anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

No abstract

Background In vitro data support the use of combination of aztreonam (ATM) with ceftazidime-avibactam (CAZ-AVI), but clinical studies are lacking. The aim of our study was to compare the outcome of patients with bloodstream infections (BSIs) due to MBLs-producing Enterobacterales treated either with CAZ-AVI plus ATM or other active antibiotics (OAAs). Methods Prospective observational study including patients admitted to three hospitals in Italy and Greece. The primary outcome measure was the 30-day all-cause mortality. Secondary outcomes were clinical failure at day 14 and length of stay (LOS) after BSI diagnosis. Cox regression analysis including a propensity score (PS) for receiving CAZ-AVI plus ATM was performed to evaluate primary and secondary outcomes. A PS-based matched analysis was also performed. Results We enrolled 102 pts with BSI, 82 had infections caused by NDM-producing (79 K.pneumoniae and 3 E.coli) and 20 by VIM-producing (14 K.pneumoniae, 5 Enterobacter spp, 1 M.morganii) strains. The 30-day mortality rate was 19.2% in CAZ-AVI/ATM group vs 44% in OAAs group (p=0.007). The PS-adjusted analysis showed that the use of CAZ-AVI/ATM was associated with lower 30-day mortality (HR 0.37, 95% CI 0.13-0.74, p=0.01), lower clinical failure at day 14 (HR 0.30, 95% CI 0.14-0.65, p=0.002) and shorter LOS (sHR 0.49, 95% CI 0.30-0.82, p=0.007). The PS-matched analysis confirmed these findings. Conclusions CAZ-AVI/ATM combination offers therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted.

CVEs, mainly those confined to the heart, complicate the course of almost one-third of patients hospitalized for CAP. More importantly, the occurrence of CVEs is associated with a 5-fold increase in CAP-associated 30-day mortality.

Using AI we identified baricitinib as possessing anti-viral and anti-cytokine efficacy. We now show a 71% (95% CI 0.15-0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age 81 years). A further 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-alpha-2 (IFNα2) significantly increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by >5-fold. RNA-Seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and super-resolution microscopy, baricitinib exerts activity rapidly through the inhibition of host proteins (numb associated kinases), uniquely amongst anti-virals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication and the cytokine storm, and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivizes further randomized controlled trials.