Estes, Leslie

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.

AbstractIn this overview, we describe important contributions from the Antibacterial Resistance Leadership Group (ARLG) to patient care, clinical trials design, and mentorship while outlining future priorities. The ARLG research agenda is focused on 3 key areas: gram-positive infections, gram-negative infections, and diagnostics. The ARLG has developed an innovative approach to clinical trials design, the desirability of outcome ranking (DOOR), which uses an ordinal measure of global outcome to assess both benefits and harms. DOOR was initially applied to observational studies to determine optimal dosing of vancomycin for methicillin-resistant Staphylcococcus aureus bacteremia and the efficacy of ceftazidime-avibactam versus colistin for the treatment of carbapenem-resistant Enterobacterales infection. DOOR is being successfully applied to the analysis of interventional trials and, in collaboration with the US Food and Drug Administration (FDA), for use in registrational trials. In the area of diagnostics, the ARLG developed Master Protocol for Evaluating Multiple Infection Diagnostics (MASTERMIND), an innovative design that allows simultaneous testing of multiple diagnostic platforms in a single study. This approach will be used to compare molecular assays for the identification of fluoroquinolone-resistant Neisseria gonorrhoeae (MASTER GC) and to compare rapid diagnostic tests for bloodstream infections. The ARLG has initiated a first-in-kind randomized, double-blind, placebo-controlled trial in participants with cystic fibrosis who are chronically colonized with Pseudomonas aeruginosa to assess the pharmacokinetics and antimicrobial activity of bacteriophage therapy. Finally, an engaged and highly trained workforce is critical for continued and future success against antimicrobial drug resistance. Thus, the ARLG has developed a robust mentoring program targeted to each stage of research training to attract and retain investigators in the field of antimicrobial resistance research.

Abstract Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward.