CRACKLE-2 Study Results Published

The World Health Organization (WHO) prioritizes carbapenem-resistant Enterobacterales (CRE) as one of the top three multidrug-resistant pathogens threatening global health today. In an effort to provide much needed clinical and epidemiological data, researchers designed the CRACKLE-2 study as an observational, multi-center study involving data from 1,040 patients with Centers for Disease Control (CDC) defined CRE.

In addition to providing clinical and whole genome sequencing data for a cohort of CRACKLE-2 study patients, researchers identified a novel subset of CDC-defined CRE. Patient outcomes for infections of all three subsets were similar. This indicates interventional efforts directed only to CPE might be less effective than hoped.

Read the full publication.


Gram-Negative Committee Calls for New Submissions

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.

Read more

Ambassadors Unite Against Antibiotic-Resistance

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.

2020 Wolcott Award Goes to Robert A. Bonomo, MD

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.

NIH Renews Funding up to $102.5M for the Antibacterial Resistance Leadership Group

As antibiotic-resistant bacteria become more urgent threats worldwide, the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, announced today up to $102.5 million in renewed funding over seven years for the Antibacterial Resistance Leadership Group (ARLG). This funding will allow the network to continue and enhance its mission to prioritize, design, and execute clinical research to reduce the public health threat of antibacterial resistance.

Composed of more than 50 leading experts working together to innovate clinical trial design, inform guidelines, and improve clinical practice in infectious diseases, the ARLG received its initial funding in 2013.

Vance Fowler, M.D., of Duke University and Henry Chambers, M.D., of the University of California, San Francisco, will continue to serve as the ARLG principal investigators. The ARLG will include several centers that will support essential network functions:

  • The Scientific Leadership Center will provide administrative guidance and oversight, prioritize the research agenda and ensure timely publication of results.
  • The Clinical Operations Center will provide clinical support for studies and trials, select sites, oversee protocol teams and ensure that the trials are aligned with ARLG priorities.
  • The Laboratory Center will oversee laboratory research and ensure that the specimens from clinical trials are processed, analyzed, and stored appropriately.
  • The Statistics and Data Management Center will assist with study design and analysis to ensure high-quality data.

With clinical operations based at the Duke Clinical Research Institute, the ARLG’s research team has collaborations in 19 countries and has initiated more than 40 clinical research studies involving more than 20,000 patients across more than 130 sites. Its three areas of research align with the Centers for Disease Control and Prevention antibiotic resistance threats and include:

  • Infections caused by Gram-negative bacteria, such as Escherichia coli;
  • Infections caused by Gram-positive bacteria, such as Staphylococcus aureus; and
  • Diagnostics such as rapid point-of-care tests to detect drug resistance, guide antibacterial therapy, and support clinical trials.

“The renewal support from the NIAID will allow the ARLG to continue its collaborative work to advance science in antibacterial research, and to provide funding opportunities for the next generation of researchers dedicated to addressing this public health threat,” said Vance Fowler, M.D., ARLG co-principal investigator, member of the DCRI, and professor of medicine at the Duke University School of Medicine.

“We are delighted to be able to continue to support efforts to fight antibiotic resistance by generating data that is used to inform dosing guidelines and developing diagnostic testing for better detection and timely treatment,” Fowler said.

To learn more, read the following releases from the NIH and the DCRI.

The ARLG is funded through grant UM1AI104681.

Practical efforts to curb antibiotic prescriptions could have large effect in small hospitals

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.

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.

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
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.