A recent study supported by the Antibacterial Resistance Leadership Group, (ARLG) called The Randomized Clinical Trial Evaluating Clinical Impact of RAPid Identification and Antimicrobial Susceptibility Testing for Gram-Negative Bacteremia (RAPIDS-GN) was recently published in Clinical Infectious Diseases. This is the largest study to evaluate the clinical impact of rapid blood culture diagnostics in the management of patients with Gram-negative bacilli bloodstream infections.

RAPIDS-GN results demonstrate that providing rapid, accurate drug susceptibility information to physicians could improve the care of patients with sepsis, a potentially life-threatening condition caused by the body’s response to an infection.

According to the study’s principal investigator, Ritu Banerjee, MD, PhD, associate professor of pediatrics at Monroe Carell Jr. Children’s Hospital at Vanderbilt, time is of the essence.

“Patients are placed on a standard course of antibiotics when they initially present with possible sepsis,” said Banerjee. “These antibiotics may be ineffective, or conversely, too broad-spectrum. Conventional culture and susceptibility testing methods take days for results to identify the bacteria and drug resistance. Instead of waiting days for results, we can now get them in hours.”

The RAPIDS-GN study receives financial and operations support from the ARLG. The study aligns well with the mission of the ARLG, which is to prioritize, design, and execute clinical research that will reduce the public threat of antibacterial resistance. The ARLG Coordinating Center is housed at the Duke Clinical Research Institute. The study was conducted at the Mayo Clinic and the University of California, Los Angeles.

Banerjee and her ARLG colleagues sought a way to shorten the wait time until the appropriate medication could be started to treat the infection.

RAPIDS-GN, is the first multicenter, prospective, randomized controlled trial to compare the outcomes of patients with Gram-negative bloodstream infections who had blood culture testing with standard-of- care culture and antibiotic susceptibility testing versus rapid organism identification and phenotype antibiotic susceptibility testing.

The study looked at the outcomes of 448 patients — 226 received conventional care while 222 were randomized to the new testing method.

The rapid organism identification and phenotype antibiotic susceptibility testing used the Accelerate Pheno System. Conventional testing can take two to three days before the bacteria in the blood and its drug resistance are fully identified. Utilizing the rapid testing method gave medical teams final results in about 12 hours.

“The time to results was significantly shorter,” said Banerjee. “The median time to the first antibiotic change was 24 hours faster in the rapid testing arm compared to the control arm. We can now tailor the antibiotics more quickly and place patients on pathogen-directed therapy rather than broad-spectrum, empiric therapy.”

“This was a very positive result. It was proof that faster actionable results led to timelier, targeted antibiotic therapy. The hope is that this, in turn, leads to better patient outcomes, less unnecessary broad-spectrum antibiotic use, and less emergence of drug resistant organisms.”

Banerjee also hopes the study results prompt more diagnostic companies to continue the development of platforms that will enable more rapid bacterial identification and resistance detection.

“One of the challenges is the cost of the testing, because rapid testing methods are more expensive than conventional methods,” she said. “The overarching goal is to improve outcomes for patients with sepsis.”

The study was presented during the IDWeek conference on Oct. 3 in Washington, D.C.

The research was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Note: This news item was modified from an original announcement in the VUMC Reporter.

Antimicrobial Agents and Chemotherapy (AAC) announced that Cesar Arias, MD, PhD, will be its new editor in chief starting July 2020. Dr. Arias is part of the ARLG Laboratory Consortium team. He has received international recognition for his work conducting basic, translational and clinical research on antibiotic resistance.

The AAC is an American Society for Microbiology (ASM) journal that covers interdisciplinary studies that increase knowledge of underlying mechanisms and therapeutic applications of antimicrobial and antiparasitic agents and chemotherapy. Dr. Arias has served as an AAC editorial board member since 2009 and an editor since 2014.

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The World Health Organization (WHO) currently classifies carbapenem-resistant Enterobacterales (CRE) as one of the top three most dangerous multidrug-resistant pathogens. With the incidence of infections from CRE increasing dramatically since the first reported case in 1996, it is considered a significant public health threat. The Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae 2 (CRACKLE-2) Study was designed to provide additional observational data to help design future randomized clinical trials on both therapeutics and diagnostics for multi-drug resistant organism (MDRO) infections.

The multi-center study conducted in in 42 U.S. hospitals collected clinical and epidemiological data on patients with MDRO isolated from clinical cultures during hospitalization. The study’s primary outcome measure was desirability of outcome ranking (DOOR) at 30 days after index culture. Study personnel also recorded epidemiological information on patients that included identifying potential clinical trial enrollment barriers as well as data on the patient outcomes resulting from various antimicrobial treatment regimens.

Study researchers further detailed information on MDRO species, strain type, and mechanism of carbapenem resistance. Since not all diagnostics detect and not all therapeutics are active against the same mechanism of carbapenem resistence, this understanding of the molecular characteristics of carbapenem resistance of the causative CRE will further inform upcoming clinical trial design.

Initially, study personnel expected the study data would show two subsets of CRE, carbapenemase-producing Enterobacterales and non-carbapenamase-producing Enterobacterales. However, a novel subset of CRE was identified comprised of Centers for Disease Control (CDC) defined CRE. It consisted of unconfirmed CRE initially reported as CRE but susceptible to carbapenems in two central laboratories. Unexpectedly, clinical outcomes were similar between patients with all three subsets of CRE.

Carbapenemase-producing Enterobacterales have been the focus of most anti-CRE dedicated efforts. This is primarily based on their extensive resistance profile and the ability of these resistance mechanisms to spread from one bacterium to the other and from one patient to the other.

The unexpected finding that outcomes were similar among patients infected with any of these subsets illustrates that any patient diagnosed with CDC-defined CRE is at risk for poor outcomes. Overall, 24% of infected patients died within 30 days of first positive culture for CRE. Of patients who survived and were discharged, almost half were readmitted to the hospital within 90 days. This illustrates that CRE that do not produce carbapenemases are also clinically important. They are a more genetically diverse group and any intervention targeting the spread of these organisms would likely be more general. Examples of such interventions may include antimicrobial stewardship and improved hand hygiene.

The sites that participated in CRACKLE-2 are now part of ARLG’s international MDRO Network dedicated to studying antimicrobial resistance. Work is underway with similar studies on carbapenem-resistant Acinetobacter baumannii and carbapenem-resistant Pseudomonas aeruginosa. In addition, the first manuscript describing the CRE epidemic in the U.S. compared to other parts of the world is in progress. Next the MDRO Network will implement follow-up clinical trials based on CRACKLE-2 therapeutics and diagnostic data.

Review this tool to interact with the summary data from CRACKLE-II.

Read the full publication.

Finding better ways to combat resistant gram-negative bacterial infections remains an ongoing challenge for health care practitioners and researchers alike. One way ARLG’s Gram-Negative Committee meets this challenge is by regularly reviewing and implementing innovative, early-stage study ideas.

Currently, the committee is seeking interventional study ideas that aim to fill the most critical knowledge gaps and have the largest impact on clinical practice. All ideas are welcome, but some areas of interest include the optimum therapy (agents, dose, duration, interval, type of administration, clinical algorithms) and its impact on efficacy, clinical outcomes, and prevention of resistance.

Synopses should be no more than a half page (250 words) in length. The deadline for idea submissions is March 31.

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In February, ARLG investigators Ritu Banerjee, M.D., Ph.D., Melinda Pettigrew, Ph.D., and committee member Kerry LaPlante, Pharm.D., gathered in Washington D.C. as ambassadors of PEW Charitable Trust’s annual Stand Up to Superbugs initiative.

The goal of the initiative is to meet with state representatives and public officials to raise awareness of the growing public health threat of antibiotic resistance. Key messages focus on the need for increased antibiotic development and innovation, the proper use of antibiotics, and increased funding to combat the issue.

More than 40 ambassadors took part in the initiative from various occupations including health care professionals, public health officials, scientists, farmers, and veterinarians as well as individuals who have had personal experiences with antibiotic resistance.

Read more about the initiative.

Robert A. Bonomo, MD, of the Louis Stokes Cleveland VA Medical Center, is the 2020 recipient of the Wolcott Award for Excellence in Clinical Care Leadership. The Wolcott Award recognizes outstanding clinical practitioners who have made monumental contributions to the practice of medicine in the VA healthcare system. It is the most prestigious clinical award for VA clinicians.

An ARLG study sheds light on the feasibility of antibiotic stewardship programs in small, community hospitals that have limited resources.

The DICON I study refers to the Duke Infection CONtrol Network that provides access to the community hospitals doing research. Led by Deverick Anderson, M.D., director of the Duke Center for Antimicrobial Stewardship and Infection Prevention, the study included four community hospitals in North Carolina. The results published in JAMA Network Open demonstrated an approach that could be expanded to the nation’s wider network of small hospitals, where more than half of the U.S. population accesses care.

“This is a matter of major consequence, because up to 50 percent of antibiotic use in our study was inappropriate, meaning there was a better choice or the prescription was simply unnecessary,” said Anderson.

Anderson and colleagues partnered with the community hospitals in North Carolina to explore how best to perform active, CDC-recommended stewardship interventions using existing hospital resources.

“We have to develop systems that are scalable and effective in helping reduce the improper or needless use of antibiotics at every level,” Anderson said, noting that overuse of these critical drugs has led to the spread of deadly superbugs that are resistant to previously effective treatments.

Two strategies were tested using hospital pharmacists as designated stewards. In one strategy, pharmacists were enlisted as the gatekeepers for antibiotic use, giving pre-approval to doctors before the drugs could be prescribed to patients.

The pre-approval aspect was quickly determined to be too difficult, because doctors wanted the flexibility and autonomy to manage their patients. Instead, a modified approach was adopted, in which doctors could prescribe the first dose of antibiotic, but that was followed by a pharmacist review.

The second tested strategy involved a post-prescription audit, where pharmacists reviewed the effectiveness of the antibiotic to determine whether it should be continued or changed after the patient received the antibiotic for three days.

All four hospitals participated in both interventions for six months, covering a total of nearly 2,700 patients.

The study found that pharmacists at the four participating hospitals performed 1,456 modified prescription approvals and 1,236 post-prescription audits. Study antimicrobials were determined to be inappropriate two-times as often under the post-prescription audit strategy compared to the modified pre-approval strategy.

Overall antibiotic utilization decreased under the audit system compared to historical controls, but the modified prescription authorization intervention did not reduce the use of antibiotics.

“Even modest decreases in antimicrobial utilization are valuable, particularly when potentially achievable in the more than 3,000 community hospitals in the U.S.,” Anderson said. “This study suggests there are approaches that can work, even in hospitals where resources might be limited.”

In addition to Anderson, study authors include Shera Watson, Rebekah W. Moehring, Lauren Komarow, Matthew Finnemeyer, Rebekka M. Arias, Jacqueline Huvane, Carol Bova Hill, Nancie Deckard and Daniel J. Sexton, along with the Antibacterial Resistance Leadership Group.

The study received support from the Antibacterial Resistance Leadership Group supported by the National Institute of Allergy and Infectious Diseases, which is part of the National Institutes of Health (UM1AI104681).

Note: Content for this article originally appeared in an announcement on Duke Health.