Robinson, Matthew L

ABSTRACT Metallo-beta-lactamase (MBL)-producing Enterobacterales are a global public health concern. Infections caused by these pathogens are often hard to treat, with few effective agents currently available. While aztreonam-avibactam only recently gained U.S. and European regulatory approval, laboratories have implemented laboratory-developed tests (LDTs) using existing aztreonam and ceftazidime-avibactam reagents. We sought to compare the performance of four phenotypic methods, up to three reagent manufacturers, and two media manufacturers. One hundred two MBL-producing Enterobacterales isolates were evaluated at two sites (Centers for Disease Control and Prevention [CDC] and Johns Hopkins University [JHU] School of Medicine). The performance of four methods was evaluated: broth disk elution (BDE), disk stacking (DS), gradient diffusion strip stacking (SS), and a strip-to-disk proximity (strip-disk) method, which were compared to reference broth microdilution (rBMD) tested in parallel. Respective category agreement for CDC and JHU was 92.2% and 96.1% for BDE, 51%–76.5% and 31%–49% for DS, 71.6%–86.3% and 83.3%–86.3% for SS, and 82.4%–87.3% and 80%–89.2% for the strip-disk method. The SS essential agreement ranged from 46.1% to 62.7% for JHU and 54.9% to 92.2% for CDC. Interlaboratory reproducibility was 93.1% for rBMD, 92.2% for BDE, 47.1%–53.1% for DS, 76.5%–80% for SS, and 87.3%–88.9% for strip-disk. BDE was the only method that exceeded acceptable performance of >90% accuracy and reproducibility. DS had the lowest and most variable performance between sites and among the different disk manufacturers used. LDTs for combination testing can be highly variable, and further work is needed to improve standardization and harmonization to achieve accurate and reliable results for clinical purposes. IMPORTANCE Carbapenem-resistant Enterobacterales are classified as an urgent public health threat in the Centers for Disease Control and Prevention’s 2019 Antibiotic Resistance Threats Report. Among the most concerning resistance mechanisms are carbapenemase enzymes encoded on mobile genetic elements, which can spread rapidly between bacteria. Of the various carbapenemases, metallo-beta-lactamases are particularly challenging, as they confer resistance to nearly all beta-lactams, and current treatment options remain limited. While aztreonam-avibactam has been U.S. Food and Drug Administration (FDA)-approved for treating certain infections with limited or no alternative treatment options, no FDA-cleared susceptibility test is yet available. In this context, laboratory-developed methods, such as combination testing of aztreonam and ceftazidime-avibactam, play a critical role in guiding therapy. Our study evaluates several of the more common laboratory-developed tests compared to reference broth microdilution and found that broth disk elution was the most accurate; in contrast, other methods had variable performance, some demonstrating limited reliability and being prone to overcalling resistance.

COVID-19 highlighted the need for use of real-world data (RWD) in critical care as a near real-time resource for clinical, research, and policy efforts. Analysis of RWD is gaining momentum and can generate important evidence for policy makers and regulators. Extracting high quality RWD from electronic health records (EHRs) requires sophisticated infrastructure and dedicated resources. We sought to customize freely available public tools, supporting all phases of data harmonization, from data quality assessments to de-identification procedures, and generation of robust, data science ready RWD from EHRs. These data are made available to clinicians and researchers through CURE ID, a free platform which facilitates access to case reports of challenging clinical cases and repurposed treatments hosted by the National Center for Advancing Translational Sciences/National Institutes of Health in partnership with the Food and Drug Administration. This commentary describes the partnership, rationale, process, use case, impact in critical care, and future directions for this collaborative effort.