The Food and Drug Association announces two Oak Ridge Institute for Science and Education (ORISE) fellowship opportunities. If you or  someone you know are interested in these one-year fellowships, please apply by February 26, 2021. The anticipated start date is June, 2021.

• FDA Antibacterial Drug Resistance (DOOR) Fellowship
  • The project will evaluate ordinal endpoints using the desirability of outcome ranking (DOOR) approach for anti-infective clinical trials for indications such as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP), complicated urinary tract infections (cUTI), complicated intra-abdominal infections (cIAI) and acute bacterial skin and skin structure infections (ABSSSI).  Under the guidance of a mentor, the selected candidate will perform analysis of the existing database of recently completed antibacterial drug trials to validate ordinal endpoints using the DOOR approach.
  • Apply at: https://www.zintellect.com/Opportunity/Details/FDA-CDER-2021-0617

• FDA Antibacterial Drug Resistance (cUTI) Fellowship
  • Currently, the primary endpoint for complicated urinary tract infection (cUTI) trials is a composite of clinical and microbiologic outcomes assessed at a fixed time point after completing therapy. In recent clinical trials, it has been noted that while some patients are classified as microbiologic failures due to persistently positive urine culture, however they are doing well clinically such that no further antibacterial therapy is needed. The reasons for this discordance are unclear and need further evaluation. For this project, data from recently completed cUTI trials will be reviewed to assess the degree of discordance between the clinical and microbiologic endpoints, the reasons for the discordance and, based on the data, consideration will be given to revising the endpoint if needed.
  • Apply at: https://www.zintellect.com/Opportunity/Details/FDA-CDER-2021-0618

In October, ARLG co-principal investigator Vance Fowler shared insight from his two decades studying Staphylococcus aureus as part of an IDWeek 2020 lecture titled “Staphylococcus aureus: Lessons Learned from 20 Years with the Persistent Pathogen.” The Finland lecture is awarded each year to someone who has made key contributions in the areas of bacterial pathogenesis, antimicrobial agents, emerging infections, and hospital-acquired infections.

Dr. Fowler began the lecture by discussing his first major lesson: “plans change.” While in residency, he thought his career would be dedicated to studying malaria in East Africa but his mentor, Ralph Corey, MD, suggested he study S. aureus instead. During his residency, he started the S. aureus Bacteremia Group (SABG) that has been central to his career.

“Dream big, start small” was the second major lesson Dr. Fowler highlighted as he described the influential clinical and translational work that has been performed through the SABG over the last 25 years. His group was able to show that patients with S. aureus bloodstream infections now have more comorbidities, higher rates of prosthetic devices, and are more likely to have severe disease with metastatic sites of infection than patients with S. aureus bacteremia 20 years ago. Dr. Fowler discussed how research through the SABG has generated key clinical practice recommendations for treating patients with S. aureus bacteremia. His group led some of the original studies showing the importance of performing echocardiography, consulting infectious diseases, and using the appropriate antibiotics. Each of these interventions was subsequently shown to significantly decrease mortality in patients with S. aureus bacteremia in large datasets and are now considered standard, evidence-based practices.

In the third and fourth major lessons presented, Dr. Fowler shared that even the most thorough bedside evaluation can be limited which is why biorepositories of patient samples can be crucial to answering clinical questions. Dr. Fowler’s lab has been able to use a large biorepository of samples from patients with S. aureus bacteremia to answer important translational question including understanding 1) which patients with S. aureus bacteremia and cardiac devices will develop a cardiac device infection and 2) which patients with methicillin-resistant S. aureus bacteremia will develop persistent bacteremia. Both of these questions were inspired by bedside clinical questions but involved using the biorepository to investigate mechanisms in the pathogen and host response. Dr. Fowler urged other institutions to create similar biorepositories as a way to promote hypothesis-generating and hypothesis-testing research.

Dr. Fowler concluded his lecture by stating that trainees led and published much of the research he presented and emphasized the importance of mentorship. He thanked his mentor, Dr. Ralph Corey, for believing in him and expressed his hope to provide the same support for current infectious diseases trainees.

Article by Jessica Howard-Anderson, MD, MSc

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.

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.