Ceftazidime-avibactam and aztreonam combination for Carbapenem-resistant Enterobacterales bloodstream infections with presumed metallo-β-lactamase production: a systematic review and meta-analysis

Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I (“Risk Of Bias In Non-randomised Studies - of Interventions”), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.

Background Reporting standards, such as PRISMA aim to ensure that the methods and results of systematic reviews are described in sufficient detail to allow full transparency. Flow diagrams in evidence syntheses allow the reader to rapidly understand the core procedures used in a review and examine the attrition of irrelevant records throughout the review process. Recent research suggests that use of flow diagrams in systematic reviews is poor and of low quality and called for standardised templates to facilitate better reporting in flow diagrams. The increasing options for interactivity provided by the Internet gives us an opportunity to support easy‐to‐use evidence synthesis tools, and here we report on the development of a tool for the production of PRISMA 2020‐compliant systematic review flow diagrams. Methods and Findings We developed a free‐to‐use, Open Source R package and web‐based Shiny app to allow users to design PRISMA flow diagrams for their own systematic reviews. Our tool allows users to produce standardised visualisations that transparently document the methods and results of a systematic review process in a variety of formats. In addition, we provide the opportunity to produce interactive, web‐based flow diagrams (exported as HTML files), that allow readers to click on boxes of the diagram and navigate to further details on methods, results or data files. We provide an interactive example here; https://prisma-flowdiagram.github.io/ . Conclusions We have developed a user‐friendly tool for producing PRISMA 2020‐compliant flow diagrams for users with coding experience and, importantly, for users without prior experience in coding by making use of Shiny ( https://estech.shinyapps.io/prisma_flowdiagram/ ). This free‐to‐use tool will make it easier to produce clear and PRISMA 2020‐compliant systematic review flow diagrams. Significantly, users can also produce interactive flow diagrams for the first time, allowing readers of their reviews to smoothly and swiftly explore and navigate to further details of the methods and results of a review. We believe this tool will increase use of PRISMA flow diagrams, improve the compliance and quality of flow diagrams, and facilitate strong science communication of the methods and results of systematic reviews by making use of interactivity. We encourage the systematic review community to make use of the tool, and provide feedback to streamline and improve their usability and efficiency.

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). 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. 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. CAZ-AVI/ATM combination offers therapeutic advantage compared to OAAs for patients with BSI due to MBL-producing Enterobacterales. Further studies are warranted.