The Future Ain't What It Used to Be…Out With the Old…In With the Better: Antibacterial Resistance Leadership Group Innovations

Abstract

Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections.

Keywords: BED-FRAME; DOOR; DOOR MAT; MASTERMIND; SMART COMPASS.

Figure 1.

Schema for a SMART COMPASS comparing 4 strategies. A patient is initially randomized to empiric therapy A or B. For definitive therapy, if AST indicates susceptibility to empiric therapy then they remain on the empiric therapy. If AST indicates resistance, then there are therapeutic adjustments and the patient is randomized a second time to empiric therapy options. Four strategies are compared. Begin with empiric therapy A. If susceptible, then remain on A. If resistant, then change to C. Begin with empiric therapy A. If susceptible, then remain on A. If resistant, then change to D. Begin with empiric therapy B. If susceptible, then remain on B. If resistant, then change to E. Begin with empiric therapy B. If susceptible, then remain on B. If resistant, then change to F. The design is efficient in that some patients contribute information to more than 1 strategy. There are 4 strategies but 6 paths. Patients on the same strategy can receive different treatments depending on AST results. Abbreviations: AST, antimicrobial susceptibility testing; BSI, bloodstream infection; LRTI, lower respiratory tract infection; R, Randomization; SMART COMPASS, Sequential, Multiple-Assignment, Randomized Trials for Comparing Personalized Antibiotic Strategies.

Figure 2.

DOOR infographic [10]. Credit: Kim Best and Kerry Stenke, Duke Clinical Research Institute. Figure used with permission. Abbreviation: DOOR, Desirability of Outcome Ranking.

Figure 3.

Example output from BED-FRAME analyses. Output from the R shiny app displaying contours of the between-platform difference (molecular beacons [MB] vs polymerase chain reaction/electrospray ionization mass spectrometry [PCR/ESI-MS]) in weighted accuracy (ie, overall percentage correctly classified, adjusted for the relative importance of a false-resistant test result relative to a false-susceptible test result) for various combinations of relative importance and imipenem susceptibility rates. Gray indicates combinations of relative importance and imipenem susceptibility rates for which MB would provide superior results. Yellow indicates combinations of relative importance and imipenem susceptibility rates for which PCR/ESI-MS would provide superior results. Black indicates the border where accuracy is equivalent. A point is shown for a resistance rate = 0.25 and relative importance = 0.25 (a false-resistant test result, which would result in avoidance of treatment with a covering drug, is 25% as important as a false-susceptible test result, which would result in treatment with a non-covering drug) where there is a weighted accuracy advantage of 5.9% for PCR/ESI-MS. Abbreviations: BED-FRAME, Benefit–Risk Evaluation of Diagnostics: A Framework; WA, weighted accuracy.

Figure 4.

Schematic for DOOR MAT. Red indicates selection of an antibiotic for which the target infection is deemed resistant (most undesirable). Green indicates selection of an antibiotic from the narrowest spectrum for which the target infection is deemed susceptible (most desirable). The shade of gray indicates selection of an antibiotic from spectrums for which the target infection is deemed susceptible but not the narrowest. Lighter shades of gray indicate more desirability—that is, closer to the most-desirable narrowest spectrum for which the target infection is deemed susceptible. Abbreviations: AST, antimicrobial susceptibility testing; DOOR MAT, Desirability of Outcome Ranking for the Management of Antimicrobial Therapy, R, Resistant; S, Susceptible.