Souli, Maria

ABSTRACT In this secondary analysis of 386 subjects with Gram-negative bacteremia enrolled in the RAPIDS GN trial, rapid antibiotic susceptibility testing had a greater benefit on the management of bacteremia caused by antibiotic-resistant compared to antibiotic-susceptible isolates, especially for Escherichia coli, Klebsiella species , and Proteus species. IMPORTANCE Rapid blood culture diagnostics are costly, and their use has not demonstrated clear clinical benefit for patients with Gram-negative sepsis, possibly because prior trials did not enroll sufficient numbers of patients with antibiotic-resistant infections. This analysis of patients with sepsis previously enrolled in a randomized controlled clinical trial demonstrates that rapid susceptibility testing of bacteria from blood cultures had the greatest impact for patients with antibiotic-resistant infections. Specifically, after rapid testing results were reported, patients infected with resistant bacteria received appropriate antibiotic therapy more quickly than patients with susceptible bacteria. These findings highlight the need to evaluate blood culture diagnostics in areas with high antibiotic resistance where these diagnostics are likely to have the greatest impact.

Abstract Background The RAPIDS GN trial, a prospective randomized controlled trial, showed that rapid blood culture antibiotic susceptibility testing (AST) led to faster antibiotic therapy changes compared to standard of care (SOC) testing for Gram negative bacteremia (Banerjee et al, Clin Infect Dis (2021) 73:e39-e46). A secondary analysis of the data was conducted to assess impact of rapid testing on appropriateness of antibiotic spectrum by pathogen and resistance profile. Empiric treatment (0 to 2 h post randomization) among subjects with antibiotic-susceptible isolates of monomicrobial, on-panel Gram negative species (N = 320). For this analysis subjects from both SOC and rapid testing groups were included. Black: Excluded from treatment definition if subjects received no antibiotics, antibiotics without susceptibility results reported, or only an aminoglycoside, azithromycin, penicillin, rifaximin, or atovaquone. Antibiotic treatment appropriateness for antibiotic-susceptible Escherichia coli, and Klebsiella and Proteus isolates (N= 240) by time after randomization and treatment arm. Black: Excluded from treatment definition if subjects received no antibiotics, antibiotics without susceptibility results reported, or only an aminoglycoside, azithromycin, penicillin, rifaximin, or atovaquone. AXDX, rapid susceptibility testing group. Methods Subjects enrolled in the RAPIDS GN trial who had blood cultures with monomicrobial Gram negative bacilli that were “on-panel” for the rapid test were included. Antibiotics administered from randomization (0 h) through 52 h were evaluated. Antibiotic therapy was classified based on SOC AST as: undertreatment (antibiotic to which the blood isolate was resistant), appropriate treatment (narrowest spectrum antibiotic to which the blood isolate was susceptible), and overtreatment [overly broad-spectrum antibiotic(s) based on blood isolate AST]. Antibiotic-resistant isolates were defined as 3rd generation cephalosporin non-susceptible or carbapenem-resistant isolates. Antibiotic treatment appropriateness for antibiotic-resistant (3rd generation cephalosporin non-susceptible or carbapenem-resistant) Escherichia coli, and Klebsiella and Proteus isolates (N= 50) by time after randomization and treatment arm. Black: Excluded from treatment definition if subjects received no antibiotics, antibiotics without susceptibility results reported, or only an aminoglycoside, azithromycin, penicillin, rifaximin, or atovaquone. AXDX, rapid susceptibility testing group. Results 388/448 (87%) subjects were included (197 SOC, 191 rapid). Among susceptible isolates, between 0 through 2 h post-randomization (before AST results), overtreatment was more common for Escherichia coli, and Klebsiella and Proteus species than for other species (72% vs. 41%, p ≤0.001; Fig 1). Among 290 E. coli, Klebsiella and Proteus isolates, treatment appropriateness improved with time after randomization in both SOC and rapid testing groups. The proportion with appropriate treatment was higher in the rapid testing group than the SOC group at all time points after 24 h post-randomization and differed by resistance. Overtreatment was common for susceptible isolates while undertreatment was common for resistant isolates (Fig. 2 and 3). Among resistant isolates, by 52 h post-randomization undertreatment decreased to 15% in the rapid testing group but only 35% in the SOC group (Fig 3). Conclusion In the RAPIDS GN trial, rapid AST had the greatest benefit on management of antibiotic-resistant E. coli, Klebsiella, and Proteus bacteremia. These findings can inform antibiotic stewardship and design of future blood culture diagnostic trials. Disclosures Ritu Banerjee, MD, Ph.D, bioMerieux: Grant/Research Support|bioMerieux: company is providing partial support for an ongoing trial unrelated to submitted abstract Sarah B. Doernberg, MD, MAS, Basilea: Clinical events committee/adjudication committee participation|F2G: Grant/Research Support|Genentech: Advisor/Consultant|Gilead: Grant/Research Support|Janssen/J+J: Advisor/Consultant|Pfizer: Grant/Research Support|Regeneron: Grant/Research Support|Shinogi: Clinical events committee/adjudication committee participation Robin Patel, MD, Abbott Laboratories: Advisor/Consultant|Adaptive Phage Therapeutics: Grant/Research Support|Adaptive Phage Therapeutics: Mayo Clinic has a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics.|BIOFIRE: Grant/Research Support|CARB-X: Advisor/Consultant|ContraFect: Grant/Research Support|Day Zero Diagnostics: Advisor/Consultant|HealthTrackRx: Advisor/Consultant|Mammoth Biosciences: Advisor/Consultant|Netflix: Advisor/Consultant|Oxford Nanopore Technologies: Advisor/Consultant|PhAST: Advisor/Consultant|See details: Patent on Bordetella pertussis/parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic|See details: continued, patent on an anti-biofilm substance issued|TenNor Therapeutics Limited: Grant/Research Support|Torus Biosystems: Advisor/Consultant|Trellis Bioscience, Inc.: Advisor/Consultant

ABSTRACT Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P . aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP 8 ), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P . aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.

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.

AbstractDeveloping and implementing the scientific agenda of the Antibacterial Resistance Leadership Group (ARLG) by soliciting input and proposals, transforming concepts into clinical trials, conducting those trials, and translating trial data analyses into actionable information for infectious disease clinical practice is the collective role of the Scientific Leadership Center, Clinical Operations Center, Statistical and Data Management Center, and Laboratory Center of the ARLG. These activities include shepherding concept proposal applications through peer review; identifying, qualifying, training, and overseeing clinical trials sites; recommending, developing, performing, and evaluating laboratory assays in support of clinical trials; and designing and performing data collection and statistical analyses. This article describes key components involved in realizing the ARLG scientific agenda through the activities of the ARLG centers.

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.

Abstract The advancement of infectious disease diagnostics, along with studies devoted to infections caused by gram-negative and gram-positive bacteria, is a top scientific priority of the Antibacterial Resistance Leadership Group (ARLG). Diagnostic tests for infectious diseases are rapidly evolving and improving. However, the availability of rapid tests designed to determine antibacterial resistance or susceptibility directly in clinical specimens remains limited, especially for gram-negative organisms. Additionally, the clinical impact of many new tests, including an understanding of how best to use them to inform optimal antibiotic prescribing, remains to be defined. This review summarizes the recent work of the ARLG toward addressing these unmet needs in the diagnostics field and describes future directions for clinical research aimed at curbing the threat of antibiotic-resistant bacterial infections.

Abstract In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.