaled Corticosteroids and Risk of Acquiring Haemophilus influenzae in Patients with Chronic Obstructive Pulmonary Disease.

Background: Inhaled corticosteroids (ICS) are widely used in chronic obstructive pulmonary disease (COPD), despite the known risk of severe adverse effects including pulmonary infections. Research Question: Our study investigates the risk of acquiring a positive Haemophilus influenzae airway culture with use of ICS in outpatients with COPD. Study Design and Methods: We conducted an epidemiological cohort study using data from 1 January 2010 to 19 February 2018, including 21,218 outpatients with COPD in Denmark. ICS use 365 days prior to cohort entry was categorised into low, moderate, and high, based on cumulated ICS dose extracted from a national registry on reimbursed prescriptions. A Cox proportional hazards regression model was used to assess the future risk of acquiring H. Influenzae within 365 days from cohort entry, and sensitivity analyses were performed using propensity score matched models. Results: In total, 801 (3.8%) patients acquired H. Influenzae during follow-up. Use of ICS was associated with a dose-dependent increased risk of acquiring H. Influenzae with hazard ratio (HR) 1.2 (95% confidence interval (CI) 0.9−1.5, p value = 0.1) for low-dose ICS; HR 1.7 (95% CI 1.3−2.1, p value < 0.0001) for moderate dose; and HR 1.9 (95% CI 1.5−2.4, p value < 0.0001) for high-dose ICS compared to no ICS use. Results were confirmed in the propensity-matched model using the same categories. Conclusions: ICS use in outpatients with COPD was associated with a dose-dependent increase in risk of isolating H. Influenzae. This observation supports that high dose ICS should be used with caution.

Decrease in All-Cause 30-Day Mortality after Bacteraemia over a 15-Year Period: A Population-Based Cohort Study in Denmark in 2000-2014.

INTRODUCTION: Bacteraemia is a frequent infectious condition that strongly affects morbidity and mortality. The incidence is increasing worldwide. This study explores all-cause 30-day mortality after bacteraemia in two out of Denmark's five healthcare regions with approximately 2.4 million inhabitants. METHODS: Clinically significant bacteraemia episodes (n = 55,257) were identified from a geographically well-defined background population between 2000 and 2014, drawing on population-based data regarding bacterial species and vital status. All-cause 30-day mortality was assessed in relation to bacteraemia episodes, number of patients with analysed blood cultures and the background population. RESULTS: We observed a decreasing trend of all-cause 30-day mortality between 2000 and 2014, both in relation to the number of bacteraemia episodes and the background population. Mortality decreased from 22.7% of the bacteraemia episodes in 2000 to 17.4% in 2014 (annual IRR [95% CI]: 0.983 [0.979-0.987]). In relation to the background population, there were 41 deaths per 100,000 inhabitants in 2000, decreasing to 39 in 2014 (annual IRR [95% CI]: 0.988 [0.982-0.993]). Numbers of inhabitants, bacteraemia episodes, and analysed persons having BCs increased during the period. CONCLUSIONS: All-cause 30-day mortality in patients with bacteraemia decreased significantly over a 15-year period.

Risk factors and prognosis of seizures in adults with community-acquired bacterial meningitis in Denmark: observational cohort studies.

OBJECTIVE: To examine predefined risk factors and outcome of seizures in community-acquired bacterial meningitis (CABM). DESIGN: Observational cohort studies SETTING: Denmark PARTICIPANTS: In the derivation cohort, we retrospectively included all adults (>15 years of age) with CABM in North Denmark Region from 1998 to 2014 and at Hvidovre and Hillerød hospitals from 2003 to 2014. In the validation cohort, we prospectively included all adults (>18 years of age) with CABM treated at all departments of infectious diseases in Denmark from 2015 to 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: In the derivation cohort, we used modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals for predefined risk factors for seizures during CABM as well as for risks of death and unfavourable outcome assessed by the Glasgow Outcome Scale score (1-4). Next, results were validated in the validation cohort. RESULTS: In the derivation cohort (n=358), risk factors for seizures at any time were pneumococcal aetiology (RR 1.69, 1.01-2.83) and abnormal cranial imaging (RR 2.27, 1.46-3.53), while the impact of age >65 years and immunocompromise was more uncertain. Examining seizures occurring after admission, risk factors were abnormal cranial imaging (RR 2.23, 1.40-3.54) and immunocompromise (RR 1.59, 1.01-2.50). Seizures at any time were associated with increased risks of in-hospital mortality (RR 1.45, 1.01-2.09) and unfavourable outcome at discharge (RR 1.27, 1.02-1.60). In the validation cohort (n=379), pneumococcal aetiology (RR 1.69, 1.10-2.59) and abnormal cranial imaging (RR 1.68, 1.09-2.59) were confirmed as risk factors for seizures at any time. For seizures occurring after admission, only pneumococcal meningitis (RR 1.92, 1.12-3.29) remained significant. Seizures at any time were also associated with in-hospital mortality (RR 3.26, 1.83-5.80) and unfavourable outcome (RR 1.23, 1.00-1.52) in this cohort. CONCLUSIONS: Pneumococcal aetiology, immunocompromise and abnormal cranial imaging were risk factors for seizures in CABM. Seizures were strongly associated with mortality and unfavourable outcome.