Background The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. Methods In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , NCT04351152 , and is completed. Findings Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Interpretation Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with CO...
Background-Controversy exists about the impact of prophylactic antibiotics on bacteremia after invasive dental procedures. The purpose of this double-blind, randomized, placebo-controlled study was to determine the impact of amoxicillin prophylaxis on the incidence, nature, and duration of bacteremia from nasotracheal intubation and dental procedures in children. Methods and Results-Children were randomly assigned before surgery to the American Heart Association (AHA)-recommended dose of amoxicillin or to a placebo. Aerobic and anaerobic blood cultures were drawn at 8 specific time points after intubation, dental restorative and cleaning procedures, and before, during, and after dental extraction(s), to include blood drawings up to 45 minutes after the last extraction. Aerobic and anaerobic blood culture results were used to determine the incidence, nature, and duration of bacteremia from these procedures. For the 100 children enrolled (mean age, 3.5 years), the overall incidence of positive blood cultures, defined as at least 1 positive culture of the 8, was significantly higher in the placebo (84%) than the amoxicillin group (33%) (PϽ0.0001). Bacteremia occurrence rates after intubation and after dental restorations and cleaning were 18% and 20% in the placebo group and 4% and 6% in the amoxicillin group (Pϭ0.05 and Pϭ0.07, respectively). At 1.5 minutes after the initiation of dental extractions, bacteremia occurred in 76% of the placebo group versus 15% of the amoxicillin group (PϽ0.001). The majority of the 152 positive cultures and of the 29 different bacteria identified were Gram-positive cocci. Bacteremia persisted longer in the placebo group. Conclusions-Bacteremia from these procedures occurs more often, from a wider variety of bacterial species, and for a longer duration after dental extractions than previously reported in any age group. Amoxicillin has a significant impact on the incidence, nature, and duration of bacteremia after nasal intubation, dental restorative and cleaning procedures, and dental extractions.
Patients' underuse of zidovudine and PCP prophylaxis was systematically associated with not having a PSAC. Lack of PSAC, in turn, predicted shorter survival but not increased hospitalization. Female gender, injecting drug use, non-white race and earlier diagnosis year also predicted poorer outcomes.
Background: Data on the effectiveness of definitive oral (PO) antibiotics for BSIs in preparation for discharge from hospital are lacking, particularly for Gram-positive bacterial BSIs (GP-BSI). The objective of this study was to determine rates of treatment failure based on bioavailability of PO antimicrobial agents used for GP-BSI. Methods: This was a single-center, retrospective cohort study of adult inpatients admitted to an academic medical center over a three-year period. Patients with a non-staphylococcal GP-BSI who received intravenous antibiotics and were then switched to PO antibiotics for at least a third of their treatment course were included. The cohort was stratified into high (⩾90%) and low (<90%) bioavailability groups. The primary endpoint was the proportion of patients experiencing clinical failure in each group. Secondary endpoints included clinical failure stratified by antibiotic group, bactericidal versus bacteriostatic PO agents, and organism. Results: A total of 103 patients met criteria for inclusion, which failed to reach the a priori power calculation. Of the patients included, 26 received high bioavailability agents and 77 received low bioavailability agents. Infections originated largely from a pulmonary source (30%) and were caused primarily by streptococcal species (75%). Treatment failure rates were 19.2% in the high bioavailability group and 23.4% in the low bioavailability group ( p = 0.66). Clinical failure stratified by subgroups also did not yield statistically significant differences. Conclusions: Clinical failure rates were similar among patients definitively treated with high or low bioavailability agents for GP-BSI, though the study was underpowered to detect such a difference.
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