ARLG study helps physicians rapidly determine whether antibiotics will be effective against certain bacterial infections

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) 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.

ARLG at IDWeek 2019

Are you attending IDWeek 2019? Connect with your ARLG colleagues at the following sessions, oral presentations, and posters.

Sessions
Day Time Session Title Presentation Title Moderators Speakers
10/2/2019 1:30-1:55 pm What’s Hot in ID and HIV What’s Hot in ID Clinical Science Cesar Arias Helen Boucher
10/2/2019 3:45-5:15 pm Opening Plenary Session: From Outbreaks to –Omics: Revolutionizing the Infectious Diseases Landscape in the Age of Big Data Cesar Arias
10/3/2019 8:05-8:20 am The Big Idea: Making the Case to Policymakers for ID and HIV Priorities The Big Idea IDSA-HIVMA Advocacy Hill Day: Lessons Learned Sarah Doernberg, Buddy Creech (panelists)
10/3/2019 9:15-10:00 am Edward H. Kass Lecture: Epidemic Infectious Diseases and Creation of the Infectious Diseases Discipline. Cesar Arias
10/3/2019 10:30-11:45 am Diagnostic Clinical Cases Kimberly Hanson (interactive moderator) Robin Patel (panelist)
10/3/2019 10:30-11:45 am We’re Part of the Problem: How ID Killed Antibiotic Development Helen Boucher, Vance Fowler Helen Boucher
10/3/2019 10:30-11:45 am Behavioral Approaches to Antibiotic Stewardship Ebbing Lautenbach
10/3/2019 10:55-11:20 am Clinical Trials that Might Change your Practice Clinical Trials in Bacterial Diseases that Might Change your Practice David van Duin
10/3/2019 11:20-11:45 am Help or Hype? Update on Biomarkers in Management of Adult and Pediatric Infectious Diseases The Next Generation of ID Host Response Biomarkers Ephraim Tsalik Ephraim Tsalik
10/3/2019 12:15- 12:45 pm Rapid Fire Poster Session: Antimicrobial Resistance Pranita Tamma
10/3/2019 12:15- 12:45 pm Rapid Fire Poster Session: Diagnostics Patricia Simner
10/3/2019 1:45-2:10 pm Antimicrobial Stewardship in Compromised Hosts Antimicrobial Stewardship in Solid Organ Transplant Patients Judith Anesi
10/3/2019 1:45-3:00 pm Applying Contact Precautions: What’s the Best Approach to Reduce Transmission? Ebbing Lautenbach
10/3/2019 2:35-3:00 pm Head Scratching Cases of MDR Gram-Negatives Other than Enterobacteriales Acinetobacter baumannii Yohei Doi,

Cesar Arias

Anthony Harris
10/3/2019 2:35-3:00 pm Who Owns Sepsis Anyway? Sepsis and Antimicrobial Stewardship: Right Drug, Right on Time Deverick Anderson
10/3/2019 3:15-4:30 pm Clinical Controversies Oral Therapy for Uncomplicated S.aureus Bacteremia Vance Fowler
10/4/2019 8:00-9:00 am Meet the Professor

Cefazolin vs Nafcillin for MSSA Infections: Pro- Con Debate

Cefazolin vs Nafcillin for MSSA Infections: Pro- Con Discussion Sarah Doernberg
10/4/2019 10:30-11:45 am Phages to the Rescue Yohei Doi,

Cesar Arias

10/4/2019 10:30-11:45 am Tackling the Big Beasts of Healthcare Epidemiology Ebbing Lautenbach
10/4/2019 10:30-11:45 am Pathogenesis and Inflammatory Response Robert Bonomo
10/4/2019 1:45-3:00 pm Big Beasts I Samuel Shelburne
10/4/2019 1:45-3:00 pm Emergent Mechanisms of Resistance and How to Prevent Them Amy Mathers
10/4/2019 1:45-3:00 pm Innovative Diagnostics Robin Patel
10/4/2019 1:45-2:04 pm Hot Topics in Pediatric Infectious Diseases Hot Topics in Pediatric Infectious Diseases-Speaker 1 Ritu Banerjee
10/4/2019 3:15-4:30 pm Challenging Cases in Infectious Diseases Henry F. Chambers
10/4/2019 3:15-4:30 pm Cutting Edge in Pediatric Osteomyelitis: Basic Scientist, ID Clinician, and Orthopedist Pranita Tamma
10/5/2019 8:00-9:00 am Meet the Professor

Registration Trials versus Clinical Practice: Challenges Associated with Newly Approved Antimicrobials

Yohei Doi,

Cesar Arias

10/5/2019 10:30-11:45 am Novel Antimicrobials and Approaches Against MDR Organisms Jose Munita
10/5/2019 2:10-2:35 pm The Etiology of Community Acquired Pneumonia: How Appropriate are Current Guidelines? New Diagnostic Platforms and Antibiotic Use in Community Acquired Pneumonia Sara Cosgrove
10/5/2019 3:15-4:30 pm This Year’s Innovations in Pediatric Infectious Diseases Buddy Creech
10/5/2019 3:15-4:30 pm Diagnosis and Management of Cryptococcal Meningitis Jose M. Miro
10/5/2019 3:15-4:30 pm Mechanistic Basis of Action and Resistance of B-lactam/B-lactamase Inhibitors Yohei Doi
10/5/2019 3:15-4:30 pm Opportunistic Infections in the ICU: From Pathophysiology to Practical Approaches Samuel Shelburne
10/5/2019 3:15-4:30 pm Fungi: Blood, Sweat, and Genes Cornelius Clancy
10/5/2019 4:45-5:15 pm Maxwell Finland Lecture Prosthetic Joint Infection: Bedside to Bench, Bath Sonication and Beyond Robin Patel
10/6/2019 8:00-9:00 am Hot Topics in Outpatient Antimicrobial Therapy of Infective Endocarditis Jose M. Miro
10/6/2019 9:15-10:45 am Closing Plenary Session: All About Vaccines: The Individual, the Community, the World Cesar Arias

 

 

 

Oral Presentations
Day Time/Room Number/Title Speakers
10/3/2019 2:45-3:00 pm/144ABC 841-Implications of C. difficile Treatment on Environmental Contamination: A Randomized, Controlled Trial with Microbiologic, Environmental, and Molecular Outcomes Nicholas A Turner, Maria Gergen, William A Rutala, Daniel J Sexton, Vance G Fowler, Rachel Addison, Deverick J Anderson
10/4/2019 3:30-3:45 pm/147AB 1878-Impact of Antibiotic Stewardship Rounds in the Intensive Care Setting: a Prospective Cluster-Randomized Crossover Study Jessica Seidelman, Nicholas A. Turner, Rebekah Wrenn, Christina Sarubbi, Deverick J. Anderson, Daniel J. Sexton, Rebekah Moehring
Posters
Day Time Number/Title Authors
10/3/2019 12:15-1:30 pm

12: 35 – 12:40 pm: A brief oral presentation will be given in the Poster/Exhibit Hot Zone area.

 

640-Randomized clinical trial evaluating clinical impact of RAPid IDentification and antimicrobial Susceptibility testing for Gram Negative bacteremia (RAPIDS-GN) Ritu Banerjee, Lauren Komarow, Abinash Virk, Nipunie Rajapakse, Audrey Schuetz, Brenda Dylla, Michelle Earley, Judith Lok, Peggy Kohner, Sherry Ihde, Nicolynn Cole, Lisa Hines, Katelyn Reed, Omai Garner, Sukantha Chandrasekaran, Annabelle de St. Maurice, Meganne Kanatani, Jennifer Curello, Rubi Arias, William Swearingen, Sarah Doernberg, Robin Patel, and the Antibacterial Resistant Leadership Group
10/3/2019 12:15-1:30 pm 636-Genome Epidemiology of Carbapenem-Resistant Acinetobacter baumannii in the United States Alina Iovleva, Mustapha M Mustapha, Eric Cober, Sandra Richter, Cesar Arias, Jesse Jacob, Robert Salata, Michael Satlin, Darren Wong, Robert Bonomo, David van Duin, Yohei Doi
10/3/2019 12:15-1:30 pm 498-High burden of CRO colonization and its association with infection among patients transferred to a tertiary care hospital in India Smita Sarma, Matthew Robinson, Yatin Mehta
10/3/2019 12:15-1:30 pm 625-Genomic Epidemiology of Carbapenem-Resistant Enterobacteriaceae from Colombia: A Prospective Multicenter Study Jinnethe Reyes, Lorena Díaz, Lina P. Carvajal, Rafael Rios, Lina V. Millán, Aura M. Echeverri, Angie K. Hernandez, Sandra Vargas, Soraya Salcedo, Adriana Marin, Laura Mora, Karen Ordoñez Diaz, Edilberto Cristancho Quintero, Sandra Valderrama, Beatriz Elena Ariza, Gloria Cortes, Laura Rojas, Henry F. Chambers, Vance G. Fowler, Barry Kreiswirth, Maria V. Villegas, Robert Bonomo, Blake Hanson, David van Duin, Cesar A. Arias
10/3/2019 12:15-1:30 pm 508-Gentamicin Non-susceptibility is Associated with Persistence of Carbapenem-Resistant Klebsiella pneumoniae in the Urinary Tract Courtney L. Luterbach, Heather Henderson, Eric Cober, Sandra Richter, Robert Salata, Keith Kaye, Yohei Doi, Richard Watkins, Robert Bonomo, David van Duin
10/04/2019 12:15-1:30 pm 1330-Evaluation of Multiple Host Response-Based Strategies to Classify Acute Respiratory Illness Melissa Ross, Ricardo Henao, Thomas Burke, Micah McClain, Geoffrey Ginsburg, Christopher Woods, Ephraim Tsalik
10/5/2019 12:15-1:30 pm 2276-Clinical Epidemiology of The Carbapenem-Resistant Enterobacteriaceae Epidemic in Colombia: A Multicenter Prospective Study Sandra Valderrama-Beltran, Lauren Komarow, Soraya Salcedo, Laura Mora, Adriana Marin, Karen Ordoñez Diaz, Edilberto Cristancho Quintero, Beatriz Helena Ariza, Gloria Cortes, Alejandro de La Hoz, Jose Oñate, Elsa Yasmin Vente, Viviana Mendez, Jairo Figueroa, Luz M. Osorio, Carlos Moreno, Jinnethe Reyes, Luis Dulcey, Christian Pallares, Henry Chambers, Vance G. Fowler, Scott Evans, Barry Kreiswirth, Maria V. Villegas, Robert Bonomo, David van Duin, Cesar A. Arias

Update from the Pharmacokinetics Special Emphasis Panel


Chair, Pharmacokinetics Special Emphasis Panel
Thomas Lodise, Pharm D, PhD
Albany College of Pharmacy and Health Sciences
Professor, Department of Pharmacy Practice

The Pharmacokinetics Special Emphasis Panel (PK SEP) is dedicated to enhancing our current understanding of antimicrobial exposure-response relationships in patients with invasive infections. Similar to other ARLG special emphasis panels and committees, the PK SEP supports the mission of the ARLG by reviewing proposals, assigning scientific merit scores, and serving as a resource in prioritizing the network’s scientific agenda. The panel’s purpose is to ensure that state-of-the-art pharmacokinetic/pharmacodynamic (PK/PD) methods are used to design innovative pharmacologic strategies that optimize the utility of the existing antibacterial agents in our armamentarium for implementation into clinical practice.

The PK SEP concentrates on development of innovative dosing regimens for antibacterial agents prioritized by the U.S. Centers for Disease Control and Prevention (CDC), U.S. Food and Drug Administration (FDA), and the National Institutes of Health (NIH) to combat antibacterial resistance. In addition, the PK SEP is most interested in identifying optimal dosing schemes for patient populations typically underrepresented in Phase III clinical trials, but likely to be encountered in clinical practice.

With support from the PK SEP, the ARLG is pioneering practice-changing research. Panel chair, Tom Lodise, PharmD, PhD, highlights three studies below:

PROVIDE: Prospective Observational Evaluation of the Association between Initial Vancomycin Exposure and Failure Rates among Adult Hospitalized Patients with MRSA Bloodstream Infection.
Recently published in Clinical Infectious Diseases, PROVIDE was a multi-center prospective study to evaluate the relationship between day-2 vancomycin exposure profiles and outcomes in patients infected with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia.Vancomycin is the most commonly administered antibiotic in United States hospitals and has been a mainstay for treatment of MRSA infections for decades, yet optimal dosing of vancomycin is unclear. For serious MRSA infections, current guidelines recommend targeting an area under the concentration time curve to minimum inhibitory concentration ratio (AUC/MIC) ≥400. Despite widespread clinical adoption of these recommendations, optimal exposure targets remain controversial.

The study took place in 14 hospitals across the United States. The primary outcome was treatment failure, defined as 30-day mortality or a positive blood culture at ≥7 days. Secondary outcomes included acute kidney injury (AKI), defined as a ≥1.5-fold increase in serum creatinine. Of the 265 eligible patients, treatment failure occurred in 18% and AKI in 26% of patients. Overall, higher day-2 vancomycin exposures for patients with MRSA bacteremia were not associated with a lower incidence of treatment failure but were associated with higher rates of AKI.  Patients with day 2 area under the curve (AUC) exposures ≤515 experienced the best global outcomes (no treatment failure and no AKI).

The results from PROVIDE have important implications for clinical practice and indicate that clinicians should reassess the balance of benefits and risks of targeting higher day-2 exposures for patients with MRSA bacteremia.  Most importantly, the findings suggest that vancomycin dosing should be guided by the AUC and day-2 AUCs should be maintained below 515 to maximize efficacy and minimize risk of AKI. Moving forward, further study is needed to define the lower bound of the therapeutic range

PROVIDE results heavily informed the draft vancomycin consensus guidelines by the American Society of Health-System Pharmacists ASHP. Based in large part on PROVIDE, the guidelines now recommend monitoring vancomycin AUCs vs. troughs in clinical practice.

ACUMIN: Acute Care Unit Minocycline

The ACUMIN study is examining the PK of intravenous (IV) minocycline in critically-ill patients with Gram-negative infections in the intensive care unit (ICU). Minocycline is a tetracycline derivative first approved in the United States as both oral and IV formulations in the 1970s. A new IV formulation of minocycline became available in 2015 and is approved by the FDA for the treatment of patients with infections due to Gram-positive and Gram-negative pathogens, including Acinetobacter baumannii.

A. baumannii is a healthcare-associated pathogen and a major cause of pneumonia, bacteremia, and wound infection among critically ill patients. A. baumannii is intrinsically resistant to many commercially available antibiotics. It also has a remarkable capacity to develop resistance to commonly used antibiotics like carbapenems, aminoglycosides, and fluoroquinolones. As a result, the terms ‘multi-drug resistant (MDR)’ and ‘extensively drug resistant’ are often used to characterize the different patterns of resistance exhibited by A. baumannii. Infections due to MDR A. baumannii is a growing world-wide problem and is classified as a serious public health threat by the CDC. Fortunately, minocycline is highly active against A. baumannii, including MDR strains, and is well tolerated, making it a potential treatment option for MDR A. baumannii infections.

While there is longstanding clinical use experience with minocycline in patients, PK studies are limited and were conducted in the 1970s in healthy volunteers. In addition, no published minocycline PK data exists in critically ill patients staying in the ICU.

ACUMIN is designed to address this PK knowledge gap by developing a population PK model to describe the plasma exposure profile of minocycline in ICU patients following a single 200-mg IV infusion over 60 minutes. Results of ACUMIN will inform optimal dosing of minocycline in the critically ill patient population. More importantly, this study will determine if dosing adjustments for the approved FDA minocycline dosing regimen are needed based on weight and estimated renal function. ACUMIN enrollment is complete and data analyses will start in fall 2019.

COMBINE: Efficacy and Safety of Ceftazidime-Avibactam in Combination with Aztreonam

COMBINE focuses on the use of ceftazidime-avibactam in combination with aztreonam (ATM) for patients with metallo-β-lactamase (MBL) – producing Gram-negative infections. Metallo-β-lactamases are carbapenemases and have the ability to inactivate all β-lactams except ATM. Infections due to MBL-producing Gram-negative bacteria (GNB) are increasing worldwide and are a major public health concern as there are limited treatment options available. Furthermore, none of the recently approved antibiotics have notable activity against MBL-producing GNB. Several antibiotics with activity against MBL-producing GNB are being developed, but none are anticipated to be available until at least 2021. This underscores the demand of redeploying our existing agents in innovative ways to meet the needs of patients today.

One strategy that is serving as a “bridge” treatment for MBL-producing GNB infections is ceftazidime-avibactam (AVYCAZ) combined with ATM. Although the precise mechanism of improved bacterial killing activity with AVYCAZ combined with ATM is not completely understood, it is likely attributable to maximal saturation of the diverse penicillin binding proteins present in GNB, flooding of periplasm with β-lactams, and maximal binding of available β-lactamases.  Aztreonam is not inactivated by MBLs but many MBL-bearing GNB co-harbor extended spectrum beta-lactamases (ESBLs) that inactivate ATM. In the combination of ATM with AVYCAZ, AVI inhibits the ESBLs and other beta-lactamases that are often present in MBL-producing GNB, allowing ATM, which is unaffected by MBLs, to effectively bind to its target site of action (i.e., bacterial penicillin binding proteins).

Before uniform adoption of this treatment, it is critical to identify the optimal combination of AVYCAZ with ATM regimens associated with maximal efficacy and safety due to the potential of cumulative toxicity from use of two beta-lactam antibiotics simultaneously. To identify the optimal treatment regimens, an in-vitro PK/PD study using the hollow fiber infection model (HFIM) system was conducted to determine the optimal AVYCAZ combined with ATM treatment regimens that result in maximal bacterial kill and resistance suppression. The HFIM studies were selected to determine optimal combination regimens as they are an integral part of the drug development process and are used to inform dose and schedule selection for Phase III clinical trials. They are particularly useful in situations when there are limited clinical data available to define optimal therapy, especially when there is interest in studying humanized drug exposure profiles, treatment durations, and starting bacterial burdens that mirror clinical practice.

In these HFIM experiments the two combination regimens that showed maximal bacterial killing and resistance suppression over 7 days were:

  • AVYCAZ 2.5 g IV as a 2-hour infusion every 8 hours combined with ATM 2g IV as a 2-hour infusion every six hours, and
  • AVYCAZ combined with ATM, each administered as a continuous infusion (CI) (AVYCAZ 7.5 g/day CI combined with ATM 8g/day CI).

The ARLG, in consultation with the PK SEP, believe it is of paramount importance to establish the safety and PK of these regimens in humans. Although AVYCAZ and ATM appear to be safe and well-tolerated, there are no available data on safety when these antibiotics are used in combination. Mild-to-moderate elevations in liver enzymes are common with ATM; however, these elevations are usually self-limiting and do not require ATM discontinuation. It is unclear if AVYCAZ combined with ATM will further exacerbate liver enzyme elevations or lead to other adverse events due to the potential of cumulative toxicity from dual-β-lactam treatment. There are also no published PK data of these antibiotics when administered concurrently, and it is therefore unknown if use of these agents in combination will lead to an altered PK profile of each agent due to inhibition of renal or other compensatory clearance mechanisms. Therefore, a Phase I study using healthy volunteers was launched to assess the safety and PK profile of AVYCAZ combined with ATM relative to its standalone counterparts.

This Phase I study is currently underway at the Duke Early Phase Clinical Research Unit. It is an open-label, single center study in 48 healthy adult male and female participants age 18-45 years old. Eligible subjects are admitted to the Phase I unit and assigned into one of six dosing cohorts. Four treatment cohorts are single-agent dosing cohorts and include AVYCAZ per label dosing, AVYCAZ as a CI, ATM per label dosing, and ATM as a CI. Single-drug treatment cohorts are being conducted to collect baseline safety and PK data. The remaining two cohorts are the two optimal AVYCAZ combined with ATM regimens identified from the HFIM experiments. Participants will stay in the study unit for a minimum of one week. Cohorts 1-4 will be completed prior to Cohorts 5 and 6.

Safety is being closely monitored using daily assessments of adverse events, vital signs, and clinical laboratory safety tests. Serial blood and urine samples are being collected for PK evaluation.  The target completion for enrollment is December 2019 with data analysis completed in early 2020.

 Future Plans

As ARLG moves forward, the PK SEP will continue to support the mission of the ARLG by reviewing proposals, assigning scientific merit scores, and serving as a resource in prioritizing the ARLG scientific agenda. The panel will continue to ensure that the best PK/PD methods are used to derive optimal treatment strategies with maximal efficacy and safety for implementation into clinical practice. The SEP will also work to ensure the populations most likely to be encountered in clinical practice are included when designing future studies.

ARLG Leaders Recognized as Experts in Staphylococcus aureus and Bacteremia by Expertscape

Congratulations to the ARLG’s co-principal investigators, Vance Fowler, MD, MHS, Duke University, and Henry “Chip” Chambers, MD, UCSF, as well as a number of other ARLG investigators who have been recognized as world experts in Staphylococcus aureus by Expertcape.

In addition, Dr. Fowler  was recognized as the number one world expert in bacteremia by Expertscape. Other ARLG leaders, such as Robert Bonomo, MD, David Paterson, MD, Ralph Corey, MD, and Tom Holland, MD, ranked high on the list.

 

 

Robert Bonomo, Antibiotic Resistance Expert, Awarded Distinguished University Professorship

Congratulations to Robert Bonomo, MD, ARLG Laboratory Center Co-Director, who was named a Distinguished University Professor at Case Western Reserve University (CWRU) during its fall convocation on August 28, 2019. CWRU awards the title of “Distinguished University Professor”— a permanent, honorific title, to acknowledge contributions of full-time, tenured faculty with exceptional records of research, scholarship, teaching, and service.

Bonomo, a professor of medicine, pharmacology, molecular biology, and microbiology at the CWRU School of Medicine, has dedicated his research career to addressing the mounting problem of antibiotic resistance. “Infections previously brought under control can resurface in resistant and more virulent new forms,” he said, “allowing disease to proliferate — potentially unchecked.”

Among his investigations, Bonomo works to uncover the genetic and amino acid determinants of bacterial enzymes that create multi-resistance to such widely used antibiotics as penicillins and cephalosporins. Nailing down these sequences and using an integrated approach can lead to new medications that overcome the antibiotic resistance, and his work is paying off. Because of his collaboration with colleagues at CWRU and elsewhere, five new antimicrobials have been approved to date. “We’re always trying to stay a step ahead of the bacteria,” he said. “Evolution rewards organisms that adapt to their environments, including those that fend off antibiotics, so there is a fundamental natural mechanism that we have to overcome.” Bonomo said his teaching and mentoring are as meaningful to him as his research. “Providing intellectual prep for the next generation helps ensure that future patients live longer, healthier lives,” he said. “Nothing can be more crucial than that.”

Read the complete article from CWRU.

ARLG Study Employs Innovative Model to Test Diagnostics for Extragenital Gonorrhea and Chlamydia

arlg1.png
Vance Fowler, MD, MHS

Molecular diagnostic assays have transformed the field of infectious diseases, allowing for swift and sensitive detection of organisms previously challenging to diagnose, but it can be difficult to study how these new tests perform. Members of the Antibacterial Resistance Leadership Group (ARLG), which is facilitated by the Duke Clinical Research Institute, recently conducted a study of several assays used to detect Neisseria gonorrhea and Chlamydia trachomatis. They say their latest research will help to quell the transmission of these infections and could change the landscape for how diagnostic tests are studied.

Prior to this study, there were no diagnostic tests approved by the U.S. Food and Drug Administration (FDA) for determining the presence of extragenital gonorrhea, despite recommendations from the U.S. Centers for Disease Control and Prevention for screening in certain populations, said the DCRI’s Vance Fowler, MD, MHS, (pictured), co-principal investigator for the ARLG.  As a result, few laboratories offered testing and clinicians lacked an FDA cleared diagnostic test. Lack of testing can result in the continued spread of the bacteria that cause chlamydial and gonorrheal infections, including infections from drug-resistant strains..

“Accurate diagnostics that are more readily available will result in better detection and timely treatment, which could help to slow the rise of antibiotic resistance,” Fowler said. “Diagnosis is a major problem in antibacterial resistance, and gonorrhea has been identified by the U.S. Centers for Disease Control and the World Health Organization as a concerning bacterium with rapidly emerging resistance.”

Investigators collaborated with the National Institute of Allergy and Infectious Diseases (NIAID), the FDA, Cepheid, and Hologic on this unique study design that incorporated simultaneous testing of samples from a single patient’s pharynx and rectum on multiple diagnostic platforms. Results from this simultaneous testing were incorporated into a reference, or gold standard, that could then be used to assess whether each of the diagnostic platforms correctly diagnosed extragenital gonorrhea and chlamydia.

After establishing the reference standard, the study team conducted a clinical trial that enrolled more than 2,500 patients. The study tested a new design that allowed evaluation of multiple diagnostics from different companies simultaneously. “This idea came from the work I do in my investigative lab, where we often reuse the same clinical samples to answer multiple questions,” Fowler said. “I began to realize that the same idea could be applied to evaluating new diagnostics — if we could test multiple diagnostics on the same patient enrolled into a single trial, we could potentially reduce costs associated with enrolling multiple patient cohorts. This is about enhancing pragmatism in the diagnostic space.”

In 2014, Fowler presented the concept of “one patient, more than one diagnostic” at a meeting sponsored by the National Institutes of Health. Evaluating diagnostics for extragenital gonorrhea was a way to test this strategy. Fowler relied on the sexually transmitted infection expertise of his ARLG colleague and primary investigator of the project, Jeffrey Klausner, MD, MPH, from the University of California-Los Angeles. On May 23, 2019, two of the devices evaluated in this study received FDA clearance for use to detect pharyngeal and rectal gonorrhea and C. trachomatis, the first two devices approved for this indication.

Fowler sees wide applications for the design and believes the same technique of testing multiple diagnostics simultaneously could be used in many other conditions, such as urinary tract infections, bloodstream infections, and pneumonia. This process could also benefit companies developing diagnostics in several ways. First, the cost of enrolling patients into a Master diagnostic trial would be only a fraction of the conventional approach. Next, each company would ultimately receive the trial data relevant to their platform along with the reference standard for submission to the FDA for clearance of their diagnostic platform.

“Employing a platform such as this could enhance and facilitate the ability to develop and ultimately commercialize new diagnostic platforms, providing clinicians with more informed decision making in managing patients with infections caused by multi-drug resistant bacteria,” Fowler said.

The ARLG develops, designs, implements, and manages a clinical research agenda to increase knowledge of antibacterial resistance. It aims to advance research by building transformational trials that will change clinical practice and reduce the impact of antibacterial resistance. The ARLG is facilitated by the DCRI and works under the centralized leadership of an executive committee and two principal investigators: Fowler and Henry ‘Chip’ Chambers, MD, of the University of California, San Francisco.

Other authors that collaborated on this study include Sarah Doernberg, MD,MAS, of the University of California-San Francisco.

Research reported in this article 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.

ARLG Joins Forces with COMBACTE on a Number of Initiatives Designed to Fight Drug-resistant Infections

April 13, 2019 – The ARLG and COMBACTE will work together on a number of initiatives designed to fight drug-resistant infections.

The U.S.-based Antibacterial Resistance Leadership Group (ARLG), part of the Duke Clinical Research Institute (DCRI) and the University Medical Center (UMC) Utrecht, the managing entity of the COMBACTE (Combatting Bacterial Resistance in Europe) consortium, will work together to solidify a comprehensive global community to combat the threat of antibiotic resistance around the world.

This collaboration is expected to take several forms, including joint design and implementation of clinical research, working meetings at scientific conferences like the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), and IDWeek, cross-entity working groups with diverse functional group participation, clinical trial innovations, data and protocol exchanges, and, contractual, regulatory, and systems harmonization.

“We at the ARLG have long admired the work being done by COMBACTE to increase the efficacy of antimicrobial drug development,” said Vance Fowler, MD, an investigator at the DCRI and co-principal investigator of the ARLG. “Combining our efforts will allow us to maximize the work we both do to stop the advancement of antibacterial resistance.”

Both organizations have been working toward the same mission since each launched in 2013, and now, the two groups will share their work to increase synergy and avoid duplicative efforts in clinical research.

“We have already made efforts to expand our reach across Europe, where an increasing number of people suffer from infections caused by antibiotic-resistant bacteria,” said Marc Bonten, MD, coordinator of COMBACTE and a professor at UMC Utrecht. “But by collaborating and sharing our progress with the ARLG, we can make a truly global impact beyond this population — an important consideration in a globally connected era in which epidemics travel across oceans quickly.”

As part of the agreement, the ARLG will have the opportunity to lead and coordinate U.S.-based studies for all clinical research initiated by COMBACTE, while COMBACTE will have the opportunity to lead and coordinate ARLG-initiated projects in Europe.

The full release can be found here.

 

ARLG at ECCMID

Support your ARLG colleagues who will be presenting at the 29th European Congress of Clinical Microbiology & Infectious Diseases (ECCMID) in Amsterdam, Netherlands from April 13-16, 2019.

Date/ Time Session Title Presenter (Chair or Moderator noted) Topic (if presenter) Place
Saturday, April 13 13:30 – 14:30 Antibacterial activity of unusual combinations Barry Kreiswirth Multifactorial treatment approaches targeting carbapenem-resistant and hypervirulent Klebsiella pneumoniae Arena 2
Saturday, April 13 14:45 – 15:45 Clinical Trials with recently approved or late- stage development antibiotics Thomas Holland An efficacy analysis by lesion size of iclaprim versus vancomcin in patients with acute bacterial skin and skin structure infections: pooled phase III REVIVE trials Arena 5
Saturday, April 13 14:45 – 15:45 Beta-lactamase inhibitors:  the “second generation” meets the “first generation” problems Robert Bonomo Imipenem-relebactam efficiently inhibits D179 variants of the KPC-2 beta-lactamase Arena 2
Saturday, April 13
10:00 – 12:00
Management of chronic bone and joint infections Robin Patel (Chair) Hall D
Sunday, April 14 11:00 – 12:00 Pathogenetic profiling to fight antimicrobial resistance Robert Bonomo (Chair) Hall K
Sunday, April 14 14:45 – 15:45 Antibodies in the flight against multidrug-resistant Gram-negative bacterial infection Robert Bonomo (Chair) Hall H
Sunday, April 14
11:00 – 12:00
Possible impact of new immunomodulators on infection and infection management David van Duin (Chair) Hall B
Sunday, April 14
14:45 – 15:45
US experiences Bettina C. Fries Antibody-mediated killing of multidrug-resistant Gram-negative bacteria: what’s the future? Hall H
Monday, April 15 07:30 – 8:30 How to use Point-of-Care tests in microbiology? European vs. Robin Patel (Chair) Robin Patel (Rochester, United States) Hall J
Monday, April 15 16:00 – 18:00 Phage therapy’s coming of age: Progress towards the application of bacteriophages in the treatment of infectious diseases Robin Patel (Chair) Hall J
Tuesday, April 16 08:45 – 10:45 MRSA, VRE and beyond Cesar Arias (chair) Hall H
Tuesday, April 16 11:00 – 12:00 Recent Clinical Trials Vance Fowler Exebacase (Lysin CF-301) Improved clinical responder rates in methicillin-resistant Staphylococcus aureus bacteraemia including endocarditis compared to standard of care antibiotics alone in a first-in patient phase 2 study Hall N
Tuesday, April 16
11:00 – 12:00
Infection in immunocompromised hosts David van Duin (Chair) Hall J
Tuesday, April 16
12:15 – 13:15
Networks for Clinical Research – no other way David van Duin (Moderators) Arena 4
Tuesday, April 16
12:15 – 13:15
Networks for Clinical Research – no other way Sarah Doernberg ARLG in the USA Arena 4
Tuesday, April 16
13:30 – 15:30
Interventions to reduce morbidity and mortality of bloodstream infection Thomas Holland Patients’ experiences with Staphylococcus aureus and Gram-negative rod bloodstream infections: a qualitative study to inform development of a quality of life measure Hall N
Tuesday,April 16 13:30 – 15:30 Bacterial resistance: evolution, plasmids and fitness Barry Kreiswirth Processes driving the evolution of antibiotic resistance Hall E

 

Michael Woodworth, MD, MSc, receives the Southern Society for Clinical Investigation Research Scholar Award

Congratulations to Michael Woodworth, MD, MSc, for being selected as a recipient of the Southern Society for Clinical Investigation (SSCI) Research Scholar Award. This award provides funding for physician-scientists with innovative research projects related to internal medicine and its subspecialties. Dr. Woodworth will use the award to provide additional project funding for the ARLG ongoing pilot clinical trial of fecal transplantation for MDRO eradication in renal transplant patients.

 

Two ARLG PI-Initiated, Laboratory-Based Trials Reached Database Lock

ARLG Principal Investigators Ritu Banerjee, MD, PhD of Vanderbilt University and Audrey Schuetz, MD, MPH, D (ABMM) of Mayo Clinic have successfully led the RAPIDS-GN and DISK trials, respectively, to completion.

The primary objective of RAPIDS-GN is to evaluate the impact of rapid identification and antimicrobial susceptibility testing (AST) on the time to first antibiotic modification in the first 72 hours after randomization. RAPIDS-GN enrolled 500 subjects in two sites over 1 year. Database lock occurred in March 2019. Dr. Banerjee expects to present the preliminary results at the American Society for Microbiology (ASM) Microbe meeting in June 2019.

The primary objective of the DISK trial is to evaluate the performance of a rapid disk diffusion test performed using positive blood culture broth (BCB) as the inoculum, read at 16-18 hours of incubation. The project enrolled 500 subjects across five sites over 7 months. Database lock occurred in February 2019. Dr. Schuetz expects to present preliminary results at the Clinical & Laboratory Standards Institute (CLSI) meeting in June 2019.

Congratulations to both ARLG PIs and study sites on this accomplishment. We are looking forward to the results for answering these important questions.