Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

Molecular epidemiology and risk factors of bloodstream infections caused by extended-spectrum beta-lactamase-producing Klebsiella pneumoniae A case-control study.

OBJECTIVES: To study the prevalence, risk factors, outcome, and molecular epidemiology in patients with bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae (Kp) (cases), in comparison with patients with bacteremia caused by a susceptible Kp (controls). METHODS: This was a retrospective case-control study including all episodes of Kp bacteremia for the period 1993 to 2002 at a referral hospital for adults in Mexico. ESBL production was tested for by E-test. All isolates were typed by pulsed field gel electrophoresis (PFGE). A subset of isolates underwent plasmid analysis, conjugal transfer of cefotaxime resistance to Escherichia coli J53-2, isoelectric focusing bioassay, colony-blot hybridization, PCR, and sequencing. RESULTS: Of the 121 patients with bacteremia due to Kp included in the study, 17 (14.0%) had an ESBL-Kp isolate (cases). Multivariate analysis identified prior use of cephalosporins (OR 7.6, 95% CI 1.1-53.5; p=0.039) and stay in the intensive care unit (ICU; OR 5.6, 95% CI 1.1-27.9; p=0.033) as significant risk factors. No differences were observed in hospital stay or mortality after the event. Multi-drug resistance was more frequent in ESBL-Kp. There was no clonal predominance. A distinct beta-lactamase profile was identified, which included a combination of TEM-1 (pI 5.4) and SHV-5 (pI 8.2) in 13/17 ESBL-Kp isolates. Cefotaxime resistance was transferred by conjugation in 14/17 isolates with a >120-kb plasmid encoding ESBL. CONCLUSIONS: The prevalence of ESBL-Kp was found to be lower than that previously reported in Latin America. ESBL-Kp bacteremia was not associated with a worse clinical outcome. We were able to identify a plasmid-mediated horizontal dissemination over the 10-year period.